Skip to content
2000
Volume 23, Issue 4
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Background

Naringin and MCC950 as an inflammasome inhibitor have exhibited numerous pharmacological activities, including antioxidant and anti-inflammatory effects. The present study has examined the combined impacts of naringin and MCC950 on the levels of oxidative stress, demyelination, and inflammation in the cuprizone (CPZ)-induced demyelination model.

Methods

In order to induce demyelination, CPZ (0.2% w/w) was added to the normal diet of mice for 42 days. Subsequently, the male C57BL/6 mice received naringin (oral administration), MCC950 (intraperitoneal injection), or their combination for 14 days. Working memory was tested by the Y maze. FluoroMyelin staining, MOG, and GFAP immunostaining assessed the demyelination extent, myelin intensity, and astrocyte activation, respectively. Oxidant/antioxidant biomarkers were measured using colorimetric techniques. The expression levels of , , , , , , , , and were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

Results

Our results indicated that the co-administration of naringin and MCC950 improved working memory and antioxidant capacity. A significant reduction was found in the extent of demyelination and inflammatory mediatorsin naringin and MCC950-treated mice. In addition, co-administration of naringin and MCC950 elevated the expression levels of pro-myelinating and antioxidant markers.

Conclusion

These findings indicated improvement of the working memory through co-administration of naringin and MCC950, which might be partly mediated by enhancing antioxidant capacity, promoting remyelination, and mitigating inflammation in the CPZ-induced demyelination model.

Loading

Article metrics loading...

/content/journals/cn/10.2174/1570159X23666241206102022
2024-12-06
2025-03-31
Loading full text...

Full text loading...

