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2000
Volume 21, Issue 17
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Parkinson's disease (PD) is an age-related progressive neurodegenerative condition characterized by dopaminergic neuronal loss in the brain's substantia nigra pars compacta (SNpc). Growing evidence suggests that apoptosis, neuroinflammation, mitochondrial dysfunction, and oxidative stress are important factors in the pathogenesis of Parkinson's disease. Isoquercetin is a natural flavanol compound possessing anti-apoptotic, anti-inflammatory, anti-oxidant, and neuroprotective activities. Isoquercetin also has the capability to modulate various signaling pathways such as Rho signaling cascade, Nrf-2, TLR4, NF-κB, MAPK, Bcl-2, Bax proteins, which are well-known causes for the progression of the disease. These pathways are involved in cellular homeostasis, transcription of proinflammatory cytokines, oxidative stress, microglial activation, and regulation of the apoptotic pathways. In this review, we have highlighted the mechanisms of the above-mentioned pathways and their modulation the flavonoid compound isoquercetin in various ways.

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2024-06-10
2025-06-23
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References

  1. AmorS. PuentesF. BakerD. Van Der ValkP. Inflammation in neurodegenerative diseases.Immunology2010129215416910.1111/j.1365‑2567.2009.03225.x 20561356
    [Google Scholar]
  2. Bossy-WetzelE. SchwarzenbacherR. LiptonS.A. Molecular pathways to neurodegeneration.Nat. Med.200410S7Suppl.S2S910.1038/nm1067 15272266
    [Google Scholar]
  3. MaitiP. DunbarG. Use of curcumin, a natural polyphenol for targeting molecular pathways in treating age-related neurodegenerative diseases.Int. J. Mol. Sci.2018196163710.3390/ijms19061637 29857538
    [Google Scholar]
  4. SinghS.S. Rai, S.N.; Birla, H.; Zahra, W.; Rathore, A.S.; Singh, S.P. NF-κB-mediated neuroinflammation in Parkinson’s disease and potential therapeutic effect of polyphenols.Neurotox. Res.202037349150710.1007/s12640‑019‑00147‑2 31823227
    [Google Scholar]
  5. StankiewiczT.R. LinsemanD.A. Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration.Front. Cell. Neurosci.2014831410.3389/fncel.2014.00314 25339865
    [Google Scholar]
  6. JohnsonD.A. JohnsonJ.A. Nrf2—a therapeutic target for the treatment of neurodegenerative diseases. Free Radic. Biol. Med.,201588Pt B25326710.1016/j.freeradbiomed.2015.07.14726281945
    [Google Scholar]
  7. XieY. PengJ. PangJ. GuoK. ZhangL. YinS. ZhouJ. GuL. TuT. MuQ. LiaoY. ZhangX. ChenL. JiangY. Biglycan regulates neuroinflammation by promoting M1 microglial activation in early brain injury after experimental subarachnoid hemorrhage.J. Neurochem.2020152336838010.1111/jnc.14926 31778579
    [Google Scholar]
  8. AhmedT. ZulfiqarA. ArguellesS. RasekhianM. NabaviS.F. SilvaA.S. NabaviS.M. Map kinase signaling as therapeutic target for neurodegeneration.Pharmacol. Res.202016010509010.1016/j.phrs.2020.105090 32707231
    [Google Scholar]
  9. WangC.P. ShiY.W. TangM. ZhangX.C. GuY. LiangX.M. WangZ.W. DingF. Isoquercetin ameliorates cerebral impairment in focal ischemia through anti-oxidative, anti-inflammatory, and anti-apoptotic effects in primary culture of rat hippocampal neurons and hippocampal CA1 region of rats.Mol. Neurobiol.20175432126214210.1007/s12035‑016‑9806‑5 26924319
    [Google Scholar]
  10. AppletonJ. Evaluating the bioavailability of isoquercetin.Nat. Med. J.20102116
    [Google Scholar]
  11. OrfaliG.C. DuarteA.C. BonadioV. MartinezN.P. de AraújoM.E.M.B. PrivieroF.B.M. CarvalhoP.O. PriolliD.G. Review of anticancer mechanisms of isoquercitin.World J. Clin. Oncol.20167218919910.5306/wjco.v7.i2.189 27081641
    [Google Scholar]
  12. MorandC. ManachC. CrespyV. RemesyC. Quercetin 3-O-β-glucoside is better absorbed than other quercetin forms and is not present in rat plasma.Free Radic. Res.200033566767610.1080/10715760000301181 11200097
    [Google Scholar]
  13. DeGeerJ. Lamarche-VaneN. Rho GTPases in neurodegeneration diseases.Exp. Cell Res.2013319152384239410.1016/j.yexcr.2013.06.016 23830879
    [Google Scholar]
