Skip to content
2000
Volume 21, Issue 4
  • ISSN: 1567-2026
  • E-ISSN: 1875-5739

Abstract

Multiple sclerosis (MS) is a progressive autoimmune condition that primarily affects young people and is characterized by demyelination and neurodegeneration of the central nervous system (CNS). This in-depth review explores the complex involvement of oligodendrocytes, the primary myelin-producing cells in the CNS, in the pathophysiology of MS. It discusses the biochemical processes and signalling pathways required for oligodendrocytes to function and remain alive, as well as how they might fail and cause demyelination to occur. We investigate developing therapeutic options that target remyelination, a fundamental component of MS treatment. Remyelination approaches promote the survival and differentiation of oligodendrocyte precursor cells (OPCs), restoring myelin sheaths. This improves nerve fibre function and may prevent MS from worsening. We examine crucial parameters influencing remyelination success, such as OPC density, ageing, and signalling pathway regulation (., Retinoid X receptor, LINGO-1, Notch). The review also examines existing neuroprotective and anti-inflammatory medications being studied to see if they can assist oligodendrocytes in surviving and reducing the severity of MS symptoms. The review focuses on medicines that target the myelin metabolism in oligodendrocytes. Altering oligodendrocyte metabolism has been linked to reversing demyelination and improving MS patient outcomes through various mechanisms. We also explore potential breakthroughs, including innovative antisense technologies, deep brain stimulation, and the impact of gut health and exercise on MS development. The article discusses the possibility of personalized medicine in MS therapy, emphasizing the importance of specific medicines based on individual molecular profiles. The study emphasizes the need for reliable biomarkers and improved imaging tools for monitoring disease progression and therapy response. Finally, this review focuses on the importance of oligodendrocytes in MS and the potential for remyelination therapy. It also underlines the importance of continued research to develop more effective treatment regimens, taking into account the complexities of MS pathology and the different factors that influence disease progression and treatment.

Loading

Article metrics loading...

/content/journals/cnr/10.2174/0115672026336440240822063430
2024-08-30
2025-04-06
Loading full text...

Full text loading...

References

  1. KapoorT. MehanS. SuriM. Forskolin, an Adenylcyclase/cAMP/CREB signaling activator restoring myelin-associated oligodendrocyte destruction in experimental ethidium bromide model of multiple sclerosis.Cells20221118277110.3390/cells11182771 36139346
    [Google Scholar]
  2. KumarN. SharmaN. KheraR. GuptaR. MehanS. Guggulsterone ameliorates ethidium bromide-induced experimental model of multiple sclerosis via restoration of behavioral, molecular, neurochemical and morphological alterations in rat brain.Metab. Brain Dis.202136591192510.1007/s11011‑021‑00691‑x 33635478
    [Google Scholar]
  3. SolomonA.J. MarrieR.A. ViswanathanS. CorrealeJ. MagyariM. RobertsonN.P. Global barriers to the diagnosis of multiple sclerosis: Data From the Multiple Sclerosis International Federation Atlas of MS, Third Edition.Neurology20231016e6243510.1212/WNL.0000000000207481
    [Google Scholar]
  4. ChhabraS. MehanS. KhanZ. GuptaG.D. NarulaA.S. Matrine mediated neuroprotective potential in experimental multiple sclerosis: Evidence from CSF, blood markers, brain samples and in-silico investigations.J. Neuroimmunol.2023384557820010.1016/j.jneuroim.2023.578200 37774554
    [Google Scholar]
  5. SajadM. ZahoorI. RashidF. CerghetM. RattanR. GiriS. Pyruvate dehydrogenase-dependent metabolic programming affects the oligodendrocyte maturation and remyelination.Mol. Neurobiol.202461139741010.1007/s12035‑023‑03546‑x 37620688
    [Google Scholar]
  6. KimH.W. KangJ.I. LeeS.H. Common variants of HTR3 genes are associated with obsessive-compulsive disorder and its phenotypic expression.Sci. Rep.2016613256410.1038/srep32564 27616601
    [Google Scholar]
  7. BolocD. MasS. RodriguezN. Genetic associations of serotoninergic and gabaergic genes in an extended collection of early-onset obsessive-compulsive disorder trios.J. Child Adolesc. Psychopharmacol.201929215215710.1089/cap.2018.0073 30351181
    [Google Scholar]
  8. HauserS.L. CreeB.A.C. Treatment of multiple sclerosis: A review.Am. J. Med.20201331213801390.e210.1016/j.amjmed.2020.05.049 32682869
    [Google Scholar]
  9. RiversT.M. SchwentkerF.F. Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys.J. Exp. Med.193561568970210.1084/jem.61.5.689 19870385
    [Google Scholar]
  10. SinopoliV.M. ErdmanL. BurtonC.L. Serotonin system gene variants and regional brain volume differences in pediatric OCD.Brain Imaging Behav.20201451612162510.1007/s11682‑019‑00092‑w 31187473
    [Google Scholar]
  11. GrünblattE. MarinovaZ. RothA. Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder.J. Psychiatr. Res.201896420921710.1016/j.jpsychires.2017.10.010 29102815
    [Google Scholar]
  12. HuwilerA. Zangemeister-WittkeU. The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives.Pharmacol. Ther.201818510344910.1016/j.pharmthera.2017.11.001 29127024
    [Google Scholar]
  13. DengM. WangY. YuS. Exploring association between serotonin and neurogenesis related genes in obsessive-compulsive disorder in chinese han people: Promising association between dmrt2, mir-30a-5p, and early-onset patients.Front. Psychiatry20221385757410.3389/fpsyt.2022.857574 35633798
    [Google Scholar]
  14. TanakaY. ArimaY. HiguchiK. EAE Induction by passive transfer of MOG-specific CD4+ T cells.Bio Protoc.2017713e237010.21769/BioProtoc.2370 34541112
    [Google Scholar]
  15. LiuJ. MoriM. SugimotoK. Peripheral blood helper T cell profiles and their clinical relevance in MOG-IgG-associated and AQP4-IgG-associated disorders and MS.J. Neurol. Neurosurg. Psychiatry202091213213910.1136/jnnp‑2019‑321988 31806723
    [Google Scholar]
  16. QuintanaF.J. PatelB. YesteA. Epitope spreading as an early pathogenic event in pediatric multiple sclerosis.Neurology201483242219222610.1212/WNL.0000000000001066 25381299
    [Google Scholar]
  17. WarringtonA.E. BieberA.J. CiricB. PeaseL.R. Van KeulenV. RodriguezM. A recombinant human IgM promotes myelin repair after a single, very low dose.J. Neurosci. Res.200785596797610.1002/jnr.21217 17304578
    [Google Scholar]
  18. BradlM. LassmannH. Oligodendrocytes: biology and pathology.Acta Neuropathol.20101191375310.1007/s00401‑009‑0601‑5 19847447
    [Google Scholar]
  19. TheodorsdottirA. LarsenP.V. NielsenH.H. IllesZ. RavnborgM.H. Multiple sclerosis impairment scale and brain MRI in secondary progressive multiple sclerosis.Acta Neurol. Scand.2022145333234710.1111/ane.13554 34799851
    [Google Scholar]
  20. WeierK. MazraehJ. NaegelinY. Biplanar MRI for the assessment of the spinal cord in multiple sclerosis.Mult. Scler.201218111560156910.1177/1352458512442754 22539086
    [Google Scholar]
  21. MarrodanM. BensiC. PappollaA. Disease activity impacts disability progression in primary progressive multiple sclerosis.Mult. Scler. Relat. Disord.20203910189210.1016/j.msard.2019.101892 31846866
    [Google Scholar]
  22. SakaieK. TakahashiM. SagiyamaK. Injury to a specific neural pathway detected by ultra-high-field MRI.Neurology201482218218310.1212/WNL.0000000000000016 24285615
    [Google Scholar]
  23. HamzaM.M. AlasB.F. HuangC. Internuclear ophthalmoplegia characterizes multiple sclerosis rather than neuromyelitis optica spectrum disease.J. Neuroophthalmol.202242223924510.1097/WNO.0000000000001534 35427281
    [Google Scholar]
  24. NabizadehF. NikfarjamM. AzamiM. SharifkazemiH. SodeifianF. Pseudobulbar affect in neurodegenerative diseases: A systematic review and meta-analysis.J. Clin. Neurosci.202210010010710.1016/j.jocn.2022.04.009 35436682
    [Google Scholar]
  25. PawlitzkiM HorbrüggerM LoeweK KaufmannJ OpferR WagnerM. MS optic neuritis-induced long-term structural changes within the visual pathway.Neurol Neuroimmunol neuroinflammation20207210.1212/NXI.0000000000000665
    [Google Scholar]
  26. TornesL. ConwayB. SheremataW. Multiple sclerosis and the cerebellum.Neurol. Clin.201432495797710.1016/j.ncl.2014.08.001 25439291
    [Google Scholar]
  27. ParmarK. StadelmannC. RoccaM.A. The role of the cerebellum in multiple sclerosis—150 years after Charcot.Neurosci. Biobehav. Rev.201889859810.1016/j.neubiorev.2018.02.012 29477616
    [Google Scholar]
  28. LucchinettiC. BrückW. ParisiJ. ScheithauerB. RodriguezM. LassmannH. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions.Brain1999122122279229510.1093/brain/122.12.2279 10581222
    [Google Scholar]
  29. GudiV. Moharregh-KhiabaniD. SkripuletzT. Regional differences between grey and white matter in cuprizone induced demyelination.Brain Res.2009128312713810.1016/j.brainres.2009.06.005 19524552
    [Google Scholar]
  30. Torkildsen BrunborgLA. MyhrKM. BøL. The cuprizone model for demyelination.Acta Neurol. Scand. Suppl.20081887276
    [Google Scholar]
  31. HiremathM.M. SaitoY. KnappG.W. TingJ.P.Y. SuzukiK. MatsushimaG.K. Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice.J. Neuroimmunol.1998921-2384910.1016/S0165‑5728(98)00168‑4 9916878
    [Google Scholar]
  32. ZirngiblM. AssinckP. SizovA. CaprarielloA.V. PlemelJ.R. Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination.Mol. Neurodegener.20221713410.1186/s13024‑022‑00538‑8 35526004
    [Google Scholar]
  33. BlakemoreW.F. Ethidium bromide induced demyelination in the spinal cord of the cat.Neuropathol. Appl. Neurobiol.19828536537510.1111/j.1365‑2990.1982.tb00305.x 7177337
    [Google Scholar]
  34. UpadhayayS. MehanS. PrajapatiA. Nrf2/HO-1 signaling stimulation through acetyl-11-keto-beta-boswellic acid (akba) provides neuroprotection in ethidium bromide-induced experimental model of multiple sclerosis.Genes (Basel)2022138132410.3390/genes13081324 35893061
    [Google Scholar]
  35. Galindo-MurilloR. CheathamT.E.III Ethidium bromide interactions with DNA: An exploration of a classic DNA–ligand complex with unbiased molecular dynamics simulations.Nucleic Acids Res.20214973735374710.1093/nar/gkab143 33764383
    [Google Scholar]
  36. GoudarzvandM. ChoopaniS. ShamsA. Focal injection of ethidium bromide as a simple model to study cognitive deficit and its improvement.Basic Clin. Neurosci.2016716372 27303601
    [Google Scholar]
  37. McMurranC.E. ZhaoC. FranklinR.J.M. Toxin-based models to investigate demyelination and remyelination.Methods Mol. Biol.20191936137739610.1007/978‑1‑4939‑9072‑6_21 30820910
    [Google Scholar]
  38. BinaméF. Pham-VanL.D. BagnardD. Manipulating oligodendrocyte intrinsic regeneration mechanism to promote remyelination.Cell. Mol. Life Sci.202178135257527310.1007/s00018‑021‑03852‑4 34019104
    [Google Scholar]
  39. IrvineK.A. BlakemoreW.F. Remyelination protects axons from demyelination-associated axon degeneration.Brain200813161464147710.1093/brain/awn080 18490361
    [Google Scholar]
  40. MeiF. Lehmann-HornK. ShenY.A.A. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.eLife20165Pt 614641477 27671734
    [Google Scholar]
  41. BodiniB. VeroneseM. García-LorenzoD. Dynamic imaging of individual remyelination profiles in multiple sclerosis.Ann. Neurol.201679572673810.1002/ana.24620 26891452
    [Google Scholar]
  42. LubetzkiC. ZalcB. WilliamsA. StadelmannC. StankoffB. Remyelination in multiple sclerosis: From basic science to clinical translation.Lancet Neurol.202019867868810.1016/S1474‑4422(20)30140‑X 32702337
    [Google Scholar]
  43. GreenA.J. GelfandJ.M. CreeB.A. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): A randomised, controlled, double-blind, crossover trial.Lancet2017390101112481248910.1016/S0140‑6736(17)32346‑2 29029896
    [Google Scholar]
  44. CohenC.C.H. PopovicM.A. KloosterJ. Saltatory conduction along myelinated axons involves a periaxonal nanocircuit.Cell20201802311322.e1510.1016/j.cell.2019.11.039 31883793
    [Google Scholar]
  45. SaabA.S. TzvetavonaI.D. TrevisiolA. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism.Neuron201691111913210.1016/j.neuron.2016.05.016 27292539
    [Google Scholar]
  46. SimonsK. IkonenE. Functional rafts in cell membranes.Nature1997387663356957210.1038/42408 9177342
    [Google Scholar]
  47. AggarwalS. YurlovaL. SimonsM. Central nervous system myelin: structure, synthesis and assembly.Trends Cell Biol.2011211058559310.1016/j.tcb.2011.06.004 21763137
    [Google Scholar]
  48. BoggsJ.M. Role of galactosylceramide and sulfatide in oligodendrocytes and CNS myelin: formation of a glycosynapse.Adv. Neurobiol.2014926329110.1007/978‑1‑4939‑1154‑7_12 25151383
    [Google Scholar]
  49. García-GarcíaÓ.D. CarrielV. Chato-AstrainJ. Myelin histology: A key tool in nervous system research.Neural Regen. Res.202419227728110.4103/1673‑5374.375318 37488878
    [Google Scholar]
  50. OzgenH. BaronW. HoekstraD. KahyaN. Oligodendroglial membrane dynamics in relation to myelin biogenesis.Cell. Mol. Life Sci.201673173291331010.1007/s00018‑016‑2228‑8 27141942
    [Google Scholar]
  51. MinY. KristiansenK. BoggsJ.M. HustedC. ZasadzinskiJ.A. IsraelachviliJ. Interaction forces and adhesion of supported myelin lipid bilayers modulated by myelin basic protein.Proc. Natl. Acad. Sci. USA200910693154315910.1073/pnas.0813110106 19218452
    [Google Scholar]
  52. BaumannN. Pham-DinhD. Biology of oligodendrocyte and myelin in the mammalian central nervous system.Physiol. Rev.200181287192710.1152/physrev.2001.81.2.871 11274346
    [Google Scholar]
  53. DietschyJ.M. TurleyS.D. Thematic review series: Brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal.J. Lipid Res.20044581375139710.1194/jlr.R400004‑JLR200 15254070
    [Google Scholar]
  54. KolesnickR.N. GoñiF.M. AlonsoA. Compartmentalization of ceramide signaling: physical foundations and biological effects.J. Cell. Physiol.2000184328530010.1002/1097‑4652(200009)184:3<285::AID‑JCP2>3.0.CO;2‑3 10911359
    [Google Scholar]
  55. KiernanJ.A. Histochemistry of staining methods for normal and degenerating myelin in the central and peripheral nervous systems.J. Histotechnol.20073028710610.1179/his.2007.30.2.87
    [Google Scholar]
  56. SaherG. BrüggerB. Lappe-SiefkeC. High cholesterol level is essential for myelin membrane growth.Nat. Neurosci.20058446847510.1038/nn1426 15793579
    [Google Scholar]
  57. ShinodaW. Permeability across lipid membranes.Biochim. Biophys. Acta Biomembr.20161858102254226510.1016/j.bbamem.2016.03.032 27085977