References

  1. Abd El AzizA.E. SayedR.H. SallamN.A. El SayedN.S. Neuroprotective effects of telmisartan and nifedipine against cuprizone-induced demyelination and behavioral dysfunction in mice: Roles of NF-κB and Nrf2.Inflammation20214441629164210.1007/s10753‑021‑01447‑6 33709265
    [Google Scholar]
  2. AloisiF. Immune function of microglia.Glia200136216517910.1002/glia.1106 11596125
    [Google Scholar]
  3. ShaoY. ChenC. ZhuT. SunZ. LiS. GongL. DongX. ShenW. ZengL. XieY. JiangP. TRPM2 contributes to neuroinflammation and cognitive deficits in a cuprizone-induced multiple sclerosis model via NLRP3 inflammasome.Neurobiol. Dis.202116010553410.1016/j.nbd.2021.105534 34673151
    [Google Scholar]
  4. KannegantiT.D. Body-MalapelM. AmerA. ParkJ.H. WhitfieldJ. FranchiL. TaraporewalaZ.F. MillerD. PattonJ.T. InoharaN. NúñezG. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.J. Biol. Chem.200628148365603656810.1074/jbc.M607594200 17008311
    [Google Scholar]
  5. CollR.C. RobertsonA.A.B. ChaeJ.J. HigginsS.C. Muñoz-PlanilloR. InserraM.C. VetterI. DunganL.S. MonksB.G. StutzA. CrokerD.E. ButlerM.S. HaneklausM. SuttonC.E. NúñezG. LatzE. KastnerD.L. MillsK.H.G. MastersS.L. SchroderK. CooperM.A. O’NeillL.A.J. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.Nat. Med.201521324825510.1038/nm.3806 25686105
    [Google Scholar]
  6. SchuhE. GroßC.J. WagnerD. SchlüterM. GroßO. KümpfelT. MCC950 blocks enhanced interleukin-1β production in patients with NLRP3 low penetrance variants.Clin. Immunol.2019203455210.1016/j.clim.2019.04.004 30974290
    [Google Scholar]
  7. JurcauA. Insights into the pathogenesis of neurodegenerative diseases: Focus on mitochondrial dysfunction and oxidative stress.Int. J. Mol. Sci.202122211184710.3390/ijms222111847 34769277
    [Google Scholar]
  8. PetriS. KörnerS. KiaeiM. Nrf2/ARE signaling pathway: key mediator in oxidative stress and potential therapeutic target in ALS.Neurol. Res. Int.201220121878030
    [Google Scholar]
  9. DeponteM. Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes.Biochim. Biophys. Acta, Gen. Subj.2013183053217326610.1016/j.bbagen.2012.09.018 23036594
    [Google Scholar]
  10. MaurerU. PreissF. Brauns-SchubertP. SchlicherL. CharvetC. GSK-3 - at the crossroads of cell death and survival.J. Cell Sci.201412771369137810.1242/jcs.138057 24687186
    [Google Scholar]
  11. CuadradoA. Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP.Free Radic. Biol. Med.201588Pt B14715710.1016/j.freeradbiomed.2015.04.02925937177
    [Google Scholar]
  12. KumarA. DograS. PrakashA. Protective effect of naringin, a citrus flavonoid, against colchicine-induced cognitive dysfunction and oxidative damage in rats.J. Med. Food201013497698410.1089/jmf.2009.1251 20673063
    [Google Scholar]
  13. XiaoS. ZhangC. RongW. PanY. CaiX. SongF. ZhaoZ. The mechanism of Naringin-enhanced remyelination after spinal cord injury.Neural Regen. Res.201712347047710.4103/1673‑5374.202923 28469664
    [Google Scholar]
  14. ChtourouY. AoueyB. KebiecheM. FetouiH. Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-κB and P53 signaling pathways.Chem. Biol. Interact.2015239768610.1016/j.cbi.2015.06.036 26120027
    [Google Scholar]
  15. PanieriE. BuhaA. Telkoparan-AkillilarP. CevikD. KouretasD. VeskoukisA. SkaperdaZ. TsatsakisA. WallaceD. SuzenS. SasoL. Potential applications of NRF2 modulators in cancer therapy.Antioxidants20209319310.3390/antiox9030193 32106613
    [Google Scholar]
  16. JeonS.M. BokS.H. JangM.K. LeeM.K. NamK.T. ParkY.B. RheeS.J. ChoiM.S. Antioxidative activity of naringin and lovastatin in high cholesterol-fed rabbits.Life Sci.200169242855286610.1016/S0024‑3205(01)01363‑7 11720089
    [Google Scholar]
  17. AcsP. SelakM.A. KomolyS. KalmanB. Distribution of oligodendrocyte loss and mitochondrial toxicity in the cuprizone-induced experimental demyelination model.J. Neuroimmunol.20132621-212813110.1016/j.jneuroim.2013.06.012 23890807
    [Google Scholar]
  18. AcsP. KomolyS. Selective ultrastructural vulnerability in the cuprizone-induced experimental demyelination.Ideggyogy. Sz.2012657-8266270 23074847
    [Google Scholar]
  19. AryanpourR. PasbakhshP. ZibaraK. NamjooZ. Beigi BoroujeniF. ShahbeigiS. KashaniI.R. BeyerC. ZendehdelA. Progesterone therapy induces an M1 to M2 switch in microglia phenotype and suppresses NLRP3 inflammasome in a cuprizone-induced demyelination mouse model.Int. Immunopharmacol.20175113113910.1016/j.intimp.2017.08.007 28830026
    [Google Scholar]