    [Google Scholar]
  58. AlmsherqiZ.A. Potential role of plasmalogens in the modulation of biomembrane morphology.Front. Cell Dev. Biol.202193567391710.3389/fcell.2021.673917 34368127
    [Google Scholar]
  59. BezineM. NamsiA. SghaierR. The effect of oxysterols on nerve impulses.Biochimie2018153465110.1016/j.biochi.2018.04.013 29684511
    [Google Scholar]
  60. MathewsE.S. AppelB. Cholesterol biosynthesis supports myelin gene expression and axon ensheathment through modulation of P13K/Akt/mTor signaling.J. Neurosci.201636297628763910.1523/JNEUROSCI.0726‑16.2016 27445141
    [Google Scholar]
  61. BlanchardJ.W. AkayL.A. Davila-VelderrainJ. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.Nature2022611793776977910.1038/s41586‑022‑05439‑w 36385529
    [Google Scholar]
  62. BoggsJ.M. GaoW. HiraharaY. Signal transduction pathways involved in interaction of galactosylceramide/sulfatide‐containing liposomes with cultured oligodendrocytes and requirement for myelin basic protein and glycosphingolipids.J. Neurosci. Res.20088671448145810.1002/jnr.21603 18189317
    [Google Scholar]
  63. PalaviciniJ.P. WangC. ChenL. Novel molecular insights into the critical role of sulfatide in myelin maintenance/function.J. Neurochem.20161391405410.1111/jnc.13738 27417284
    [Google Scholar]
  64. LuomaA.M. KuoF. CakiciO. Plasmalogen phospholipids protect internodal myelin from oxidative damage.Free Radic. Biol. Med.20158429631010.1016/j.freeradbiomed.2015.03.012 25801291
    [Google Scholar]
  65. KoivuniemiA. The biophysical properties of plasmalogens originating from their unique molecular architecture. FEBS Lett. 2017;591(18):2700-13. 66. Furse S, de Kroon AIPM. Phosphatidylcholine’s functions beyond that of a membrane brick.Mol. Membr. Biol.2015324117119 26306852
    [Google Scholar]
  66. KahanI. MoscarelloM.A. The intramembranous domains of lipophilin in phosphatidylcholine vesicles are similar to those in the myelin membrane.Biochim. Biophys. Acta Biomembr.1986862122322610.1016/0005‑2736(86)90487‑6 3768366
    [Google Scholar]
  67. WangZ. WuZ. MiaoY. The protective effects of ligustrazine on ischemic stroke: A systematic review and meta-analysis of preclinical evidence and possible mechanisms.Front. Pharmacol.202415137366310.3389/fphar.2024.1373663 38545549
    [Google Scholar]
  68. SádabaM.C. RothhammerV. MuñozÚ. SebalC. EscuderoE. KivisäkkP. Serum antibodies to phosphatidylcholine in MS.Neurol. Neuroimmunol. Neuroinflamm.202074e76510.1212/NXI.0000000000000765
    [Google Scholar]
  69. NaffaaV. MagnyR. RegazzettiA. Shift in phospholipid and fatty acid contents accompanies brain myelination.Biochimie20222033203110.1016/j.biochi.2022.08.010 36055603
    [Google Scholar]
  70. SlotteJ.P. Biological functions of sphingomyelins.Prog. Lipid Res.201352442443710.1016/j.plipres.2013.05.001 23684760
    [Google Scholar]
  71. García-ArribasA.B. AlonsoA. GoñiF.M. Cholesterol interactions with ceramide and sphingomyelin.Chem. Phys. Lipids20161991263410.1016/j.chemphyslip.2016.04.002 27132117
    [Google Scholar]
  72. PatwardhanG.A. BeverlyL.J. SiskindL.J. Sphingolipids and mitochondrial apoptosis.J. Bioenerg. Biomembr.201648215316810.1007/s10863‑015‑9602‑3 25620271
    [Google Scholar]
  73. RuskamoS. RaasakkaA. PedersenJ.S. Human myelin proteolipid protein structure and lipid bilayer stacking.Cell. Mol. Life Sci.202279841910.1007/s00018‑022‑04428‑6 35829923
    [Google Scholar]
  74. KlugmannM. SchwabM.H. PühlhoferA. Assembly of CNS myelin in the absence of proteolipid protein.Neuron1997181597010.1016/S0896‑6273(01)80046‑5 9010205
    [Google Scholar]
  75. SteyerA.M. BuschamT.J. LorenzC. Focused ion beam‐scanning electron microscopy links pathological myelin outfoldings to axonal changes in mice lacking Plp1 or Mag.Glia202371350952310.1002/glia.24290 36354016
    [Google Scholar]
  76. KnappP.E. Proteolipid protein: is it more than just a structural component of myelin?Dev. Neurosci.199618429730810.1159/000111420 8911768
    [Google Scholar]
  77. LüdersK.A. PatzigJ. SimonsM. NaveK.A. WernerH.B. Genetic dissection of oligodendroglial and neuronal Plp1 function in a novel mouse model of spastic paraplegia type 2.Glia201765111762177610.1002/glia.23193 28836307
    [Google Scholar]
  78. InoueK. Pelizaeus-Merzbacher disease: Molecular and cellular pathologies and associated phenotypes.Adv. Exp. Med. Biol.20191190420121610.1007/978‑981‑32‑9636‑7_13 31760646
    [Google Scholar]
  79. DongX. SunS. LiJ. Identification of potential functional peptides involved in demyelinating injury in the central nervous system.PeerJ2023114e1584610.7717/peerj.15846 37637167
    [Google Scholar]
  80. LinY. SakurabaS. MassilamanyC. Harnessing autoimmunity with dominant self-peptide: Modulating the sustainability of tissue-preferential antigen-specific Tregs by governing the binding stability via peptide flanking residues.J. Autoimmun.2023140410309410.1016/j.jaut.2023.103094 37716077
    [Google Scholar]
  81. RamyaL. Helina HildaS. Structural dynamics of moonlighting intrinsically disordered proteins - A black box in multiple sclerosis.J. Mol. Graph. Model.2023124410857210.1016/j.jmgm.2023.108572 37494873
    [Google Scholar]
  82. HarauzG. BoggsJ.M. Myelin management by the 18.5‐kDa and 21.5‐kDa classic myelin basic protein isoforms.J. Neurochem.2013125333436110.1111/jnc.12195 23398367
    [Google Scholar]
  83. OmlinF.X. WebsterH.D. PalkovitsC.G. CohenS.R. Immunocytochemical localization of basic protein in major dense line regions of central and peripheral myelin.J. Cell Biol.198295124224810.1083/jcb.95.1.242 6183269
    [Google Scholar]
  84. AggarwalS. SnaideroN. PählerG. FreyS. SánchezP. ZweckstetterM. Myelin membrane assembly is driven by a phase transition of myelin basic proteins into a cohesive protein meshwork.PLoS Biol.2013116e100157710.1371/journal.pbio.1001577
    [Google Scholar]
  85. McLaurinJ. YongV.W. Oligodendrocytes and Myelin.Neurol. Clin.1995131234910.1016/S0733‑8619(18)30060‑4 7739504
    [Google Scholar]
  86. ChangA. TourtellotteW.W. RudickR. TrappB.D. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis.N. Engl. J. Med.2002346316517310.1056/NEJMoa010994 11796850
    [Google Scholar]
  87. GontikaM. SkarlisC. ArtemiadisA. HLA-DRB1 allele impact on pediatric multiple sclerosis in a Hellenic cohort.Mult. Scler. J. Exp. Transl. Clin.202061205521732090804610.1177/2055217320908046 32133149
    [Google Scholar]
  88. BarresB.A. RaffM.C. Axonal control of oligodendrocyte development.J. Cell Biol.199914761123112810.1083/jcb.147.6.1123 10601327
    [Google Scholar]
  89. ZemmarA. ChenC.C. WeinmannO. Oligodendrocyte- and neuron-specific nogo-a restrict dendritic branching and spine density in the adult mouse motor cortex.Cereb. Cortex20182862109211710.1093/cercor/bhx116 28505229
    [Google Scholar]
  90. BerglesD.E. RichardsonW.D. Oligodendrocyte development and plasticity.Cold Spring Harb. Perspect. Biol.201682a02045310.1101/cshperspect.a020453 26492571
    [Google Scholar]
  91. SimonsM. NaveK.A. Oligodendrocytes: Myelination and axonal support.Cold Spring Harb. Perspect. Biol.201681a02047910.1101/cshperspect.a020479 26101081
    [Google Scholar]
  92. GibsonE.M. PurgerD. MountC.W. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain.Science20143446183125230410.1126/science.1252304 24727982
    [Google Scholar]
  93. ShermanD.L. BrophyP.J. Mechanisms of axon ensheathment and myelin growth.Nat. Rev. Neurosci.20056968369010.1038/nrn1743 16136172
    [Google Scholar]
  94. GalloV. DeneenB. Glial development: The crossroads of regeneration and repair in the CNS.Neuron201483228330810.1016/j.neuron.2014.06.010 25033178
    [Google Scholar]
  95. BoggsJ.M. Myelin basic protein: a multifunctional protein.Cell. Mol. Life Sci.200663171945196110.1007/s00018‑006‑6094‑7 16794783
    [Google Scholar]
  96. StysP.K. ZamponiG.W. van MinnenJ. GeurtsJ.J.G. Will the real multiple sclerosis please stand up?Nat. Rev. Neurosci.201213750751410.1038/nrn3275 22714021
    [Google Scholar]
  97. LeeS. LeachM.K. RedmondS.A. A culture system to study oligodendrocyte myelination processes using engineered nanofibers.Nat. Methods20129991792210.1038/nmeth.2105 22796663
    [Google Scholar]
  98. RonD. WalterP. Signal integration in the endoplasmic reticulum unfolded protein response.Nat. Rev. Mol. Cell Biol.20078751952910.1038/nrm2199 17565364
    [Google Scholar]
  99. LinW. BaileyS.L. HoH. The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage.J. Clin. Invest.2007117244845610.1172/JCI29571 17273557
    [Google Scholar]
  100. SaherG. SimonsM. Cholesterol and myelin biogenesis.Subcell. Biochem.20105148950810.1007/978‑90‑481‑8622‑8_18
    [Google Scholar]
  101. SchmittS. CastelvetriL.C. SimonsM. Metabolism and functions of lipids in myelin.Biochim. Biophys. Acta Mol. Cell Biol. Lipids201518518999100510.1016/j.bbalip.2014.12.016 25542507
    [Google Scholar]
  102. ShiM. ChaiY. ZhangJ. ChenX. Endoplasmic reticulum stress-associated neuronal death and innate immune response in neurological diseases.Front. Immunol.202212879458010.3389/fimmu.2021.794580 35082783
    [Google Scholar]
  103. RoskoL. SmithV.N. YamazakiR. HuangJ.K. Oligodendrocyte bioenergetics in health and disease.Neuroscientist201925433434310.1177/1073858418793077 30122106
    [Google Scholar]
  104. NguyenH MeserveyLM Ishiko-SilveriaN ZhouM HuangTT FuM Fear deficits in hypomyelinated Tppp knock-out mice.eNeuro202075ENEURO.0170-20.202010.1523/ENEURO.0170‑20.202032878961
    [Google Scholar]
  105. PaezP.M. LyonsD.A. Calcium signaling in the oligodendrocyte lineage: Regulators and consequences.Annu. Rev. Neurosci.202043116318610.1146/annurev‑neuro‑100719‑093305 32075518
    [Google Scholar]
  106. RuizA. MatuteC. AlberdiE. Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes.Cell Death Dis.201017e5410.1038/cddis.2010.31 21364659
    [Google Scholar]
  107. ChenH. ChanD.C. Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases.Hum. Mol. Genet.200918R2R169R17610.1093/hmg/ddp326 19808793
    [Google Scholar]
  108. GilM. GamaV. Emerging mitochondrial‐mediated mechanisms involved in oligodendrocyte development.J. Neurosci. Res.2023101335436610.1002/jnr.25151 36461887
    [Google Scholar]
  109. SimonsM. TrotterJ. Wrapping it up: The cell biology of myelination.Curr. Opin. Neurobiol.200717553354010.1016/j.conb.2007.08.003 17923405
    [Google Scholar]
  110. FuM. McAlearT.S. NguyenH. The golgi outpost protein tppp nucleates microtubules and is critical for myelination.Cell20191791132146.e1410.1016/j.cell.2019.08.025 31522887
    [Google Scholar]
  111. DengS. LiuJ. WuX. LuW. Golgi apparatus: A potential therapeutic target for autophagy-associated neurological diseases.Front. Cell Dev. Biol.20208156497510.3389/fcell.2020.564975 33015059
    [Google Scholar]
  112. BergerJ. DorningerF. Forss-PetterS. KunzeM. Peroxisomes in brain development and function.Biochim. Biophys. Acta Mol. Cell Res.20161863593495510.1016/j.bbamcr.2015.12.005 26686055
    [Google Scholar]
  113. DringenR. PawlowskiP.G. HirrlingerJ. Peroxide detoxification by brain cells.J. Neurosci. Res.2005791-215716510.1002/jnr.20280 15573410
    [Google Scholar]
  114. KassmannC.M. Lappe-SiefkeC. BaesM. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes.Nat. Genet.200739896997610.1038/ng2070 17643102
    [Google Scholar]
  115. BernardoA. BianchiD. MagnaghiV. MinghettiL. Peroxisome proliferator-activated receptor-gamma agonists promote differentiation and antioxidant defenses of oligodendrocyte progenitor cells.J. Neuropathol. Exp. Neurol.200968779780810.1097/NEN.0b013e3181aba2c1 19535992
    [Google Scholar]
  116. YangC. WangX. Lysosome biogenesis: Regulation and functions.J. Cell Biol.20212206e20210200110.1083/jcb.202102001 33950241
    [Google Scholar]
  117. BankstonA.N. ForstonM.D. HowardR.M. Autophagy is essential for oligodendrocyte differentiation, survival, and proper myelination.Glia20196791745175910.1002/glia.23646 31162728
    [Google Scholar]
  118. TylerW.A. GangoliN. GokinaP. Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation.J. Neurosci.200929196367637810.1523/JNEUROSCI.0234‑09.2009 19439614
    [Google Scholar]
  119. CarosiJ.M. FourrierC. BensalemJ. SargeantT.J. The mTOR–lysosome axis at the centre of ageing.FEBS Open Bio202212473975710.1002/2211‑5463.13347 34878722
    [Google Scholar]
  120. FerreiraC.R. GahlW.A. Lysosomal storage diseases.Transl. Sci. Rare Dis.201721-217110.3233/TRD‑160005 29152458
    [Google Scholar]
  121. CampagnoniA.T. MacklinW.B. Cellular and molecular aspects of myelin protein gene expression.Mol. Neurobiol.198821418910.1007/BF02935632 3077065
    [Google Scholar]
  122. NielsenJ.A. HudsonL.D. ArmstrongR.C. Nuclear organization in differentiating oligodendrocytes.J. Cell Sci.2002115214071407910.1242/jcs.00103 12356912
    [Google Scholar]
  123. EmeryB. LuQ.R. Transcriptional and epigenetic regulation of oligodendrocyte development and myelination in the central nervous system.Cold Spring Harb. Perspect. Biol.201579a02046110.1101/cshperspect.a020461 26134004
    [Google Scholar]
  124. HaiderL. FischerM.T. FrischerJ.M. Oxidative damage in multiple sclerosis lesions.Brain201113471914192410.1093/brain/awr128 21653539
    [Google Scholar]
  125. DeloulmeJ.C. LucasM. GaberC. Expression of the neuron-specific enolase gene by rat oligodendroglial cells during their differentiation.J. Neurochem.199666393694510.1046/j.1471‑4159.1996.66030936.x 8769852
    [Google Scholar]
  126. BjörkhemI. MeaneyS. Brain cholesterol: long secret life behind a barrier.Arterioscler. Thromb. Vasc. Biol.200424580681510.1161/01.ATV.0000120374.59826.1b 14764421
    [Google Scholar]
  127. NiewegK. SchallerH. PfriegerF.W. Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats.J. Neurochem.2009109112513410.1111/j.1471‑4159.2009.05917.x 19166509
    [Google Scholar]
  128. GoldsteinJ.L. BrownM.S. Regulation of the mevalonate pathway.Nature1990343625742543010.1038/343425a0 1967820
    [Google Scholar]
  129. FaulknerR. JoY. Synthesis, function, and regulation of sterol and nonsterol isoprenoids.Front. Mol. Biosci.202296257100682210.3389/fmolb.2022.1006822 36275615
    [Google Scholar]
  130. CerqueiraN.M.F.S.A. OliveiraE.F. GestoD.S. Cholesterol biosynthesis: A mechanistic overview.Biochemistry201655395483550610.1021/acs.biochem.6b00342 27604037
    [Google Scholar]
  131. HublerZ. AllimuthuD. BedermanI. Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination.Nature2018560771837237610.1038/s41586‑018‑0360‑3 30046109
    [Google Scholar]
  132. LahiriD.K. Apolipoprotein E as a target for developing new therapeutics for Alzheimer’s disease based on studies from protein, RNA, and regulatory region of the gene.J. Mol. Neurosci.200423322523410.1385/JMN:23:3:225 15181251
    [Google Scholar]
  133. BjörkhemI. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain.J. Intern. Med.2006260649350810.1111/j.1365‑2796.2006.01725.x 17116000
    [Google Scholar]
  134. ShankaranM. MohammedH. TsangE. 24-hydroxycholesterol replacement rate measured in blood is a non-invasive biomarker of brain demyelination and remyelination in cuprizone-treated mice.Exp. Neurol.20233643911439510.1016/j.expneurol.2023.114395 37003487
    [Google Scholar]
  135. NohturfftA. DeBose-BoydR.A. ScheekS. GoldsteinJ.L. BrownM.S. Sterols regulate cycling of SREBP cleavage-activating protein (SCAP) between endoplasmic reticulum and Golgi.Proc. Natl. Acad. Sci. USA19999620112351124010.1073/pnas.96.20.11235 10500160
    [Google Scholar]
  136. SchonerK. Witsch-BaumgartnerM. BehunovaJ. Smith‐Lemli‐Opitz syndrome — Fetal phenotypes with special reference to the syndrome‐specific internal malformation pattern.Birth Defects Res.2020112217518510.1002/bdr2.1620 31840946
    [Google Scholar]
  137. NeklasonD.W. AndrewsK.M. KelleyR.I. MetherallJ.E. Biochemical variants of Smith-Lemli-Opitz syndrome.Am. J. Med. Genet.199985551752310.1002/(SICI)1096‑8628(19990827)85:5<517::AID‑AJMG18>3.0.CO;2‑1 10405455
    [Google Scholar]
  138. FierroM. MartinezA.J. HarbisonJ.W. HayS.H. Smith-Lemli-Opitz syndrome: neuropathological and ophthalmological observations.Dev. Med. Child Neurol.1977191576210.1111/j.1469‑8749.1977.tb08021.x 844667
    [Google Scholar]
  139. HaasD. HoffmannG.F. Mevalonate kinase deficiencies: From mevalonic aciduria to hyperimmunoglobulinemia D syndrome.Orphanet J. Rare Dis.2006111310.1186/1750‑1172‑1‑13 16722536
    [Google Scholar]
  140. Ben-ZachariaA.B. Therapeutics for multiple sclerosis symptoms.Mt. Sinai J. Med.201178217619110.1002/msj.20245 21425263
    [Google Scholar]
  141. OchiaiY. UchidaY. OhtsukiS. TachikawaM. AizawaS. TerasakiT. The blood‐brain barrier fatty acid transport protein 1 (FATP 1/SLC 27A1) supplies docosahexaenoic acid to the brain, and insulin facilitates transport.J. Neurochem.2017141340041210.1111/jnc.13943 28035674
    [Google Scholar]
  142. DimasP. MontaniL. PereiraJ.A. CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes.eLife201983400412 31063129
    [Google Scholar]
  143. Rodriguez-CuencaS. BarbarrojaN. Vidal-PuigA. Dihydroceramide desaturase 1, the gatekeeper of ceramide induced lipotoxicity.Biochim. Biophys. Acta Mol. Cell Biol. Lipids201518511405010.1016/j.bbalip.2014.09.021 25283058
    [Google Scholar]
  144. MillerL.G.Jr YoungJ.A. RayS.K. Sphingosine toxicity in eae and ms: evidence for ceramide generation via serine-palmitoyltransferase activation.Neurochem. Res.201742102755276810.1007/s11064‑017‑2280‑2 28474276
    [Google Scholar]
  145. NortonW.T. PodusloS.E. Myelination in rat brain: Method of myelin isolation.J. Neurochem.197321474975710.1111/j.1471‑4159.1973.tb07519.x 4271082
    [Google Scholar]
  146. KokJ.W. BabiaT. KlappeK. EgeaG. HoekstraD. Ceramide transport from endoplasmic reticulum to Golgi apparatus is not vesicle-mediated.Biochem. J.1998Pt 377978610.1042/bj3330779
    [Google Scholar]
  147. HalterD. NeumannS. van DijkS.M. Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis.J. Cell Biol.2007179110111510.1083/jcb.200704091 17923531
    [Google Scholar]
  148. StahlN. JurevicsH. MorellP. SuzukiK. PopkoB. Isolation, characterization, and expression of cDNA clones that encode rat UDP‐galactose: Ceramide galactosyltransferase.J. Neurosci. Res.199438223424210.1002/jnr.490380214 7521399
    [Google Scholar]
  149. YuR.K. TsaiY.T. ArigaT. YanagisawaM. Structures, biosynthesis, and functions of gangliosides-an overview.J. Oleo Sci.2011601053754410.5650/jos.60.537 21937853
    [Google Scholar]
  150. HynesR.O. Methods for Identification of Fibronectins. In: Fibronectins Springer Series in Molecular Biology.SpringerNew York199010.1007/978‑1‑4612‑3264‑3_2
    [Google Scholar]
  151. RegierD.S. ProiaR.L. D’AzzoA. TifftC.J. The GM1 and GM2 gangliosidoses: Natural history and progress toward therapy.Pediatr. Endocrinol. Rev.201613 Suppl.663673
    [Google Scholar]
  152. HerdtA.R. PengH. DicksonD.W. GoldeT.E. EckmanE.A. LeeC.W. Brain targeted aav1-galc gene therapy reduces psychosine and extends lifespan in a mouse model of krabbe disease.Genes (Basel)2023148151710.3390/genes14081517 37628569
    [Google Scholar]
  153. CesaniM. LorioliL. GrossiS. Mutation update of ARSA and PSAP genes causing metachromatic leukodystrophy.Hum. Mutat.2016371162710.1002/humu.22919 26462614
    [Google Scholar]
  154. EdvardsonS. HamaH. ShaagA. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia.Am. J. Hum. Genet.200883564364810.1016/j.ajhg.2008.10.010 19068277
    [Google Scholar]
  155. FagoneP. JackowskiS. Phosphatidylcholine and the CDP–choline cycle.Biochim. Biophys. Acta Mol. Cell Biol. Lipids20131831352353210.1016/j.bbalip.2012.09.009 23010477
    [Google Scholar]
  156. Martínez-UñaM. Varela-ReyM. CanoA. Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis.Hepatology20135841296130510.1002/hep.26399 23505042
    [Google Scholar]
  157. JavaidS. FarooqT. RehmanZ. Dynamics of choline-containing phospholipids in traumatic brain injury and associated comorbidities.Int. J. Mol. Sci.202122211131310.3390/ijms222111313 34768742
    [Google Scholar]
  158. MullenT.D. HannunY.A. ObeidL.M. Ceramide synthases at the centre of sphingolipid metabolism and biology.Biochem. J.2012441378980210.1042/BJ20111626 22248339
    [Google Scholar]
  159. DengY. Rivera-MolinaF.E. ToomreD.K. BurdC.G. Sphingomyelin is sorted at the trans Golgi network into a distinct class of secretory vesicle.Proc. Natl. Acad. Sci. USA2016113246677668210.1073/pnas.1602875113 27247384
    [Google Scholar]
  160. BajwaH. AzharW. Niemann-Pick Disease. In: StatPearls.2024113667782
    [Google Scholar]
  161. ZeidanY.H. HannunY.A. The acid sphingomyelinase/ceramide pathway: Biomedical significance and mechanisms of regulation.Curr. Mol. Med.201010545446610.2174/156652410791608225 20540705
    [Google Scholar]
  162. TaniM. ItoM. IgarashiY. Ceramide/sphingosine/sphingosine 1-phosphate metabolism on the cell surface and in the extracellular space.Cell. Signal.200719222923710.1016/j.cellsig.2006.07.001 16963225
    [Google Scholar]
  163. PassaroA.P. LebosA.L. YaoY. SticeS.L. Immune response in neurological pathology: Emerging role of central and peripheral immune crosstalk.Front. Immunol.202112267662110.3389/fimmu.2021.676621 34177918
    [Google Scholar]
  164. KimH.Y. HuangB.X. SpectorA.A. Phosphatidylserine in the brain: Metabolism and function.Prog. Lipid Res.201456211810.1016/j.plipres.2014.06.002 24992464
    [Google Scholar]
  165. NagataS. SuzukiJ. SegawaK. FujiiT. Exposure of phosphatidylserine on the cell surface.Cell Death Differ.201623695296110.1038/cdd.2016.7 26891692
    [Google Scholar]
  166. SassaT. KiharaA. Metabolism of very long-chain Fatty acids: genes and pathophysiology.Biomol. Ther. (Seoul)2014222839210.4062/biomolther.2014.017 24753812
    [Google Scholar]
  167. BozelliJ.C.Jr AzherS. EpandR.M. Plasmalogens and chronic inflammatory diseases.Front. Physiol.202112273082910.3389/fphys.2021.730829 34744771
    [Google Scholar]
  168. FerreiraH.B. MeloT. MonteiroA. PaivaA. DominguesP. DominguesM.R. Serum phospholipidomics reveals altered lipid profile and promising biomarkers in multiple sclerosis.Arch. Biochem. Biophys.2021697210867210.1016/j.abb.2020.108672 33189653
    [Google Scholar]
  169. ThelenA.M. ZoncuR. Emerging roles for the lysosome in lipid metabolism.Trends Cell Biol.2017271183385010.1016/j.tcb.2017.07.006 28838620
    [Google Scholar]
  170. JahnO. SiemsS.B. KuschK. The CNS myelin proteome: deep profile and persistence after post-mortem delay.Front. Cell. Neurosci.2020141123910.3389/fncel.2020.00239 32973451
    [Google Scholar]
  171. BaronW. OzgenH. KlunderB. The major myelin-resident protein PLP is transported to myelin membranes via a transcytotic mechanism: involvement of sulfatide.Mol. Cell. Biol.201535128830210.1128/MCB.00848‑14 25368380
    [Google Scholar]
  172. McMahonR.M. FriisL. SieboldC. FrieseM.A. FuggerL. JonesE.Y. Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: Insights into the role of HLA-A alleles in susceptibility to multiple sclerosis.Acta Crystallogr. D Biol. Crystallogr.201167544745410.1107/S0907444911007888 21543847
    [Google Scholar]
  173. GreerJ.M. TrifilieffE. PenderM.P. Correlation between anti-myelin proteolipid protein (plp) antibodies and disease severity in multiple sclerosis patients with plp response-permissive HLA types.Front. Immunol.202011Pt 5189110.3389/fimmu.2020.01891 32973782
    [Google Scholar]
  174. MüllerC. BauerN.M. SchäferI. WhiteR. Making myelin basic protein -from mRNA transport to localized translation.Front. Cell. Neurosci.20137Pt 516910.3389/fncel.2013.00169 24098271
    [Google Scholar]
  175. BammV.V. De AvilaM. SmithG.S.T. AhmedM.A.M. HarauzG. Structured functional domains of myelin basic protein: Cross talk between actin polymerization and Ca(2+)-dependent calmodulin interaction.Biophys. J.201110151248125610.1016/j.bpj.2011.07.035 21889463
    [Google Scholar]
  176. TrägerJ. WidderK. KerthA. HarauzG. HinderbergerD. Effect of cholesterol and myelin basic protein (MBP) content on lipid monolayers mimicking the cytoplasmic membrane of myelin.Cells20209352910.3390/cells9030529 32106542
    [Google Scholar]
  177. RaasakkaA. JonesN.C. HoffmannS.V. KursulaP. Ionic strength and calcium regulate membrane interactions of myelin basic protein and the cytoplasmic domain of myelin protein zero.Biochem. Biophys. Res. Commun.2019511171210.1016/j.bbrc.2019.02.025 30755303
    [Google Scholar]
  178. BairdL. YamamotoM. The molecular mechanisms regulating the KEAP1-NRF2 pathway.Mol. Cell. Biol.20204013e00099e2010.1128/MCB.00099‑20 32284348
    [Google Scholar]
  179. YoshikawaH. Myelin-associated oligodendrocytic basic protein modulates the arrangement of radial growth of the axon and the radial component of myelin.Med. Electron Microsc.200134316016410.1007/s007950100009 11793190
    [Google Scholar]
  180. PronkerM.F. LemstraS. SnijderJ. Structural basis of myelin-associated glycoprotein adhesion and signalling.Nat. Commun.2016711358410.1038/ncomms13584 27922006
    [Google Scholar]
  181. MontgomeryTL PeipertD KrementsovDN Modulation of multiple sclerosis risk and pathogenesis by the gut microbiota: Complex interactions between host genetics, bacterial metabolism, and diet.Immunol Rev2024imr.1334310.1111/imr.1334338717158
    [Google Scholar]
  182. ZhouP. GuanT. JiangZ. NamakaM. HuangQ.J. KongJ.M. Monocarboxylate transporter 1 and the vulnerability of oligodendrocyte lineage cells to metabolic stresses.CNS Neurosci. Ther.201824212613410.1111/cns.12782 29205833
    [Google Scholar]
  183. WangL. PavlouS. DuX. BhuckoryM. XuH. ChenM. Glucose transporter 1 critically controls microglial activation through facilitating glycolysis.Mol. Neurodegener.2019141210.1186/s13024‑019‑0305‑9 30634998
    [Google Scholar]
  184. LiH. GuglielmettiC. SeiY.J. Neurons require glucose uptake and glycolysis in vivo.Cell Rep.202342411233510.1016/j.celrep.2023.112335 37027294
    [Google Scholar]
  185. FoxP.T. RaichleM.E. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects.Proc. Natl. Acad. Sci. USA19868341140114410.1073/pnas.83.4.1140 3485282
    [Google Scholar]
  186. XuL.Z. HarrisonR.W. WeberI.T. PilkisS.J. Human β-Cell Glucokinase.J. Biol. Chem.1995270179939994610.1074/jbc.270.17.9939 7730377
    [Google Scholar]
  187. SnyderC.D. WilsonJ.E. Relative levels of hexokinase in isolated neuronal, astrocytic, and oligodendroglial fractions from rat brain.J. Neurochem.19834041178118110.1111/j.1471‑4159.1983.tb08111.x 6834050
    [Google Scholar]
  188. KowalikM.A. ColumbanoA. PerraA. Emerging role of the pentose phosphate pathway in hepatocellular carcinoma.Front. Oncol.2017748710.3389/fonc.2017.00087 28553614
    [Google Scholar]
  189. SykesJ.E.C. Lopes-CardozoM. Van Den BerghS.G. Relationship between the pentose-phosphate pathway and the de novo synthesis of fatty acids and cholesterol in oligodendrocyte-enriched glial cultures.Neurochem. Int.198681778210.1016/0197‑0186(86)90103‑8 20493032
    [Google Scholar]
  190. PanequeA. FortusH. ZhengJ. WerlenG. JacintoE. The hexosamine biosynthesis pathway: regulation and function.Genes (Basel)202314493310.3390/genes14040933 37107691
    [Google Scholar]
  191. WackerM. HolickM.F. Sunlight and Vitamin D: A global perspective for health.Dermatoendocrinol2013515110810.4161/derm.24494 24494042
    [Google Scholar]
  192. ZhangF. QianX. QinC. Phosphofructokinase-1 negatively regulates neurogenesis from neural stem cells.Neurosci. Bull.201632320521610.1007/s12264‑016‑0032‑y 27146165
    [Google Scholar]
  193. RaoM. HuangY.K. LiuC.C. Aldose reductase inhibition decelerates optic nerve degeneration by alleviating retinal microglia activation.Sci. Rep.2023131559210.1038/s41598‑023‑32702‑5 37019993
    [Google Scholar]
  194. Echaniz-LagunaA. NadjarY. BéhinA. Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study.J. Inherit. Metab. Dis.201942580380810.1002/jimd.12087 30887539
    [Google Scholar]
  195. KimuraA. KishimotoT. IL-6: regulator of Treg/Th17 balance.Eur. J. Immunol.20104071830183510.1002/eji.201040391 20583029
    [Google Scholar]
  196. ZhangY. ArgawA.T. GurfeinB.T. Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination.Proc. Natl. Acad. Sci. USA200910645191621916710.1073/pnas.0902834106 19855010
    [Google Scholar]
  197. HaqueA. PolcynR. MatzelleD. BanikN.L. New insights into the role of neuron-specific enolase in neuro-inflammation, Neurodegeneration, and Neuroprotection.Brain Sci.2018823310.3390/brainsci8020033 29463007
    [Google Scholar]
  198. GianfrancescoM. BarcellosL. Obesity and multiple sclerosis susceptibility: a review.J. Neurol. Neuromedicine2016171510.29245/2572.942X/2016/7.1064 27990499
    [Google Scholar]
  199. RoneM.B. CuiQ.L. FangJ. Oligodendrogliopathy in multiple sclerosis: low glycolytic metabolic rate promotes oligodendrocyte survival.J. Neurosci.201636174698470710.1523/JNEUROSCI.4077‑15.2016 27122029
    [Google Scholar]
  200. MehanS. Editorial: Therapeutic modulators inhibiting neuromuscular and motor neuron degeneration.Front. Neurosci.2023174118894510.3389/fnins.2023.1188945 37090793
    [Google Scholar]
  201. YsrraelitM.C. CorrealeJ. Impact of sex hormones on immune function and multiple sclerosis development.Immunology2019156192210.1111/imm.13004 30222193