  20. KhodayarM.J. KalantariH. MahdaviniaM. KhorsandiL. AlboghobeishS. SamimiA. AlizadehS. ZeidooniL. Protective effect of naringin against BPA-induced cardiotoxicity through prevention of oxidative stress in male Wistar rats.Drug Chem. Toxicol.2020431859510.1080/01480545.2018.1504958 30264589
    [Google Scholar]
  21. XuX. YinD. RenH. GaoW. LiF. SunD. WuY. ZhouS. LyuL. YangM. XiongJ. HanL. JiangR. ZhangJ. Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury.Neurobiol. Dis.2018117152710.1016/j.nbd.2018.05.016 29859317
    [Google Scholar]
  22. SanadgolN. BaratiM. HoushmandF. HassaniS. ClarnerT. shahlaeiM. GolabF. Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period.Pharmacol. Rep.202072364165810.1007/s43440‑019‑00019‑8 32048246
    [Google Scholar]
  23. HeJ. LuoH. YanB. YuY. WangH. WeiZ. ZhangY. XuH. TempierA. LiX. LiX.M. Beneficial effects of quetiapine in a transgenic mouse model of Alzheimer’s disease.Neurobiol. Aging20093081205121610.1016/j.neurobiolaging.2007.11.001 18079026
    [Google Scholar]
  24. OmotosoG.O. GbadamosiI.T. AfolabiT.T. AbdulwahabA.B. AkinloluA.A. Ameliorative effects of Moringa on cuprizone-induced memory decline in rat model of multiple sclerosis.Anat. Cell Biol.201851211912710.5115/acb.2018.51.2.119 29984057
    [Google Scholar]
  25. BaradaranS. HajizadehM.A. Ghasemi-KasmanM. Hesperetin reduces myelin damage and ameliorates glial activation in lysolecithin-induced focal demyelination model of rat optic chiasm.Life Sci.201820747147910.1016/j.lfs.2018.07.001 30056861
    [Google Scholar]
  26. AnsariN. MüllerS. StelzerE.H. PampaloniF. Quantitative 3D cell-based assay performed with cellular spheroids and fluorescence microscopy.Methods in cell biology. 113Elsevier2013295309
    [Google Scholar]
  27. GerçekE. ZenginH. Erdem ErişirF. YılmazÖ. Biochemical changes and antioxidant capacity of naringin and naringenin against malathion toxicity in Saccharomyces cerevisiae.Comp. Biochem. Physiol. C Toxicol. Pharmacol.202124110896910.1016/j.cbpc.2020.108969 33412300
    [Google Scholar]
  28. JiaoJ. ZhaoG. WangY. RenP. WuM. MCC950, a selective inhibitor of NLRP3 inflammasome, reduces the inflammatory response and improves neurological outcomes in mice model of spinal cord injury.Front. Mol. Biosci.202073710.3389/fmolb.2020.00037 32195267
    [Google Scholar]
  29. ZhangJ. YangL. FangZ. KongJ. HuangQ. XuH. Adenosine promotes the recovery of mice from the cuprizone-induced behavioral and morphological changes while effecting on microglia and inflammatory cytokines in the brain.J. Neuroimmune Pharmacol.201813341242510.1007/s11481‑018‑9799‑0 30069711
    [Google Scholar]
  30. ZhangH. WangD. SunJ. WangY. WuS. WangJ. Huperzine—A improved animal behavior in cuprizone-induced mouse model by alleviating demyelination and neuroinflammation.Int. J. Mol. Sci.202223241618210.3390/ijms232416182 36555825
    [Google Scholar]
  31. MengX. FuM. WangS. ChenW. WangJ. ZhangN. Naringin ameliorates memory deficits and exerts neuroprotective effects in a mouse model of Alzheimer’s disease by regulating multiple metabolic pathways.Mol. Med. Rep.202123533210.3892/mmr.2021.11971 33760152
    [Google Scholar]
  32. RenY. WangQ. YangZ. FengL. ZhangY. MCC950 ameliorates the dementia symptom at the early age of line M83 mouse and reduces hippocampal α-synuclein accumulation.Biochem. Biophys. Res. Commun.2022611233010.1016/j.bbrc.2022.04.076 35472607
    [Google Scholar]
  33. HouB. YinJ. LiuS. GuoJ. ZhangB. ZhangZ. Inhibiting the NLRP3 inflammasome with MCC950 alleviates neurological impairment in the brain of EAE Mice.Mol. Neurobiol.2024613131830 37702910
    [Google Scholar]
  34. FengJ. ChenX. LuS. LiW. YangD. SuW. WangX. ShenJ. Naringin attenuates cerebral ischemia-reperfusion injury through inhibiting peroxynitrite-mediated mitophagy activation.Mol. Neurobiol.201855129029904210.1007/s12035‑018‑1027‑7 29627876
    [Google Scholar]
  35. 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]
  36. NaveK.A. WernerH.B. Myelination of the nervous system: Mechanisms and functions.Annu. Rev. Cell Dev. Biol.201430150353310.1146/annurev‑cellbio‑100913‑013101 25288117
    [Google Scholar]
  37. WegenerA. DebouxC. BachelinC. FrahM. KerninonC. SeilheanD. WeiderM. WegnerM. Nait-OumesmarB. Gain of Olig2 function in oligodendrocyte progenitors promotes remyelination.Brain2015138112013510.1093/brain/awu375 25564492
    [Google Scholar]