    [Google Scholar]
  202. WangY. WangJ. FengJ. Multiple sclerosis and pregnancy: Pathogenesis, influencing factors, and treatment options.Autoimmun. Rev.2023221110344910.1016/j.autrev.2023.103449 37741528
    [Google Scholar]
  203. ManouchehriniaA. TenchC.R. MaxtedJ. BibaniR.H. BrittonJ. ConstantinescuC.S. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study.Brain201313672298230410.1093/brain/awt139 23757766
    [Google Scholar]
  204. OskariV.J. VirusesJ.S. SclerosisM. Viruses and multiple sclerosis.CNS Neurol. Disord. Drug Targets201211552854410.2174/187152712801661220 22583435
    [Google Scholar]
  205. KapoorT. MehanS. neuroprotective methodologies in the treatment of multiple sclerosis current status of clinical and pre-clinical findings.Curr. Drug Discov. Technol.2021181314610.2174/1570163817666200207100903 32031075
    [Google Scholar]
  206. McArdleB. MackenzieI.C.K. WebsterG.R. Studies on intermediate carbohydrate metabolism in multiple sclerosis.J. Neurol. Neurosurg. Psychiatry196023212713210.1136/jnnp.23.2.127 21610891
    [Google Scholar]
  207. LeviteM. Glutamate, T cells and multiple sclerosis.J. Neural Transm. (Vienna)2017124777579810.1007/s00702‑016‑1661‑z 28236206
    [Google Scholar]
  208. LancasterM.S. GrahamB.H. Succinyl-CoA synthetase dysfunction as a mechanism of mitochondrial encephalomyopathy: more than just an oxidative energy deficit.Int. J. Mol. Sci.202324131072510.3390/ijms241310725 37445899
    [Google Scholar]
  209. KimY. RohE.J. JoshiH.P. Bazedoxifene, a selective estrogen receptor modulator, promotes functional recovery in a spinal cord injury rat model.Int. J. Mol. Sci.202122201101210.3390/ijms222011012 34681670
    [Google Scholar]
  210. PicaudS. KavanaghK.L. YueW.W. Structural basis of fumarate hydratase deficiency.J. Inherit. Metab. Dis.201134367167610.1007/s10545‑011‑9294‑8 21445611
    [Google Scholar]
  211. TangX. FengC. ZhaoY. A study of genetic heterogeneity in autism spectrum disorders based on plasma proteomic and metabolomic analysis: multiomics study of autism heterogeneity.MedComm202345e38010.1002/mco2.380 37752942
    [Google Scholar]
  212. LuM. ZhouL. StanleyW.C. CabreraM.E. SaidelG.M. YuX. Role of the malate–aspartate shuttle on the metabolic response to myocardial ischemia.J. Theor. Biol.2008254246647510.1016/j.jtbi.2008.05.033 18603266
    [Google Scholar]
  213. Nolfi-DoneganD. BraganzaA. ShivaS. Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement.Redox Biol.202037210167410.1016/j.redox.2020.101674 32811789
    [Google Scholar]
  214. WikströmM. KrabK. SharmaV. Oxygen activation and energy conservation by cytochrome c oxidase.Chem. Rev.201811852469249010.1021/acs.chemrev.7b00664 29350917
    [Google Scholar]
  215. VyshkinaT. BanisorI. ShugartY.Y. LeistT.P. KalmanB. Genetic variants of Complex I in multiple sclerosis.J. Neurol. Sci.20052281556410.1016/j.jns.2004.09.027 15607211
    [Google Scholar]
  216. FarshbafM.J. Kiani-EsfahaniA. Succinate dehydrogenase: Prospect for neurodegenerative diseases.Mitochondrion2018421778310.1016/j.mito.2017.12.002 29225013
    [Google Scholar]
  217. KhalilianB. MadadiS. FattahiN. AbouhamzehB. Coenzyme Q10 enhances remyelination and regulate inflammation effects of cuprizone in corpus callosum of chronic model of multiple sclerosis.J. Mol. Histol.202152112513410.1007/s10735‑020‑09929‑x 33245472
    [Google Scholar]
  218. HeidariE. RasoulinezhadM. PakN. Defective complex III mitochondrial respiratory chain due to a novel variant in CYC1 gene masquerades acute demyelinating syndrome or Leber hereditary optic neuropathy.Mitochondrion2021601122010.1016/j.mito.2021.07.001 34252606
    [Google Scholar]
  219. DiazF. GarciaS. PadgettK.R. MoraesC.T. A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain regions.Hum. Mol. Genet.201221235066507710.1093/hmg/dds350 22914734
    [Google Scholar]
  220. SnaideroN. MöbiusW. CzopkaT. Myelin membrane wrapping of CNS axons by PI(3,4,5)P3-dependent polarized growth at the inner tongue.Cell20141561-227729010.1016/j.cell.2013.11.044 24439382
    [Google Scholar]
  221. ComanI. AigrotM.S. SeilheanD. Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis.Brain2006129123186319510.1093/brain/awl144 16766541
    [Google Scholar]
  222. ÇolakoğluG. Bergstrom-TyrbergU. BerglundE.O. RanschtB. Contactin-1 regulates myelination and nodal/paranodal domain organization in the central nervous system.Proc. Natl. Acad. Sci. USA20141113E394E40310.1073/pnas.1313769110 24385581
    [Google Scholar]
  223. Schaeren-WiemersN. BonnetA. ErbM. The raft-associated protein MAL is required for maintenance of proper axon–glia interactions in the central nervous system.J. Cell Biol.2004166573174210.1083/jcb.200406092 15337780
    [Google Scholar]
  224. LuC. XuW. ZhangF. Ligustrazine prevents alcohol-induced liver injury by attenuating hepatic steatosis and oxidative stress.Int. Immunopharmacol.201529261362110.1016/j.intimp.2015.09.020 26459052
    [Google Scholar]
  225. PopkoB. Notch signaling.Dev. Cell20035566866910.1016/S1534‑5807(03)00331‑9 14602066
    [Google Scholar]
  226. PhilipsT. MironovaY.A. JouroukhinY. MCT1 deletion in oligodendrocyte lineage cells causes late-onset hypomyelination and axonal degeneration.Cell Rep.202134210861010.1016/j.celrep.2020.108610 33440165
    [Google Scholar]
  227. PanD. LiuW. ZhuS. Potential of different cells-derived exosomal microRNA cargos for treating spinal cord injury.J. Orthop. Translat.2021312334010.1016/j.jot.2021.09.008 34760623
    [Google Scholar]
  228. MukherjeeC. KlingT. RussoB. Oligodendrocytes provide antioxidant defense function for neurons by secreting ferritin heavy chain.Cell Metab.2020322259272.e1010.1016/j.cmet.2020.05.019 32531201
    [Google Scholar]
  229. SchirmerL. MöbiusW. ZhaoC. Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity.eLife201872e3642810.7554/eLife.36428 30204081
    [Google Scholar]
  230. JensenA.M. ChiuS.Y. Expression of glutamate receptor genes in white matter: developing and adult rat optic nerve.J. Neurosci.19931341664167510.1523/JNEUROSCI.13‑04‑01664.1993 8463842
    [Google Scholar]
  231. BarresB.A. KoroshetzW.J. SwartzK.J. ChunL.L.Y. CoreyD.P. Ion channel expression by white matter Glia: The O-2A glial progenitor cell.Neuron19904450752410.1016/0896‑6273(90)90109‑S 1691005
    [Google Scholar]
  232. GautierH.O.B. EvansK.A. VolbrachtK. Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors.Nat. Commun.201561851810.1038/ncomms9518 26439639
    [Google Scholar]
  233. KáradóttirR. CavelierP. BergersenL.H. AttwellD. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia.Nature200543870711162116610.1038/nature04302 16372011
    [Google Scholar]
  234. NishiyamaA. LinX.H. GieseN. HeldinC.H. StallcupW.B. Co-localization of NG2 proteoglycan and PDGF? -receptor on O2A progenitor cells in the developing rat brain.J. Neurosci. Res.199643329931410.1002/(SICI)1097‑4547(19960201)43:3<299::AID‑JNR5>3.0.CO;2‑E 8714519
    [Google Scholar]
  235. ArellanoR.O. Sánchez-GómezM.V. AlberdiE. Axon-to-glia interaction regulates gabaa receptor expression in oligodendrocytes.Mol. Pharmacol.2016891637410.1124/mol.115.100594 26538574
    [Google Scholar]
  236. Vélez-FortM. MaldonadoP.P. ButtA.M. AudinatE. AnguloM.C. Postnatal switch from synaptic to extrasynaptic transmission between interneurons and NG2 cells.J. Neurosci.201030206921692910.1523/JNEUROSCI.0238‑10.2010 20484634
    [Google Scholar]
  237. ZonouziM. ScafidiJ. LiP. GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury.Nat. Neurosci.201518567468210.1038/nn.3990 25821912
    [Google Scholar]
  238. Serrano-RegalM.P. Bayón-CorderoL. OrdazR.P. Expression and function of gaba receptors in myelinating cells.Front. Cell. Neurosci.202014525610.3389/fncel.2020.00256 32973453
    [Google Scholar]
  239. LiD. HuangL.T. ZhangC. LiQ. WangJ.H. Insights into the role of platelet-derived growth factors: implications for Parkinson’s disease pathogenesis and treatment.Front. Aging Neurosci.20221489050910.3389/fnagi.2022.890509 35847662
    [Google Scholar]
  240. ZhouL. ShaoC.Y. XieY.J. Gab1 mediates PDGF signaling and is essential to oligodendrocyte differentiation and CNS myelination.eLife20209e5205610.7554/eLife.52056 31944179
    [Google Scholar]
  241. YueB. Biology of the extracellular matrix: an overview.J. Glaucoma2014238Suppl. 1S20S2310.1097/IJG.0000000000000108 25275899
    [Google Scholar]
  242. O’MearaR.W. CummingsS.E. MichalskiJ.P. KotharyR. A new in vitro mouse oligodendrocyte precursor cell migration assay reveals a role for integrin-linked kinase in cell motility.BMC Neurosci.2016171710.1186/s12868‑016‑0242‑2 26831726
    [Google Scholar]
  243. SuoN. GuoY. HeB. GuH. XieX. Inhibition of MAPK/ERK pathway promotes oligodendrocytes generation and recovery of demyelinating diseases.Glia20196771320133210.1002/glia.23606 30815939
    [Google Scholar]
  244. IshiiA. Fyffe-MaricichS.L. FurushoM. MillerR.H. BansalR. ERK1/ERK2 MAPK signaling is required to increase myelin thickness independent of oligodendrocyte differentiation and initiation of myelination.J. Neurosci.201232268855886410.1523/JNEUROSCI.0137‑12.2012 22745486
    [Google Scholar]
  245. JurewiczA. MatysiakM. TyborK. SelmajK. TNF‐induced death of adult human oligodendrocytes is mediated by c‐jun NH2‐terminal kinase‐3.Brain200312661358137010.1093/brain/awg146 12764057
    [Google Scholar]
  246. NellessenA. NyamoyaS. ZendedelA. Nrf2 deficiency increases oligodendrocyte loss, demyelination, neuroinflammation and axonal damage in an MS animal model.Metab. Brain Dis.202035235336210.1007/s11011‑019‑00488‑z 31529356
    [Google Scholar]
  247. RyterS.W. ChoiA.M.K. Heme oxygenase-1/carbon monoxide: from metabolism to molecular therapy.Am. J. Respir. Cell Mol. Biol.200941325126010.1165/rcmb.2009‑0170TR 19617398
    [Google Scholar]
  248. De NuccioC. BernardoA. TroianoC. NRF2 and PPAR-γ pathways in oligodendrocyte progenitors: focus on ros protection, mitochondrial biogenesis and promotion of cell differentiation.Int. J. Mol. Sci.20202119721610.3390/ijms21197216 33003644
    [Google Scholar]
  249. DaiZ.M. SunS. WangC. Stage-specific regulation of oligodendrocyte development by Wnt/β-catenin signaling.J. Neurosci.201434258467847310.1523/JNEUROSCI.0311‑14.2014 24948802
    [Google Scholar]
  250. BoccazziM. MacchiaruloG. LebonS. G protein-coupled receptor 17 is regulated by WNT pathway during oligodendrocyte precursor cell differentiation.Neurobiol. Dis.20231872510631510.1016/j.nbd.2023.106315 37783234
    [Google Scholar]
  251. GenoudS. Lappe-SiefkeC. GoebbelsS. Notch1 control of oligodendrocyte differentiation in the spinal cord.J. Cell Biol.2002158470971810.1083/jcb.200202002 12186854
    [Google Scholar]
  252. NagarajanB. HarderA. JappA. CNS myelin protein 36K regulates oligodendrocyte differentiation through Notch.Glia202068350952710.1002/glia.23732 31702067
    [Google Scholar]
  253. TranL.N. LoewS.K. FrancoS.J. Notch signaling plays a dual role in regulating the neuron-to-oligodendrocyte switch in the developing dorsal forebrain.J. Neurosci.202343416854687110.1523/JNEUROSCI.0144‑23.2023 37640551
    [Google Scholar]
  254. MosaddeghzadehN. AhmadianM.R. The RHO family gtpases: mechanisms of regulation and signaling.Cells2021107183110.3390/cells10071831 34359999
    [Google Scholar]
  255. LiB. XuY. QuanY. Inhibition of RhoA/ROCK pathway in the early stage of hypoxia ameliorates depression in mice via protecting myelin sheath.ACS Chem. Neurosci.202011172705271610.1021/acschemneuro.0c00352 32667781
    [Google Scholar]
  256. PaintliaA.S. PaintliaM.K. SinghA.K. SinghI. Modulation of Rho‐Rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR‐α‐dependent mechanism.Glia20136191500151710.1002/glia.22537 23839981
    [Google Scholar]
  257. TzavlakiK. MoustakasA. TGF-β Signaling.Biomolecules202010348710.3390/biom10030487 32210029
    [Google Scholar]
  258. DettmanR.W. BirchD. FernandoA. KesslerJ.A. DizonM.L.V. Targeted knockdown of bone morphogenetic protein signaling within neural progenitors protects the brain and improves motor function following postnatal hypoxia-ischemia.Dev. Neurosci.2018401233810.1159/000485379 29324456
    [Google Scholar]
  259. PetersenM.A. RyuJ.K. ChangK.J. Fibrinogen activates bmp signaling in oligodendrocyte progenitor cells and inhibits remyelination after vascular damage.Neuron201796510031012.e710.1016/j.neuron.2017.10.008 29103804
    [Google Scholar]
  260. BhatiaR. BaliP. ChowdharyR. Epidemiology and genetic aspects of multiple sclerosis in India.Ann. Indian Acad. Neurol.2015185Suppl. 1610.4103/0972‑2327.164814 26538851
    [Google Scholar]
  261. LevinL.I. MungerK.L. RubertoneM.V. Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis.JAMA2005293202496250010.1001/jama.293.20.2496 15914750
    [Google Scholar]
  262. HassaniA. CorboyJ.R. Al-SalamS. KhanG. Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells.PLoS One2018132e019210910.1371/journal.pone.0192109 29394264
    [Google Scholar]
  263. PenderM.P. The essential role of Epstein-Barr virus in the pathogenesis of multiple sclerosis.Neuroscientist201117435136710.1177/1073858410381531 21075971
    [Google Scholar]
  264. AlcinaA. Abad-GrauM.M. FedetzM. Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations.PLoS One201271e2981910.1371/journal.pone.0029819 22253788
    [Google Scholar]
  265. ScholzE.M. MarcillaM. DauraX. Arribas-LaytonD. JamesE.A. AlvarezI. Human leukocyte antigen (HLA)-DRB1*15:01 and HLA-DRB5*01:01 present complementary peptide repertoires.Front. Immunol.20178198410.3389/fimmu.2017.00984 28871256
    [Google Scholar]
  266. MenegattiJ. SchubD. SchäferM. GrässerF.A. RuprechtK. HLA‐DRB1*15:01 is a co‐receptor for Epstein–Barr virus, linking genetic and environmental risk factors for multiple sclerosis.Eur. J. Immunol.20215192348235010.1002/eji.202149179 34019695
    [Google Scholar]
  267. IrizarH. Muñoz-CullaM. ZuriarrainO. HLA-DRB1*15:01 and multiple sclerosis: a female association?Mult. Scler.201218556957710.1177/1352458511426813 22127897
    [Google Scholar]
  268. AscherioA. MungerK.L. WhiteR. Vitamin D as an early predictor of multiple sclerosis activity and progression.JAMA Neurol.201471330631410.1001/jamaneurol.2013.5993 24445558
    [Google Scholar]
  269. GombashS.E. LeeP.W. SawdaiE. Lovett-RackeA.E. Vitamin D as a risk factor for multiple sclerosis: Immunoregulatory or neuroprotective?Front. Neurol.202213379693310.3389/fneur.2022.796933 35651353
    [Google Scholar]
  270. LassmannH. van HorssenJ. Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions.Biochim. Biophys. Acta Mol. Basis Dis.20161862350651010.1016/j.bbadis.2015.09.018 26432481
    [Google Scholar]
  271. QuinnP.M.J. AmbrósioA.F. AlvesC.H. Oxidative stress, neuroinflammation and neurodegeneration: The chicken, the egg and the dinosaur.Antioxidants2022118155410.3390/antiox11081554 36009273
    [Google Scholar]
  272. GovermanJ.M. Immune tolerance in multiple sclerosis.Immunol. Rev.2011241122824010.1111/j.1600‑065X.2011.01016.x 21488900
    [Google Scholar]
  273. ConstantinescuC.S. FarooqiN. O’BrienK. GranB. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS).Br. J. Pharmacol.201116441079110610.1111/j.1476‑5381.2011.01302.x 21371012
    [Google Scholar]
  274. van ZwamM. HuizingaR. HeijmansN. Surgical excision of CNS‐draining lymph nodes reduces relapse severity in chronic‐relapsing experimental autoimmune encephalomyelitis.J. Pathol.2009217454355110.1002/path.2476 19023878
    [Google Scholar]
  275. HoppA.K. RuppA. Lukacs-KornekV. Self-antigen presentation by dendritic cells in autoimmunity.Front. Immunol.2014545510.3389/fimmu.2014.00055 24592266
    [Google Scholar]
  276. ShahK. Al-HaidariA. SunJ. KaziJ.U. T cell receptor (TCR) signaling in health and disease.Signal Transduct. Target. Ther.20216141210.1038/s41392‑021‑00823‑w 34897277
    [Google Scholar]
  277. HedegaardC.J. KrakauerM. BendtzenK. LundH. SellebjergF. NielsenC.H. T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis.Immunology2008125216116910.1111/j.1365‑2567.2008.02837.x 18397264
    [Google Scholar]
  278. AbbasA.K. MurphyK.M. SherA. Functional diversity of helper T lymphocytes.Nature1996383660378779310.1038/383787a0 8893001
    [Google Scholar]
  279. MosmannT.R. CoffmanR.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.Annu. Rev. Immunol.19897114517310.1146/annurev.iy.07.040189.001045 2523712
    [Google Scholar]
  280. ValeriM. RaffatelluM. Cytokines IL-17 and IL-22 in the host response to infection.Pathog. Dis.2016749ftw11110.1093/femspd/ftw111 27915228
    [Google Scholar]
  281. KarabonL. KosmaczewskaA. BilinskaM. The CTLA‐4 gene polymorphisms are associated with CTLA-4 protein expression levels in multiple sclerosis patients and with susceptibility to disease.Immunology20091281pt2e787e79610.1111/j.1365‑2567.2009.03083.x 19740340
    [Google Scholar]
  282. EngelhardtB. RansohoffR.M. Capture, crawl, cross: the T cell code to breach the blood–brain barriers.Trends Immunol.2012331257958910.1016/j.it.2012.07.004 22926201
    [Google Scholar]
  283. BuiT.M. WiesolekH.L. SumaginR. ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis.J. Leukoc. Biol.2020108378779910.1002/JLB.2MR0220‑549R 32182390
    [Google Scholar]
  284. Pyka-FościakG. LisG.J. LitwinJ.A. Adhesion molecule profile and the effect of Anti-VLA-4 mAb treatment in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis.Int. J. Mol. Sci.2022239463710.3390/ijms23094637 35563027
    [Google Scholar]
  285. MarchettiL. EngelhardtB. Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation.Vascular Biology202021H1H1810.1530/VB‑19‑0033 32923970
    [Google Scholar]
  286. PopkoB. CorbinJ.G. BaerwaldK.D. DupreeJ. GarciaA.M. The effects of interferon-γ on the central nervous system.Mol. Neurobiol.1997141-2193510.1007/BF02740619 9170099
    [Google Scholar]
  287. RempeR.G. HartzA.M.S. BauerB. Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers.J. Cereb. Blood Flow Metab.20163691481150710.1177/0271678X16655551 27323783
    [Google Scholar]
  288. FletcherJ.M. LalorS.J. SweeneyC.M. TubridyN. MillsK.H.G. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.Clin. Exp. Immunol.2010162111110.1111/j.1365‑2249.2010.04143.x 20682002
    [Google Scholar]
  289. WuC. XueY. WangP. IFN-γ primes macrophage activation by increasing phosphatase and tensin homolog via downregulation of miR-3473b.J. Immunol.201419363036304410.4049/jimmunol.1302379 25092892
    [Google Scholar]
  290. GuerreroB.L. SicotteN.L. Microglia in multiple sclerosis: friend or foe?Front. Immunol.202011637410.3389/fimmu.2020.00374 32265902
    [Google Scholar]
  291. HoffmanW. LakkisF.G. ChalasaniG. B cells, antibodies, and more.Clin. J. Am. Soc. Nephrol.201611113715410.2215/CJN.09430915 26700440
    [Google Scholar]
  292. YuX. GranerM. KennedyP.G.E. LiuY. The role of antibodies in the pathogenesis of multiple sclerosis.Front. Neurol.202011153338810.3389/fneur.2020.533388 33192968
    [Google Scholar]
  293. JacobsenM. CepokS. QuakE. Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients.Brain2002125353855010.1093/brain/awf059 11872611
    [Google Scholar]
  294. AlizadehA. DyckS.M. Karimi-AbdolrezaeeS. Myelin damage and repair in pathologic CNS: challenges and prospects.Front. Mol. Neurosci.2015833510.3389/fnmol.2015.00035 26283909
    [Google Scholar]
  295. MeyG.M. MahajanK.R. DeSilvaT.M. Neurodegeneration in multiple sclerosis.WIREs Mech. Dis.2023151e158310.1002/wsbm.1583 35948371
    [Google Scholar]
  296. SrinivasanR. SailasutaN. HurdR. NelsonS. PelletierD. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T.Brain200512851016102510.1093/brain/awh467 15758036
    [Google Scholar]
  297. O’GradyK.P. DulaA.N. LyttleB.D. Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis.Mult. Scler.201925121580159210.1177/1352458518799583 30230400
    [Google Scholar]
  298. KosticM. DzopalicT. ZivanovicS. IL-17 and glutamate excitotoxicity in the pathogenesis of multiple sclerosis.Scand. J. Immunol.201479318118610.1111/sji.12147 24383677
    [Google Scholar]
  299. MatuteC. AlberdiE. DomercqM. Excitotoxic damage to white matter.J. Anat.2007210669370210.1111/j.1469‑7580.2007.00733.x 17504270
    [Google Scholar]
  300. GiacciM.K. BartlettC.A. SmithN.M. Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma In Vivo.J. Neurosci.201838296491650410.1523/JNEUROSCI.1898‑17.2018 29915135
    [Google Scholar]
  301. TakaseH. LiangA.C. MiyamotoN. Protective effects of a radical scavenger edaravone on oligodendrocyte precursor cells against oxidative stress.Neurosci. Lett.20186682912012510.1016/j.neulet.2018.01.018 29337010
    [Google Scholar]
  302. FaiziM. SalimiA. SeydiE. Toxicity of cuprizone a Cu2+ chelating agent on isolated mouse brain mitochondria: a justification for demyelination and subsequent behavioral dysfunction.Toxicol. Mech. Methods201626427628310.3109/15376516.2016.1172284 27088566
    [Google Scholar]
  303. López-MuguruzaE. MatuteC. Alterations of oligodendrocyte and myelin energy metabolism in multiple sclerosis.Int. J. Mol. Sci.202324161291210.3390/ijms241612912 37629092
    [Google Scholar]
  304. MingX. LiW. MaedaY. Caspase-1 expression in multiple sclerosis plaques and cultured glial cells.J. Neurol. Sci.20021971-291810.1016/S0022‑510X(02)00030‑8 11997061
    [Google Scholar]
  305. BeheshtiM. SalehiZ. AbolfazliR. ShirzadH. IzadM. Increased level of caspase-1 in the serum of relapsing-remitting multiple sclerosis (RRMS) Patients.Iran. J. Allergy Asthma Immunol.202019553453810.18502/ijaai.v19i5.4470 33463121
    [Google Scholar]
  306. GuC. Casaccia-BonnefilP. SrinivasanA. ChaoM.V. Oligodendrocyte apoptosis mediated by caspase activation.J. Neurosci.19991983043304910.1523/JNEUROSCI.19‑08‑03043.1999 10191321
    [Google Scholar]
  307. NagataS. Apoptosis by death factor.Cell199788335536510.1016/S0092‑8674(00)81874‑7 9039262
    [Google Scholar]
  308. Mc GuireC. VolckaertT. WolkeU. Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination.J. Immunol.2010185127646765310.4049/jimmunol.1000930 21068410
    [Google Scholar]
  309. JiangM. LiuL. HeX. Regulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes.Nat. Commun.2016711218510.1038/ncomms12185 27416896
    [Google Scholar]
  310. SunL.O. MulinyaweS.B. CollinsH.Y. Spatiotemporal control of cns myelination by oligodendrocyte programmed cell death through the TFEB-PUMA axis.Cell2018175718111826.e2110.1016/j.cell.2018.10.044 30503207
    [Google Scholar]
  311. PopescuBFG PirkoI LucchinettiCF Pathology of multiple sclerosis: where do we stand?Continuum (Minneap Minn)2013194 Multiple Sclerosis9012110.1212/01.CON.0000433291.23091.6523917093
    [Google Scholar]
  312. GiovannoniG. PopescuV. WuerfelJ. Smouldering multiple sclerosis: the ‘real MS’.Ther. Adv. Neurol. Disord.202215717562864211066751 35096143
    [Google Scholar]
  313. PatelJ. BalabanovR. Molecular mechanisms of oligodendrocyte injury in multiple sclerosis and experimental autoimmune encephalomyelitis.Int. J. Mol. Sci.2012138106471065910.3390/ijms130810647 22949885
    [Google Scholar]
  314. KhaibullinT. IvanovaV. MartynovaE. Elevated levels of proinflammatory cytokines in cerebrospinal fluid of multiple sclerosis patients.Front. Immunol.20178853110.3389/fimmu.2017.00531 28572801
    [Google Scholar]
  315. BaakliniC.S. RawjiK.S. DuncanG.J. HoM.F.S. PlemelJ.R. Central nervous system remyelination: roles of Glia and innate immune cells.Front. Mol. Neurosci.201912822510.3389/fnmol.2019.00225 31616249
    [Google Scholar]
  316. van der WeijdenC.W.J. MeilofJ.F. van der HoornA. Quantitative assessment of myelin density using [11C]MeDAS PET in patients with multiple sclerosis: a first-in-human study.Eur. J. Nucl. Med. Mol. Imaging202249103492350710.1007/s00259‑022‑05770‑4 35366079
    [Google Scholar]
  317. PhilipsT. RothsteinJ.D. Oligodendroglia: metabolic supporters of neurons.J. Clin. Invest.201712793271328010.1172/JCI90610 28862639
    [Google Scholar]
  318. DuncanG.J. SimkinsT.J. EmeryB. Neuron-Oligodendrocyte interactions in the structure and integrity of axons.Front. Cell Dev. Biol.20219965310110.3389/fcell.2021.653101 33763430
    [Google Scholar]
  319. StidworthyM.F. GenoudS. SuterU. ManteiN. FranklinR.J.M. Quantifying the early stages of remyelination following cuprizone-induced demyelination.Brain Pathol.200313332933910.1111/j.1750‑3639.2003.tb00032.x 12946022
    [Google Scholar]
  320. FrischerJ.M. WeigandS.D. GuoY. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque.Ann. Neurol.201578571072110.1002/ana.24497 26239536
    [Google Scholar]
  321. NeumannB. BarorR. ZhaoC. Metformin restores cns remyelination capacity by rejuvenating aged stem cells.Cell Stem Cell2019254473485.e810.1016/j.stem.2019.08.015 31585093
    [Google Scholar]
  322. PackerD. FresenkoE.E. HarringtonE.P. Remyelination in animal models of multiple sclerosis: finding the elusive grail of regeneration.Front. Mol. Neurosci.2023164120700710.3389/fnmol.2023.1207007 37448959
    [Google Scholar]
  323. SimonJ. Nuñez-GarcíaM. Fernández-TussyP. Targeting hepatic glutaminase 1 ameliorates non-alcoholic steatohepatitis by restoring very-low-density lipoprotein triglyceride assembly.Cell Metab.2020313605622.e1010.1016/j.cmet.2020.01.013 32084378
    [Google Scholar]
  324. IslamM.S. TatsumiK. OkudaH. ShiosakaS. WanakaA. Olig2-expressing progenitor cells preferentially differentiate into oligodendrocytes in cuprizone-induced demyelinated lesions.Neurochem. Int.2009543-419219810.1016/j.neuint.2008.10.011 19070638
    [Google Scholar]
  325. PolitoA. ReynoldsR. NG2‐expressing cells as oligodendrocyte progenitors in the normal and demyelinated adult central nervous system.J. Anat.2005207670771610.1111/j.1469‑7580.2005.00454.x 16367798
    [Google Scholar]
  326. JanowskaJ. GargasJ. Ziemka-NaleczM. ZalewskaT. SypeckaJ. Oligodendrocyte response to pathophysiological conditions triggered by episode of perinatal hypoxia-ischemia: role of IGF-1 secretion by glial cells.Mol. Neurobiol.202057104250426810.1007/s12035‑020‑02015‑z 32691304
    [Google Scholar]
  327. RosenbergS.S. KellandE.E. TokarE. De La TorreA.R. ChanJ.R. The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation.Proc. Natl. Acad. Sci. USA200810538146621466710.1073/pnas.0805640105 18787118
    [Google Scholar]
  328. CzopkaT. ffrench-ConstantC LyonsDA. Individual oligodendrocytes have only a few hours in which to generate new myelin sheaths in vivo.Dev. Cell201325659960910.1016/j.devcel.2013.05.013 23806617
    [Google Scholar]
  329. TianY. YinH. DengX. TangB. RenX. JiangT. CXCL12 induces migration of oligodendrocyte precursor cells through the CXCR4 activated MEK/ERK and PI3K/AKT pathways.Mol. Med. Rep.20181854374438010.3892/mmr.2018.9444 30221695
    [Google Scholar]
  330. CalverA.R. HallA.C. YuW.P. Oligodendrocyte population dynamics and the role of PDGF in vivo.Neuron199820586988210.1016/S0896‑6273(00)80469‑9 9620692
    [Google Scholar]
  331. van SchaikP.E.M. ZuhornI.S. BaronW. Targeting fibronectin to overcome remyelination failure in multiple sclerosis: the need for brain- and lesion-targeted drug delivery.Int. J. Mol. Sci.20222315841810.3390/ijms23158418 35955549
    [Google Scholar]
  332. FancyS.P.J. BaranziniS.E. ZhaoC. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS.Genes Dev.200923131571158510.1101/gad.1806309 19515974
    [Google Scholar]
  333. WangL.C. AlmazanG. Role of sonic hedgehog signaling in oligodendrocyte differentiation.Neurochem. Res.201641123289329910.1007/s11064‑016‑2061‑3 27639396
    [Google Scholar]
  334. TianeA. SchepersM. ReijndersR.A. From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions.Acta Neuropathol.2023146228329910.1007/s00401‑023‑02596‑8 37286732
    [Google Scholar]
  335. SintzelM.B. RamettaM. RederA.T. Vitamin D and multiple sclerosis: a comprehensive review.Neurol. Ther.201871598510.1007/s40120‑017‑0086‑4 29243029
    [Google Scholar]
  336. HuJ. DengL. WangX. XuX.M. Effects of extracellular matrix molecules on the growth properties of oligodendrocyte progenitor cells in vitro.J. Neurosci. Res.200987132854286210.1002/jnr.22111 19472225
    [Google Scholar]
  337. DugasJ.C. CuellarT.L. ScholzeA. Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination.Neuron201065559761110.1016/j.neuron.2010.01.027 20223197
    [Google Scholar]
  338. ZoupiL. SavvakiM. KalemakiK. KalafatakisI. SidiropoulouK. KaragogeosD. The function of contactin‐2/TAG‐1 in oligodendrocytes in health and demyelinating pathology.Glia201866357659110.1002/glia.23266 29165835
    [Google Scholar]
  339. LinS. BerglesD.E. Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus.Nat. Neurosci.200471243210.1038/nn1162 14661022
    [Google Scholar]
  340. CooperJ.J.M. PolancoJ.J. SaraswatD. Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation.Glia20237141018103510.1002/glia.24324 36537341
    [Google Scholar]
  341. BoydA. ZhangH. WilliamsA. Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models.Acta Neuropathol.2013125684185910.1007/s00401‑013‑1112‑y 23595275
    [Google Scholar]
  342. DuncanG.J. PlemelJ.R. AssinckP. Myelin regulatory factor drives remyelination in multiple sclerosis.Acta Neuropathol.2017134340342210.1007/s00401‑017‑1741‑7 28631093
    [Google Scholar]