  38. GardA.L. BurrellM.R. PfeifferS.E. RudgeJ.S. WilliamsW.C. II Astroglial control of oligodendrocyte survival mediated by PDGF and leukemia inhibitory factor-like protein.Development199512172187219710.1242/dev.121.7.2187 7635062
    [Google Scholar]
  39. MurtieJ.C. ZhouY.X. LeT.Q. VanaA.C. ArmstrongR.C. PDGF and FGF2 pathways regulate distinct oligodendrocyte lineage responses in experimental demyelination with spontaneous remyelination.Neurobiol. Dis.2005191-217118210.1016/j.nbd.2004.12.006 15837572
    [Google Scholar]
  40. DraheimT. LiessemA. ScheldM. WilmsF. WeißflogM. DeneckeB. KenslerT.W. ZendedelA. BeyerC. KippM. WruckC.J. FragoulisA. ClarnerT. Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model.Glia201664122219223010.1002/glia.23058 27641725
    [Google Scholar]
  41. ChowdhryS. ZhangY. McMahonM. SutherlandC. CuadradoA. HayesJ.D. Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity.Oncogene201332323765378110.1038/onc.2012.388 22964642
    [Google Scholar]
  42. XingB. BrinkL.E. MaersK. SullivanM.L. BodnarR.J. StolzD.B. CambiF. Conditional depletion of GSK 3b protects oligodendrocytes from apoptosis and lessens demyelination in the acute cuprizone model.Glia20186691999201210.1002/glia.23453 29761559
    [Google Scholar]
  43. ElbazE.M. SenousyM.A. El-TanboulyD.M. SayedR.H. Neuroprotective effect of linagliptin against cuprizone-induced demyelination and behavioural dysfunction in mice: A pivotal role of AMPK/SIRT1 and JAK2/STAT3/NF-κB signalling pathway modulation.Toxicol. Appl. Pharmacol.201835215316110.1016/j.taap.2018.05.035 29864483
    [Google Scholar]
  44. GopinathK. SudhandiranG. Naringin modulates oxidative stress and inflammation in 3-nitropropionic acid-induced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway.Neuroscience201222713414310.1016/j.neuroscience.2012.07.060 22871521
    [Google Scholar]
  45. ShiY. ZhaoL. WangJ. LiuS. ZhangY. QinQ. The selective NLRP3 inflammasome inhibitor MCC950 improves isoproterenol-induced cardiac dysfunction by inhibiting cardiomyocyte senescence.Eur. J. Pharmacol.202293717536410.1016/j.ejphar.2022.175364 36336012
    [Google Scholar]
  46. NiB. PeiW. QuY. ZhangR. ChuX. WangY. HuangX. YouH. MCC950, the NLRP3 inhibitor, protects against cartilage degradation in a mouse model of osteoarthritis.Oxid. Med. Cell. Longev.2021202110.1155/2021/4139048
    [Google Scholar]
  47. ShelestakJ. SinghalN. FrankleL. TomorR. SternbachS. McDonoughJ. FreemanE. ClementsR. Increased blood-brain barrier hyperpermeability coincides with mast cell activation early under cuprizone administration.PLoS One2020156e023400110.1371/journal.pone.0234001 32511268
    [Google Scholar]
  48. GopinathK. SudhandiranG. Protective effect of naringin on 3-nitropropionic acid-induced neurodegeneration through the modulation of matrix metalloproteinases and glial fibrillary acidic protein.Can. J. Physiol. Pharmacol.2016941657110.1139/cjpp‑2015‑0035 26544788
    [Google Scholar]
  49. LiddelowS.A. GuttenplanK.A. ClarkeL.E. BennettF.C. BohlenC.J. SchirmerL. BennettM.L. MünchA.E. ChungW.S. PetersonT.C. WiltonD.K. FrouinA. NapierB.A. PanickerN. KumarM. BuckwalterM.S. RowitchD.H. DawsonV.L. DawsonT.M. StevensB. BarresB.A. Neurotoxic reactive astrocytes are induced by activated microglia.Nature2017541763848148710.1038/nature21029 28099414
    [Google Scholar]
  50. HouB. ZhangY. LiangP. HeY. PengB. LiuW. HanS. YinJ. HeX. Inhibition of the NLRP3-inflammasome prevents cognitive deficits in experimental autoimmune encephalomyelitis mice via the alteration of astrocyte phenotype.Cell Death Dis.202011537710.1038/s41419‑020‑2565‑2 32415059
    [Google Scholar]
  51. 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]
  52. SmithJ.A. DasA. RayS.K. BanikN.L. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases.Brain Res. Bull.2012871102010.1016/j.brainresbull.2011.10.004 22024597
    [Google Scholar]
  53. VafeiadouK. VauzourD. LeeH.Y. Rodriguez-MateosA. WilliamsR.J. SpencerJ.P.E. The citrus flavanone naringenin inhibits inflammatory signalling in glial cells and protects against neuroinflammatory injury.Arch. Biochem. Biophys.2009484110010910.1016/j.abb.2009.01.016 19467635
    [Google Scholar]
/content/journals/cn/10.2174/1570159X23666241206102022
Loading
/content/journals/cn/10.2174/1570159X23666241206102022
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.


  • Article Type:
    Research Article
Keyword(s): cuprizone; demyelination; inflammation; MCC950; Naringin; oxidative stress
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