  343. ShenS. SandovalJ. SwissV.A. Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency.Nat. Neurosci.20081191024103410.1038/nn.2172 19160500
    [Google Scholar]
  344. ShieldsS.A. GilsonJ.M. BlakemoreW.F. FranklinR.J.M. Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination.Glia1999281778310.1002/(SICI)1098‑1136(199910)28:1<77::AID‑GLIA9>3.0.CO;2‑F 10498825
    [Google Scholar]
  345. DimovasiliC. FairA.E. GarzaI.R. Aging compromises oligodendrocyte precursor cell maturation and efficient remyelination in the monkey brain.Geroscience202345124926410.1007/s11357‑022‑00621‑4 35930094
    [Google Scholar]
  346. AlfredssonL. OlssonT. Lifestyle and environmental factors in multiple sclerosis.Cold Spring Harb. Perspect. Med.201994a02894410.1101/cshperspect.a028944 29735578
    [Google Scholar]
  347. Santos-GilD.F. ArboledaG. Sandoval-HernándezA.G. Retinoid X receptor activation promotes re-myelination in a very old triple transgenic mouse model of Alzheimer’s disease.Neurosci. Lett.2021750113576410.1016/j.neulet.2021.135764 33621639
    [Google Scholar]
  348. GauntC.M. RainbowD.B. MackenzieR.J. The MS remyelinating drug bexarotene (an RXR agonist) promotes induction of human tregs and suppresses Th17 differentiation in vitro.Front. Immunol.202112171224110.3389/fimmu.2021.712241 34447379
    [Google Scholar]
  349. NatrajanM.S. de la FuenteA.G. CrawfordA.H. Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination.Brain2015138123581359710.1093/brain/awv289 26463675
    [Google Scholar]
  350. NimmerjahnA KirchhoffF HelmchenF Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.Science (80-)2005308572613148
    [Google Scholar]
  351. PlemelJ.R. StrattonJ.A. MichaelsN.J. Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion.Sci. Adv.202063eaay632410.1126/sciadv.aay6324 31998844
    [Google Scholar]
  352. WangY. KyaukR.V. ShenY.A.A. TREM2 ‐dependent microglial function is essential for remyelination and subsequent neuroprotection.Glia20237151247125810.1002/glia.24335 36625077
    [Google Scholar]
  353. MiS. LeeX. ShaoZ. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex.Nat. Neurosci.20047322122810.1038/nn1188 14966521
    [Google Scholar]
  354. KalafatakisI. PapagianniF. TheodorakisK. KaragogeosD. Nogo-A and LINGO-1: two important targets for remyelination and regeneration.Int. J. Mol. Sci.2023245447910.3390/ijms24054479 36901909
    [Google Scholar]
  355. MoradbeygiK. ParvizM. RezaeizadehH. Anti-LINGO-1 improved remyelination and neurobehavioral deficit in cuprizone-induced demyelination.Iran. J. Basic Med. Sci.2021247900907 34712419
    [Google Scholar]
  356. WangX. ChunS.J. TreloarH. VartanianT. GreerC.A. StrittmatterS.M. Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact.J. Neurosci.200222135505551510.1523/JNEUROSCI.22‑13‑05505.2002 12097502
    [Google Scholar]
  357. HuF. LiuB.P. BudelS. Nogo-A interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist.J. Neurosci.200525225298530410.1523/JNEUROSCI.5235‑04.2005 15930377
    [Google Scholar]
  358. MandemakersW.J. BarresB.A. Axon regeneration: it’s getting crowded at the gates of TROY.Curr. Biol.2005158R302R30510.1016/j.cub.2005.04.002 15854897
    [Google Scholar]
  359. TaveggiaC. ThakerP. PetrylakA. Type III neuregulin‐1 promotes oligodendrocyte myelination.Glia200856328429310.1002/glia.20612 18080294
    [Google Scholar]
  360. KatariaH. AlizadehA. ShahriaryG.M. Neuregulin‐1 promotes remyelination and fosters a pro‐regenerative inflammatory response in focal demyelinating lesions of the spinal cord.Glia201866353856110.1002/glia.23264 29148104
    [Google Scholar]
  361. LyskoD.E. TalbotW.S. Unmyelinated sensory neurons use Neuregulin signals to promote myelination of interneurons in the CNS.Cell Rep.202241711166910.1016/j.celrep.2022.111669 36384112
    [Google Scholar]
  362. KopanR. IlaganM.X.G. The canonical Notch signaling pathway: unfolding the activation mechanism.Cell2009137221623310.1016/j.cell.2009.03.045 19379690
    [Google Scholar]
  363. BrosnanC.F. JohnG.R. Revisiting Notch in remyelination of multiple sclerosis lesions.J. Clin. Invest.2008137221623310.1172/JCI37786 19104146
    [Google Scholar]
  364. LiuA. LiJ. Marin-HusstegeM. A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players.EMBO J.200625204833484210.1038/sj.emboj.7601352 17006542
    [Google Scholar]
  365. Fyffe-MaricichS.L. SchottA. KarlM. KrasnoJ. MillerR.H. Signaling through ERK1/2 controls myelin thickness during myelin repair in the adult central nervous system.J. Neurosci.20133347184021840810.1523/JNEUROSCI.2381‑13.2013 24259565
    [Google Scholar]
  366. HuangH. ZhouF. ZhouS. QiuM. MYRF: a mysterious membrane-bound transcription factor involved in myelin development and human diseases.Neurosci. Bull.202137688188410.1007/s12264‑021‑00678‑9 33864620
    [Google Scholar]
  367. SinghA. UpadhayayS. MehanS. Inhibition of c-JNK/p38MAPK signaling pathway by Apigenin prevents neurobehavioral and neurochemical defects in ethidium bromide-induced experimental model of multiple sclerosis in rats: Evidence from CSF, blood plasma and brain samples.Phytomedicine Plus202114100139
    [Google Scholar]
  368. ApratoJ. SockE. WeiderM. ElsesserO. FröbF. WegnerM. Myrf guides target gene selection of transcription factor Sox10 during oligodendroglial development.Nucleic Acids Res.20204831254127010.1093/nar/gkz1158 31828317
    [Google Scholar]
  369. ZhouQ. AndersonD.J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification.Cell20021091617310.1016/S0092‑8674(02)00677‑3 11955447
    [Google Scholar]
  370. JakovcevskiI. ZecevicN. Olig transcription factors are expressed in oligodendrocyte and neuronal cells in human fetal CNS.J. Neurosci.20052544100641007310.1523/JNEUROSCI.2324‑05.2005 16267213
    [Google Scholar]
  371. WegenerA. DebouxC. BachelinC. Gain of Olig2 function in oligodendrocyte progenitors promotes remyelination.Brain2015138112013510.1093/brain/awu375 25564492
    [Google Scholar]
  372. MaratheH.G. MehtaG. ZhangX. SWI/SNF enzymes promote SOX10- mediated activation of myelin gene expression.PLoS One201387e6903710.1371/journal.pone.0069037 23874858
    [Google Scholar]
  373. WeiderM. StarostL.J. GrollK. Nfat/calcineurin signaling promotes oligodendrocyte differentiation and myelination by transcription factor network tuning.Nat. Commun.20189189910.1038/s41467‑018‑03336‑3 29500351
    [Google Scholar]
  374. CaiJ. ZhuQ. ZhengK. Co‐localization of Nkx6.2 and Nkx2.2 homeodomain proteins in differentiated myelinating oligodendrocytes.Glia201058445846810.1002/glia.20937 19780200
    [Google Scholar]
  375. ZhuQ. ZhaoX. ZhengK. Genetic evidence that Nkx2.2 and Pdgfra are major determinants of the timing of oligodendrocyte differentiation in the developing CNS.Development2014141354855510.1242/dev.095323 24449836
    [Google Scholar]
  376. ChenH.P. ZhaoY.T. ZhaoT.C. Histone deacetylases and mechanisms of regulation of gene expression.Crit. Rev. Oncog.2015201-2354710.1615/CritRevOncog.2015012997 25746103
    [Google Scholar]
  377. LiuX.S. ChoppM. KassisH. Valproic acid increases white matter repair and neurogenesis after stroke.Neuroscience20122201–231332110.1016/j.neuroscience.2012.06.012 22704966
    [Google Scholar]
  378. DumanM. VaquiéA. NoceraG. EEF1A1 deacetylation enables transcriptional activation of remyelination.Nat. Commun.2020111342010.1038/s41467‑020‑17243‑z 32647127
    [Google Scholar]
  379. JablonskaB. GierdalskiM. ChewL.J. Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury.Nat. Commun.2016711386610.1038/ncomms13866 27991597
    [Google Scholar]
  380. MaX.R. ZhuX. XiaoY. Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing.Nat. Commun.2022131122510.1038/s41467‑022‑28844‑1 35264567
    [Google Scholar]
  381. WangH. MoyanoA.L. MaZ. miR-219 cooperates with mir-338 in myelination and promotes myelin repair in the CNS.Dev. Cell2017406566582.e510.1016/j.devcel.2017.03.001 28350989
    [Google Scholar]
  382. LeccaD. MarangonD. CoppolinoG.T. MiR-125a-3p timely inhibits oligodendroglial maturation and is pathologically up-regulated in human multiple sclerosis.Sci. Rep.2016613450310.1038/srep34503 27698367
    [Google Scholar]
  383. SantraM. ZhangZ.G. YangJ. Thymosin β4 up-regulation of microRNA-146a promotes oligodendrocyte differentiation and suppression of the Toll-like proinflammatory pathway.J. Biol. Chem.201428928195081951810.1074/jbc.M113.529966 24828499
    [Google Scholar]
  384. BuddeH. SchmittS. FitznerD. OpitzL. Salinas-RiesterG. SimonsM. Control of oligodendroglial cell number by the miR-17-92 cluster.Development2010137132127213210.1242/dev.050633 20504959
    [Google Scholar]
  385. HeD. WangJ. LuY. lncRNA functional networks in oligodendrocytes reveal stage-specific myelination control by an lncOL1/Suz12 complex in the CNS.Neuron201793236237810.1016/j.neuron.2016.11.044 28041882
    [Google Scholar]
  386. Blecharz-LangK.G. PatsourisV. Nieminen-KelhäM. SeiffertS. SchneiderU.C. VajkoczyP. Minocycline attenuates microglia/macrophage phagocytic activity and inhibits sah-induced neuronal cell death and inflammation.Neurocrit. Care202237241042310.1007/s12028‑022‑01511‑5 35585424
    [Google Scholar]
  387. MetzL.M. LiD. TraboulseeA. Glatiramer acetate in combination with minocycline in patients with relapsing—remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial.Mult. Scler.200915101183119410.1177/1352458509106779 19776092
    [Google Scholar]
  388. Camara-LemarroyC. MetzL. KuhleJ. Minocycline treatment in clinically isolated syndrome and serum NfL, GFAP, and metalloproteinase levels.Mult. Scler.202228132081208910.1177/13524585221109761 35848622
    [Google Scholar]
  389. CostaB. ValeN. Understanding lamotrigine’s role in the CNS and possible future evolution.Int. J. Mol. Sci.2023247605010.3390/ijms24076050 37047022
    [Google Scholar]
  390. BechtoldD.A. MillerS.J. DawsonA.C. Axonal protection achieved in a model of multiple sclerosis using lamotrigine.J. Neurol.2006253121542155110.1007/s00415‑006‑0204‑1 17219031
    [Google Scholar]
  391. KapoorR. FurbyJ. HaytonT. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial.Lancet Neurol.20109768168810.1016/S1474‑4422(10)70131‑9 20621711
    [Google Scholar]
  392. KadotaN. YoshidaA. SawamotoA. OkuyamaS. NakajimaM. Ibudilast reduces IL-6 levels and ameliorates symptoms in lipopolysaccharide-induced sepsis mice.Biol. Pharm. Bull.20224581180118410.1248/bpb.b22‑00284 35908899
    [Google Scholar]
  393. AngelopoulouE. PyrgelisE.S. PiperiC. Emerging potential of the phosphodiesterase (PDE) inhibitor ibudilast for neurodegenerative diseases: an update on preclinical and clinical evidence.Molecules20222723844810.3390/molecules27238448 36500540
    [Google Scholar]
  394. SharifianA. VarshosazJ. AliomraniM. KazemiM. Nose to brain delivery of ibudilast micelles for treatment of multiple sclerosis in an experimental autoimmune encephalomyelitis animal model.Int. J. Pharm.20236382312293610.1016/j.ijpharm.2023.122936 37030640
    [Google Scholar]
  395. FoxR.J. CoffeyC.S. ConwitR. Phase 2 trial of ibudilast in progressive multiple sclerosis.N. Engl. J. Med.2018379984685510.1056/NEJMoa1803583 30157388
    [Google Scholar]
  396. MoransardM. BednarM. FreiK. GassmannM. OgunsholaO.O. Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms.J. Neuroinflammation201714120210.1186/s12974‑017‑0976‑5 29029628
    [Google Scholar]
  397. SchreiberK. MagyariM. SellebjergF. High-dose erythropoietin in patients with progressive multiple sclerosis: A randomized, placebo-controlled, phase 2 trial.Mult. Scler.201723567568510.1177/1352458516661048 27481206
    [Google Scholar]
  398. KrämerJ. Bar-OrA. TurnerT.J. WiendlH. Bruton tyrosine kinase inhibitors for multiple sclerosis.Nat. Rev. Neurol.202319528930410.1038/s41582‑023‑00800‑7 37055617
    [Google Scholar]
  399. TorkeS. PretzschR. HäuslerD. Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease.Acta Neuropathol.2020140453554810.1007/s00401‑020‑02204‑z 32761407
    [Google Scholar]
  400. MontalbanX. ArnoldD.L. WeberM.S. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis.N. Engl. J. Med.2019380252406241710.1056/NEJMoa1901981 31075187
    [Google Scholar]
  401. ZhouL. TianZ. YaoM. Riluzole promotes neurological function recovery and inhibits damage extension in rats following spinal cord injury: a meta‐analysis and systematic review.J. Neurochem.2019150162710.1111/jnc.14686 30786027
    [Google Scholar]
  402. RotoloR.A. DemuroJ. DrummondG. LittleC. JohnsL.D. BetzA.J. Prophylactic exposure to oral riluzole reduces the clinical severity and immune-related biomarkers of experimental autoimmune encephalomyelitis.J. Neuroimmunol.2021356157760310.1016/j.jneuroim.2021.577603 33992861
    [Google Scholar]
  403. RistoriG. RomanoS. ViscontiA. Riluzole in cerebellar ataxia.Neurology2010741083984510.1212/WNL.0b013e3181d31e23 20211908
    [Google Scholar]
  404. KuhleJ. NourbakhshB. GrantD. Serum neurofilament is associated with progression of brain atrophy and disability in early MS.Neurology201788982683110.1212/WNL.0000000000003653 28148632
    [Google Scholar]
  405. SulkowskiG. Dąbrowska-BoutaB. ChalimoniukM. StrużyńskaL. Effects of antagonists of glutamate receptors on pro-inflammatory cytokines in the brain cortex of rats subjected to experimental autoimmune encephalomyelitis.J. Neuroimmunol.20132611-2677610.1016/j.jneuroim.2013.05.006 23746391
    [Google Scholar]
  406. NourbakhshB. RevirajanN. MorrisB. Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial.Lancet Neurol.2021201384810.1016/S1474‑4422(20)30354‑9 33242419
    [Google Scholar]
  407. CohenJ.A. CameronM.H. GoldmanM.D. A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment.Mult. Scler.202228581783010.1177/13524585211035333 34449295
    [Google Scholar]
  408. AmezcuaL. McCauleyJ.L. Race and ethnicity on MS presentation and disease course.Mult. Scler.202026556156710.1177/1352458519887328 31965878
    [Google Scholar]
  409. SeifertH.A. BenedekG. NguyenH. KentG. VandenbarkA.A. OffnerH. Estrogen protects both sexes against EAE by promoting common regulatory cell subtypes independent of endogenous estrogen.Metab. Brain Dis.20173251747175410.1007/s11011‑017‑0063‑8 28689297
    [Google Scholar]
  410. De StefanoN. SormaniM.P. GiovannoniG. Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies.Mult. Scler.202228111112010.1177/13524585211010294 33969750
    [Google Scholar]
  411. GiovannoniG. ComiG. RammohanK. Long-term disease stability assessed by the expanded disability status scale in patients treated with cladribine tablets 3.5 mg/kg for relapsing multiple sclerosis: an exploratory post hoc analysis of the CLARITY and CLARITY extension studies.Adv. Ther.20213894975498510.1007/s12325‑021‑01865‑w 34370275
    [Google Scholar]
  412. MarangonA.V. SilvaG.F. de MoraesC.F.V. Protective effect of HLA-DRB1 11 and predisposition of HLA-C 04 in the development of severe liver damage in Brazilian patients with chronic hepatitis C virus infection.Scand. J. Immunol.201276444044710.1111/j.1365‑3083.2012.02755.x 22803655
    [Google Scholar]
  413. KomakiH. FarajiN. KomakiA. Investigation of protective effects of coenzyme Q10 on impaired synaptic plasticity in a male rat model of Alzheimer’s disease.Brain Res. Bull.201914721142110.1016/j.brainresbull.2019.01.025 30721766
    [Google Scholar]
  414. SanoobarM. EghtesadiS. AzimiA. Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial.Nutr. Neurosci.201518416917610.1179/1476830513Y.0000000106 24621064
    [Google Scholar]
  415. MocciaM. CapacchioneA. LanzilloR. Coenzyme Q10 supplementation reduces peripheral oxidative stress and inflammation in interferon-β1a-treated multiple sclerosis.Ther. Adv. Neurol. Disord.201912410.1177/1756286418819074
    [Google Scholar]
  416. IaciJ.F. ParryT.J. HuangZ. Dalfampridine improves sensorimotor function in rats with chronic deficits after middle cerebral artery occlusion.Stroke20134471942195010.1161/STROKEAHA.111.000147 23652269
    [Google Scholar]
  417. MacdonellR. NagelsG. LaplaudD.A. Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine.Mult. Scler.201622794495410.1177/1352458515606809 26447066
    [Google Scholar]
  418. AllartE. BenoitA. Blanchard-DauphinA. Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.J. Neurol.201526281936194510.1007/s00415‑015‑7797‑1 26041616
    [Google Scholar]
  419. HobartJ. ZiemssenT. FeysP. Assessment of Clinically Meaningful Improvements in Self-Reported Walking Ability in Participants with Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III ENHANCE Trial of Prolonged-Release Fampridine.CNS Drugs2019331617910.1007/s40263‑018‑0586‑5 30535670
    [Google Scholar]
  420. CollonguesN. BeckerG. JolivelV. A Narrative review on axonal neuroprotection in multiple sclerosis.Neurol. Ther.2022113981104210.1007/s40120‑022‑00363‑7 35610531
    [Google Scholar]
  421. KosaP. WuT. PhillipsJ. Idebenone does not inhibit disability progression in primary progressive MS.Mult. Scler. Relat. Disord.202045310243410.1016/j.msard.2020.102434 32784117
    [Google Scholar]
  422. LoveraJ.F. FrohmanE. BrownT.R. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial.Mult. Scler.201016671572310.1177/1352458510367662 20483885
    [Google Scholar]
  423. Metzger-PeterK. KremerL.D. EdanG. The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial.Trials202021159110.1186/s13063‑020‑04517‑6 32600454
    [Google Scholar]
  424. ReichD.S. ArnoldD.L. VermerschP. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial.Lancet Neurol.202120972973810.1016/S1474‑4422(21)00237‑4 34418400
    [Google Scholar]
  425. RaftopoulosR. HickmanS.J. ToosyA. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial.Lancet Neurol.201615325926910.1016/S1474‑4422(16)00004‑1 26822749
    [Google Scholar]
  426. GhajarzadehM. RomanS. VegaL. NourbakhshB. Low-dose ketamine infusion for the treatment of multiple sclerosis fatigue (INKLING-MS): Study protocol for a randomized, double-blind, active placebo-controlled phase II trial.Contemp. Clin. Trials2023126310710610.1016/j.cct.2023.107106 36738917
    [Google Scholar]
  427. LiuJ. DupreeJ.L. GaciasM. Clemastine enhances myelination in the prefrontal cortex and rescues behavioral changes in socially isolated mice.J. Neurosci.201636395796210.1523/JNEUROSCI.3608‑15.2016 26791223
    [Google Scholar]
  428. DuW. DengY. JiangR. TongL. LiR. JiangX. Clemastine enhances myelination, delays axonal loss and promotes functional recovery in spinal cord injury.Neurochem. Res.202247250351510.1007/s11064‑021‑03465‑0 34661796
    [Google Scholar]
  429. CadavidD. BalcerL. GalettaS. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial.Lancet Neurol.201716318919910.1016/S1474‑4422(16)30377‑5 28229892
    [Google Scholar]
  430. CadavidD. MellionM. HuppertsR. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial.Lancet Neurol.201918984585610.1016/S1474‑4422(19)30137‑1 31285147
    [Google Scholar]
  431. HuntemannN. RolfesL. PawlitzkiM. Failed, interrupted, or inconclusive trials on neuroprotective and neuroregenerative treatment strategies in multiple sclerosis: Update 2015–2020.Drugs20218191031106310.1007/s40265‑021‑01526‑w 34086251
    [Google Scholar]
  432. YoussefA.E.H. DiefA.E. El AzharyN.M. AbdelmonsifD.A. El-fetianyO.S. LINGO-1 siRNA nanoparticles promote central remyelination in ethidium bromide-induced demyelination in rats.J. Physiol. Biochem.2019751899910.1007/s13105‑018‑00660‑6 30759305
    [Google Scholar]
  433. MironV.E. LudwinS.K. DarlingtonP.J. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices.Am. J. Pathol.201017662682269410.2353/ajpath.2010.091234 20413685
    [Google Scholar]
  434. GärtnerJ. ChitnisT. GhezziA. Relapse rate and mri activity in young adult patients with multiple sclerosis: a post hoc analysis of phase 3 fingolimod trials.Mult. Scler. J. Exp. Transl. Clin.20184210.1177/2055217318778610 29854416
    [Google Scholar]
  435. GurevichM. WakninR. StoneE. AchironA. Fingolimod‐improved axonal and myelin integrity of white matter tracts associated with multiple sclerosis‐related functional impairments.CNS Neurosci. Ther.201824541241910.1111/cns.12796 29316271
    [Google Scholar]
  436. LaskaM.J. BrudekT. NissenK.K. Expression of HERV-Fc1, a human endogenous retrovirus, is increased in patients with active multiple sclerosis.J. Virol.20128673713372210.1128/JVI.06723‑11 22278236
    [Google Scholar]
  437. Wang-JohanningF. RycajK. PlummerJ.B. Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors.J. Natl. Cancer Inst.2012104318921010.1093/jnci/djr540 22247020
    [Google Scholar]
  438. HartungH.P. DerfussT. CreeB.A.C. Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study.Mult. Scler.202228342944010.1177/13524585211024997 34240656
    [Google Scholar]
  439. MounierA. GeorgievD. NamK.N. Bexarotene-activated retinoid x receptors regulate neuronal differentiation and dendritic complexity.J. Neurosci.20153534118621187610.1523/JNEUROSCI.1001‑15.2015 26311769
    [Google Scholar]
  440. BrownJ.W.L. PradosF. AltmannD.R. Remyelination varies between and within lesions in multiple sclerosis following bexarotene.Ann. Clin. Transl. Neurol.20229101626164210.1002/acn3.51662 36116011
    [Google Scholar]
  441. BrownJ.W.L. CunniffeN.G. PradosF. Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study.Lancet Neurol.202120970972010.1016/S1474‑4422(21)00179‑4 34418398
    [Google Scholar]
  442. GreggC. ShikarV. LarsenP. White matter plasticity and enhanced remyelination in the maternal CNS.J. Neurosci.20072781812182310.1523/JNEUROSCI.4441‑06.2007 17314279
    [Google Scholar]
  443. De GiglioL. MarinelliF. ProsperiniL. Relationship between prolactin plasma levels and white matter volume in women with multiple sclerosis.Mediators Inflamm.20152015173253910.1155/2015/732539 26236110
    [Google Scholar]
  444. ZhornitskyS. JohnsonT.A. MetzL.M. WeissS. YongV.W. Prolactin in combination with interferon-β reduces disease severity in an animal model of multiple sclerosis.J. Neuroinflammation20151215510.1186/s12974‑015‑0278‑8 25889599
    [Google Scholar]
  445. KochM.W. SageK. KaurS. Repurposing domperidone in secondary progressive multiple sclerosis.Neurology20219618e2313e232210.1212/WNL.0000000000011863 34038379
    [Google Scholar]
  446. ZorinaY. StrickerJ. CaggianoA.O. ButtonD.C. Human IgM antibody rHIgM22 promotes phagocytic clearance of myelin debris by microglia.Sci. Rep.201881939210.1038/s41598‑018‑27559‑y 29925848
    [Google Scholar]
  447. EisenA. GreenbergB.M. BowenJ.D. ArnoldD.L. CaggianoA.O. A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis.Mult. Scler. J. Exp. Transl. Clin.20173410.1177/2055217317743097 29348926
    [Google Scholar]
  448. HataK. FujitaniM. YasudaY. RGMa inhibition promotes axonal growth and recovery after spinal cord injury.J. Cell Biol.20061731475810.1083/jcb.200508143 16585268
    [Google Scholar]
  449. JacobsonP.B. GoodyR. LawrenceM. Elezanumab, a human anti-RGMa monoclonal antibody, promotes neuroprotection, neuroplasticity, and neurorecovery following a thoracic hemicompression spinal cord injury in non-human primates.Neurobiol. Dis.2021155110538510.1016/j.nbd.2021.105385 33991647
    [Google Scholar]
  450. KalluriH.V. RosebraughM.R. MiskoT.P. ZiemannA. LiuW. CreeB.A.C. Phase 1 Evaluation of Elezanumab (anti–repulsive guidance molecule a monoclonal antibody) in healthy and multiple sclerosis participants.Ann. Neurol.202393228529610.1002/ana.26503 36093738
    [Google Scholar]
  451. CreeB.A.C. CutterG. WolinskyJ.S. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Neurol.2020191298899710.1016/S1474‑4422(20)30347‑1 33222767
    [Google Scholar]
  452. DziedzicA. Saluk-BijakJ. MillerE. BijakM. Metformin as a potential agent in the treatment of multiple sclerosis.Int. J. Mol. Sci.20202117595710.3390/ijms21175957 32825027
    [Google Scholar]
  453. LaGankeC. SamkoffL. EdwardsK. Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial.Neurol. Neuroimmunol. Neuroinflamm.201744e36710.1212/NXI.0000000000000367 28642891
    [Google Scholar]
  454. ZhornitskyS. YongV.W. KochM.W. Quetiapine fumarate for the treatment of multiple sclerosis: focus on myelin repair.CNS Neurosci. Ther.2013191073774410.1111/cns.12154 23870612
    [Google Scholar]
  455. NylanderA. AndersonA. RowlesW. Re-WRAP (Remyelination for women at risk of axonal loss and progression): A phase II randomized placebo-controlled delayed-start trial of bazedoxifene for myelin repair in multiple sclerosis.Contemp. Clin. Trials2023134110733310.1016/j.cct.2023.107333 37739167
    [Google Scholar]
  456. GharagozlooM. BannonR. CalabresiP.A. Breaking the barriers to remyelination in multiple sclerosis.Curr. Opin. Pharmacol.202263110219410.1016/j.coph.2022.102194 35255453
    [Google Scholar]
  457. SchwartzbachC.J. GroveR.A. BrownR. TompsonD. BerghF.T. ArnoldD.L. Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: A randomised, single-blind, phase II study.J. Neurol.2017264230431510.1007/s00415‑016‑8341‑7 27888416
    [Google Scholar]
  458. SedelF BernardD MockDM TourbahA Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.Neuropharmacology2016110Pt B6445310.1016/j.neuropharm.2015.08.02826327679
    [Google Scholar]
  459. TourbahA. Lebrun-FrenayC. EdanG. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.Mult. Scler.201622131719173110.1177/1352458516667568 27589059
    [Google Scholar]
  460. XuJ. HilpertJ. WuK. An adaptive design to investigate the effect of ketoconazole on pharmacokinetics of GSK239512 in healthy male volunteers.J. Clin. Pharmacol.201555550551110.1002/jcph.441 25470032
    [Google Scholar]
  461. ChamberlainK.A. ChapeyK.S. NanescuS.E. HuangJ.K. Creatine enhances mitochondrial-mediated oligodendrocyte survival after demyelinating injury.J. Neurosci.20173761479149210.1523/JNEUROSCI.1941‑16.2016 28069926
    [Google Scholar]
  462. MalinS.K. CotugnaN. FangC.S. Effect of creatine supplementation on muscle capacity in individuals with multiple sclerosis.J. Diet. Suppl.200851203210.1080/19390210802328974 22433042
    [Google Scholar]
  463. ChatawayJ. SchuererN. AlsanousiA. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.Lancet201438399362213222110.1016/S0140‑6736(13)62242‑4 24655729
    [Google Scholar]
  464. SundaramA.N.E. GelkopfM.J. Abducens nerve palsy as a presenting symptom of multiple sclerosis.Turk. J. Ophthalmol.202252429129410.4274/tjo.galenos.2022.13245 36017545
    [Google Scholar]
  465. WuY.Q. XiongJ. HeZ.J. Metformin promotes microglial cells to facilitate myelin debris clearance and accelerate nerve repairment after spinal cord injury.Acta Pharmacol. Sin.202243613601371
    [Google Scholar]
  466. KosarajuJ. SeegobinM. GouveiaA. Metformin promotes CNS remyelination and improves social interaction following focal demyelination through CBP Ser436 phosphorylation.Exp. Neurol.2020334611345410.1016/j.expneurol.2020.113454 32877653
    [Google Scholar]
  467. RobinsonA.P. ZhangJ.Z. TitusH.E. Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis.Sci. Rep.2020101193610.1038/s41598‑020‑58709‑w 32041968
    [Google Scholar]
  468. BielekovaB. MartinR. Development of biomarkers in multiple sclerosis.Brain200412771463147810.1093/brain/awh176 15180926
    [Google Scholar]
  469. TorkildsenØ. WergelandS. BakkeS. ω-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial.Arch. Neurol.20126981044105110.1001/archneurol.2012.283 22507886
    [Google Scholar]
  470. KapposL. FoxR.J. BurcklenM. Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM study.JAMA Neurol.202178555856710.1001/jamaneurol.2021.0405 33779698
    [Google Scholar]
  471. YangJ. HamadeM. WuQ. Current and Future Biomarkers in Multiple Sclerosis.Int. J. Mol. Sci.20222311587710.3390/ijms23115877 35682558
    [Google Scholar]
  472. La FlammeA.C. AbernethyD. SimD. Safety and acceptability of clozapine and risperidone in progressive multiple sclerosis: A phase I, randomised, blinded, placebo-controlled trial.BMJ Neurology Open202021e00006010.1136/bmjno‑2020‑000060 33681788
    [Google Scholar]
  473. HainesJ.D. IngleseM. CasacciaP. Axonal damage in multiple sclerosis.Mt. Sinai J. Med.201178223124310.1002/msj.20246
    [Google Scholar]
  474. AlvarezG. Núñez-CortésR. SolàI. Sample size, study length, and inadequate controls were the most common self-acknowledged limitations in manual therapy trials: A methodological review.J. Clin. Epidemiol.202113029610610.1016/j.jclinepi.2020.10.018 33144246
    [Google Scholar]
  475. WellekS. BlettnerM. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications.Dtsch. Arztebl. Int.201210915276281 22567063
    [Google Scholar]
  476. DuanR. QuM. YuanY. Clinical benefit of rehabilitation training in spinal cord injury.Spine2021466E398E41010.1097/BRS.0000000000003789 33620185
    [Google Scholar]
  477. LearmonthY.C. MotlR.W. Exercise training for multiple sclerosis: a narrative review of history, benefits, safety, guidelines, and promotion.Int. J. Environ. Res. Public Health202118241324510.3390/ijerph182413245 34948854
    [Google Scholar]
  478. ChoiI.Y. PiccioL. ChildressP. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms.Cell Rep.201615102136214610.1016/j.celrep.2016.05.009 27239035
    [Google Scholar]
  479. WąsikN. SokółB. HołyszM. Serum myelin basic protein as a marker of brain injury in aneurysmal subarachnoid haemorrhage.Acta Neurochir. (Wien)2020162354555210.1007/s00701‑019‑04185‑9 31915942
    [Google Scholar]
  480. HeidariM. RadcliffA.B. McLellanG.J. Evoked potentials as a biomarker of remyelination.Proc. Natl. Acad. Sci. USA201911652270742708310.1073/pnas.1906358116 31843913
    [Google Scholar]
  481. CordanoC. SinJ.H. TimmonsG. Validating visual evoked potentials as a preclinical, quantitative biomarker for remyelination efficacy.Brain2022145113943395210.1093/brain/awac207 35678509
    [Google Scholar]
  482. MallikS. SamsonR.S. Wheeler-KingshottC.A.M. MillerD.H. Imaging outcomes for trials of remyelination in multiple sclerosis.J. Neurol. Neurosurg. Psychiatry201485121396140410.1136/jnnp‑2014‑307650 24769473
    [Google Scholar]
  483. WeiW. PoirionE. BodiniB. Predicting PET-derived myelin content from multisequence MRI for individual longitudinal analysis in multiple sclerosis.Neuroimage20202231211730810.1016/j.neuroimage.2020.117308 32889117
    [Google Scholar]
  484. Ben-ShalomI. KarniA. KolbH. The role of molecular imaging as a marker of remyelination and repair in multiple sclerosis.Int. J. Mol. Sci.202123147410.3390/ijms23010474 35008899
    [Google Scholar]
  485. DeshmukhV.A. TardifV. LyssiotisC.A. A regenerative approach to the treatment of multiple sclerosis.Nature2013502747132733210.1038/nature12647 24107995
    [Google Scholar]
  486. ScheifeR. TakedaM. Central nervous system safety of anticholinergic drugs for the treatment of overactive bladder in the elderly.Clin. Ther.200527214415310.1016/j.clinthera.2005.02.014 15811477
    [Google Scholar]
  487. AncelinM.L. ArteroS. PortetF. DupuyA.M. TouchonJ. RitchieK. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study.BMJ2006332753945545910.1136/bmj.38740.439664.DE 16452102
    [Google Scholar]
  488. BarchetT.M. AmijiM.M. Challenges and opportunities in CNS delivery of therapeutics for neurodegenerative diseases.Expert Opin. Drug Deliv.20096321122510.1517/17425240902758188 19290842
    [Google Scholar]
  489. LeeD. MinkoT. Nanotherapeutics for nose-to-brain drug delivery: an approach to bypass the blood brain barrier.Pharmaceutics20211312204910.3390/pharmaceutics13122049 34959331
    [Google Scholar]
  490. VolarevicV. MarkovicB.S. GazdicM. Ethical and safety issues of stem cell-based therapy.Int. J. Med. Sci.2018151364510.7150/ijms.21666 29333086
    [Google Scholar]
  491. RothschildJ. Ethical considerations of gene editing and genetic selection.J. Gen. Fam. Med.2020213374710.1002/jgf2.321 32489755
    [Google Scholar]
  492. LugtenbergM. BurgersJ.S. ClancyC. WestertG.P. SchneiderE.C. Current guidelines have limited applicability to patients with comorbid conditions: a systematic analysis of evidence-based guidelines.PLoS One2011610e2598710.1371/journal.pone.0025987
    [Google Scholar]
  493. KadamR. Informed consent process: A step further towards making it meaningful!Perspect. Clin. Res.20178310711210.4103/picr.PICR_147_16 28828304
    [Google Scholar]
  494. Pajoohesh-GanjiA. MillerR.H. Targeted oligodendrocyte apoptosis in optic nerve leads to persistent demyelination.Neurochem. Res.202045358059010.1007/s11064‑019‑02754‑z 30848441
    [Google Scholar]
  495. KleinsorgeM.T. EbertA. FörsterA. MRI topography of lesions related to internuclear ophthalmoplegia in patients with multiple sclerosis or ischemic stroke.J. Neuroimaging202131347147410.1111/jon.12847 33793026
    [Google Scholar]
  496. GhaffarO. ChamelianL. FeinsteinA. Neuroanatomy of pseudobulbar affect.J. Neurol.2008255340641210.1007/s00415‑008‑0685‑1 18297331
    [Google Scholar]
  497. VidovićV. RovazdiM.Č. KramlO. KesV.B. Pseudobulbar affect in multiple sclerosis patients.Acta Clin. Croat.2015542159163 26415311
    [Google Scholar]
  498. MarchesiO. BonacchiR. ValsasinaP. RoccaM.A. FilippiM. Resting state effective connectivity abnormalities of the Papez circuit and cognitive performance in multiple sclerosis.Mol. Psychiatry20222793913391910.1038/s41380‑022‑01625‑4 35624146
    [Google Scholar]
  499. NguyenT.H. VaussyA. Le GauduV. The brainstem in multiple sclerosis: MR identification of tracts and nuclei damage.Insights Imaging202112115110.1186/s13244‑021‑01101‑7 34674050
    [Google Scholar]
  500. BaoJ. TuH. LiY. Diffusion tensor imaging revealed microstructural changes in normal-appearing white matter regions in relapsing–remitting multiple sclerosis.Front. Neurosci.202216Mar83745210.3389/fnins.2022.837452 35310094
    [Google Scholar]
  501. GeorgeT. CiciletS. HoisalaR. RoutP. Multifocal tumefactive demyelination mimicking intracranial neoplasm.J. Clin. Diagn. Res.2016103TD10TD11 27134967
    [Google Scholar]
  502. KutzelniggA. Faber-RodJ.C. BauerJ. Widespread demyelination in the cerebellar cortex in multiple sclerosis.Brain Pathol.2007171384410.1111/j.1750‑3639.2006.00041.x 17493036
    [Google Scholar]
  503. D’AmbrosioA. PaganiE. RiccitelliG.C. Cerebellar contribution to motor and cognitive performance in multiple sclerosis: An MRI sub-regional volumetric analysis.Mult. Scler.20172391194120310.1177/1352458516674567 27760859
    [Google Scholar]
  504. MitomaH. BuffoA. GelfoF. Consensus paper. cerebellar reserve: from cerebellar physiology to cerebellar disorders.Cerebellum202019113115310.1007/s12311‑019‑01091‑9 31879843
    [Google Scholar]
  505. FröhlichK. WinderK. LinkerR.A. Lesion correlates of secondary paroxysmal dyskinesia in multiple sclerosis.J. Neurol.2018265102277228310.1007/s00415‑018‑8989‑2 30066284
    [Google Scholar]
  506. BlancoY. ComptaY. GrausF. SaizA. Midbrain lesions and paroxysmal dysarthria in multiple sclerosis.Mult. Scler.200814569469710.1177/1352458507087846 18566032
    [Google Scholar]
  507. MarinoM.M. RegaC. RussoR. Interactome mapping defines BRG1, a component of the SWI/SNF chromatin remodeling complex, as a new partner of the transcriptional regulator CTCF.J. Biol. Chem.2019294386187310.1074/jbc.RA118.004882 30459231
    [Google Scholar]
  508. WangJ. YangL. DuY. BRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination.J. Cell Biol.20242237e20231014310.1083/jcb.202310143 38652118
    [Google Scholar]
  509. FröhlichK. KnottM. HockS. DörflerA. SeifertF. WinderK. Voxel-wise lesion mapping of restless legs syndrome in multiple sclerosis.Neurol. Sci.20224384953495910.1007/s10072‑022‑06103‑x 35513748
    [Google Scholar]
  510. WinderK. LinkerR.A. SeifertF. Insular multiple sclerosis lesions are associated with erectile dysfunction.J. Neurol.2018265478379210.1007/s00415‑018‑8763‑5 29392463
    [Google Scholar]
  511. FröhlichK. LinkerR.A. EngelhornT. Brain MRI lesions are related to bowel incontinence in multiple sclerosis.J. Neuroimaging201929221121710.1111/jon.12589 30537408
    [Google Scholar]
  512. ZackowskiK.M. SmithS.A. ReichD.S. Sensorimotor dysfunction in multiple sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord.Brain200913251200120910.1093/brain/awp032 19297508
    [Google Scholar]
  513. SeixasD. FoleyP. PalaceJ. LimaD. RamosI. TraceyI. Pain in multiple sclerosis: A systematic review of neuroimaging studies.Neuroimage Clin.20145532233110.1016/j.nicl.2014.06.014 25161898
    [Google Scholar]
  514. Padilla-MartínezF. CollinF. KwasniewskiM. KretowskiA. Systematic review of polygenic risk scores for Type 1 and Type 2 diabetes.Int. J. Mol. Sci.2020215170310.3390/ijms21051703 32131491
    [Google Scholar]
  515. SamaranchL. SalegioE.A. San SebastianW. KellsA.P. FoustK.D. BringasJ.R. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates.Hum. Gene Ther.2011 22201473
    [Google Scholar]
  516. CotsapasC. MitrovicM. Genome‐wide association studies of multiple sclerosis.Clin. Transl. Immunology201876e101810.1002/cti2.1018 29881546
    [Google Scholar]
  517. KimH. LeeE.J. LimY.M. KimK.K. Glial fibrillary acidic protein in blood as a disease biomarker of neuromyelitis optica spectrum disorders.Front. Neurol.202213Mar86573010.3389/fneur.2022.865730 35370870
    [Google Scholar]
  518. VujosevicS. ParraM.M. HartnettM.E. Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children.Eye (Lond.)202337220321910.1038/s41433‑022‑02056‑9 35428871
    [Google Scholar]
  519. GafsonA. CranerM.J. MatthewsP.M. Personalised medicine for multiple sclerosis care.Mult. Scler.201723336236910.1177/1352458516672017 27672137
    [Google Scholar]
  520. GiovannoniG. Personalized medicine in multiple sclerosis.Neurodegener Dis Manag20177sup613710.2217/nmt‑2017‑003529143582
    [Google Scholar]
  521. HočevarK. RistićS. PeterlinB. Pharmacogenomics of multiple sclerosis: a systematic review.Front. Neurol.2019106s13410.3389/fneur.2019.00134 30863357
    [Google Scholar]
  522. SmithJ.A. NicaiseA.M. IonescuR.B. HamelR. Peruzzotti-JamettiL. PluchinoS. Stem cell therapies for progressive multiple sclerosis.Front. Cell Dev. Biol.202196s69643410.3389/fcell.2021.696434 34307372
    [Google Scholar]
  523. RushC.A. AtkinsH.L. FreedmanM.S. Autologous hematopoietic stem cell transplantation in the treatment of multiple sclerosis.Cold Spring Harb. Perspect. Med.201993a02908210.1101/cshperspect.a029082 29610145
    [Google Scholar]
  524. SharrackB. SaccardiR. AlexanderT. Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE).Bone Marrow Transplant.202055228330610.1038/s41409‑019‑0684‑0 31558790
    [Google Scholar]
  525. ZhukovskyC. SandgrenS. SilfverbergT. Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing–remitting multiple sclerosis: an observational study.J. Neurol. Neurosurg. Psychiatry202192218919410.1136/jnnp‑2020‑323992 33106366
    [Google Scholar]
  526. SongN. ScholtemeijerM. ShahK. Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential.Trends Pharmacol. Sci.202041965366410.1016/j.tips.2020.06.009 32709406
    [Google Scholar]
  527. PetrouP. KassisI. GinzbergA. Long-term clinical and immunological effects of repeated mesenchymal stem cell injections in patients with progressive forms of multiple sclerosis.Front. Neurol.202112963931510.3389/fneur.2021.639315 34135843
    [Google Scholar]
  528. MojaverrostamiS. BojnordiM.N. Ghasemi-KasmanM. EbrahimzadehM.A. HamidabadiH.G. A review of herbal therapy in multiple sclerosis.Adv. Pharm. Bull.20188457559010.15171/apb.2018.066 30607330
    [Google Scholar]
  529. ThompsonA.J. BanwellB.L. BarkhofF. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.Lancet Neurol.201817216217310.1016/S1474‑4422(17)30470‑2 29275977
    [Google Scholar]
  530. LamV. TakechiR. HackettM.J. FrancisR. ByneveltM. CelliersL.M. Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.PLoS Biol.2021199e300135810.1371/journal.pbio.3001358
    [Google Scholar]
  531. YounossiZ. AnsteeQ.M. MariettiM. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat. Rev. Gastroenterol. Hepatol.2018151112010.1038/nrgastro.2017.109 28930295
    [Google Scholar]
  532. LimmrothV. BarkhofF. DesemN. DiamondM.P. TachasG. CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS.Neurology201483201780178810.1212/WNL.0000000000000926 25239835
    [Google Scholar]
  533. ChiribogaC.A. SwobodaK.J. DarrasB.T. Results from a phase 1 study of nusinersen (ISIS-SMN Rx) in children with spinal muscular atrophy.Neurology2016861089089710.1212/WNL.0000000000002445 26865511
    [Google Scholar]
  534. EdwardsA.L. CollinsJ.A. JungeC. Exploratory tau biomarker results from a multiple ascending-dose study of biib080 in Alzheimer disease.JAMA Neurol.202380121344135210.1001/jamaneurol.2023.3861 37902726
    [Google Scholar]
  535. FanH. ZhaoJ.G. YanJ.Q. Effect of Notch1 gene on remyelination in multiple sclerosis in mouse models of acute demyelination.J. Cell. Biochem.2018119119284929410.1002/jcb.27197 30010211
    [Google Scholar]
  536. DoiY. OkiS. OzawaT. HohjohH. MiyakeS. YamamuraT. Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines.Proc. Natl. Acad. Sci. USA2008105248381838610.1073/pnas.0803454105 18550828
    [Google Scholar]
  537. RoyH.A. AzizT.Z. Deep brain stimulation and multiple sclerosis: Therapeutic applications.Mult. Scler. Relat. Disord.20143443143910.1016/j.msard.2014.02.003 25877053
    [Google Scholar]
  538. BrandmeirN.J. MurrayA. CheyuoC. FerariC. RezaiA.R. Deep brain stimulation for multiple sclerosis tremor: a meta-analysis.Neuromodulation202023446346810.1111/ner.13063 31755637
    [Google Scholar]
  539. AgüeraE. Caballero-VillarrasoJ. FeijóoM. Clinical and neurochemical effects of transcranial magnetic stimulation (tms) in multiple sclerosis: a study protocol for a randomized clinical trial.Front. Neurol.202011475010.3389/fneur.2020.00750 32849212
    [Google Scholar]
  540. ChagotC. Bustuchina VlaicuM. FrismandS. Colnat-CoulboisS. NguyenJ.P. PalfiS. Deep brain stimulation in multiple sclerosis-associated tremor. A large, retrospective, longitudinal open label study, with long-term follow-up.Mult. Scler. Relat. Disord.202379410492810.1016/j.msard.2023.104928 37657308
    [Google Scholar]
  541. SiddiqiS.H. KhosravaniS. RolstonJ.D. FoxM.D. The future of brain circuit-targeted therapeutics.Neuropsychopharmacology202449117918810.1038/s41386‑023‑01670‑9 37524752
    [Google Scholar]
  542. TangW. ZhuH. FengY. GuoR. WanD. The impact of gut microbiota disorders on the blood-brain barrier.Infect. Drug Resist.2020133351336310.2147/IDR.S254403 33061482
    [Google Scholar]
  543. KumarN. SahooN.K. MehanS. vermaB. The importance of gut-brain axis and use of probiotics as a treatment strategy for multiple sclerosis.Mult. Scler. Relat. Disord.202371410454710.1016/j.msard.2023.104547 36805171
    [Google Scholar]
  544. MafteiN.M. RaileanuC.R. BaltaA.A. The potential impact of probiotics on human health: an update on their health-promoting properties.Microorganisms202412223410.3390/microorganisms12020234 38399637
    [Google Scholar]
  545. JiangJ. ChuC. WuC. Efficacy of probiotics in multiple sclerosis: a systematic review of preclinical trials and meta-analysis of randomized controlled trials.Food Funct.20211262354237710.1039/D0FO03203D 33629669
    [Google Scholar]
  546. SavšekL. StergarT. StrojnikV. Impact of aerobic exercise on clinical and magnetic resonance imaging biomarkers in persons with multiple sclerosis: An exploratory randomized controlled trial.J. Rehabil. Med.2021534jrm0017810.2340/16501977‑2814 33739437
    [Google Scholar]
  547. Langeskov-ChristensenM. HvidL.G. JensenH.B. Efficacy of high‐intensity aerobic exercise on common multiple sclerosis symptoms.Acta Neurol. Scand.2022145222923810.1111/ane.13540 34687036
    [Google Scholar]
/content/journals/cnr/10.2174/0115672026336440240822063430
Loading
/content/journals/cnr/10.2174/0115672026336440240822063430
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test