  14. IyerM. SubramaniamM.D. VenkatesanD. ChoS.G. RydingM. MeyerM. VellingiriB. Role of RhoA-ROCK signaling in Parkinson’s disease.Eur. J. Pharmacol.202189417381510.1016/j.ejphar.2020.173815 33345850
    [Google Scholar]
  15. SaalK.A. KochJ.C. TatenhorstL. Szegő,; É.M.; Ribas, V.T.; Michel, U.; Bähr, M.; Tönges, L.; Lingor, P. AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson’s disease in vitro and in vivo.Neurobiol. Dis.20157315016210.1016/j.nbd.2014.09.013 25283984
    [Google Scholar]
  16. Villar-ChedaB. Dominguez-MeijideA. JoglarB. Rodriguez-PerezA.I. GuerraM.J. Labandeira-GarciaJ.L. Involvement of microglial RhoA/Rho-Kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors.Neurobiol. Dis.201247226827910.1016/j.nbd.2012.04.010 22542954
    [Google Scholar]
  17. PalazzoloG. HorvathP. Zenobi-WongM. The flavonoid isoquercitrin promotes neurite elongation by reducing RhoA activity.PLoS One2012711e4997910.1371/journal.pone.0049979 23209630
    [Google Scholar]
  18. BrandesM.S. GrayN.E. NRF2 as a therapeutic target in neurodegenerative diseases.ASN Neuro20201210.1177/1759091419899782 31964153
    [Google Scholar]
  19. FãoL. MotaS.I. RegoA.C. Shaping the Nrf2-ARE-related pathways in Alzheimer’s and Parkinson’s diseases.Ageing Res. Rev.20195410094210.1016/j.arr.2019.100942 31415806
    [Google Scholar]
  20. Villavicencio TejoF. QuintanillaR.A. Contribution of the Nrf2 pathway on oxidative damage and mitochondrial failure in Parkinson and Alzheimer’s disease.Antioxidants2021107106910.3390/antiox10071069 34356302
    [Google Scholar]
  21. Bento-PereiraC. Dinkova-KostovaA.T. Activation of transcription factor Nrf2 to counteract mitochondrial dysfunction in Parkinson’s disease.Med. Res. Rev.202141278580210.1002/med.21714 32681666
    [Google Scholar]
  22. Ammal KaideryN. AhujaM. ThomasB. Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson’s disease.Mol. Cell. Neurosci.201910110341310.1016/j.mcn.2019.103413 31644952
    [Google Scholar]
  23. ShenG. HebbarV. NairS. XuC. LiW. LinW. KeumY.S. HanJ. GalloM.A. KongA.N.T. Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein.J. Biol. Chem.200427922230522306010.1074/jbc.M401368200 15020583
    [Google Scholar]
  24. KimS. Indu ViswanathA.N. ParkJ.H. LeeH.E. ParkA.Y. ChoiJ.W. KimH.J. LondheA.M. JangB.K. LeeJ. HwangH. LimS.M. PaeA.N. ParkK.D. Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson’s disease animal model.Neuropharmacology202016710798910.1016/j.neuropharm.2020.107989 32032607
    [Google Scholar]
  25. ChenM. DaiL.H. FeiA. PanS.M. WangH.R. Isoquercetin activates the ERK1/2-Nrf2 pathway and protects against cerebral ischemia-reperfusion injury in vivo and in vitro.Exp. Ther. Med.20171341353135910.3892/etm.2017.4093 28413477
    [Google Scholar]
  26. KouliA. HorneC.B. Williams-GrayC.H. Toll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies.Brain Behav. Immun.201981415110.1016/j.bbi.2019.06.042 31271873
    [Google Scholar]
  27. KaurK. GillJ.S. BansalP.K. DeshmukhR. Neuroinflammation - A major cause for striatal dopaminergic degeneration in Parkinson’s disease.J. Neurol. Sci.201738130831410.1016/j.jns.2017.08.3251 28991704
    [Google Scholar]
  28. NoelkerC. MorelL. LescotT. OsterlohA. Alvarez-FischerD. BreloerM. HenzeC. DepboyluC. SkrzydelskiD. MichelP.P. DodelR.C. LuL. HirschE.C. HunotS. HartmannA. Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease.Sci. Rep.201331139310.1038/srep01393 23462811
    [Google Scholar]
  29. KimE.K. ChoiE.J. Compromised MAPK signaling in human diseases: An update.Arch. Toxicol.201589686788210.1007/s00204‑015‑1472‑2 25690731
    [Google Scholar]
  30. CampoloM. PaternitiI. SiracusaR. FilipponeA. EspositoE. CuzzocreaS. TLR4 absence reduces neuroinflammation and inflammasome activation in Parkinson’s diseases in vivo model.Brain Behav. Immun.20197623624710.1016/j.bbi.2018.12.003 30550933
    [Google Scholar]
  31. WangC.P. LiJ.L. ZhangL.Z. ZhangX.C. YuS. LiangX.M. DingF. WangZ.W. Isoquercetin protects cortical neurons from oxygen–glucose deprivation–reperfusion induced injury via suppression of TLR4–NF-кB signal pathway.Neurochem. Int.201363874174910.1016/j.neuint.2013.09.018 24099731
    [Google Scholar]
  32. SpagnuoloC. MocciaS. RussoG.L. Anti-inflammatory effects of flavonoids in neurodegenerative disorders.Eur. J. Med. Chem.201815310511510.1016/j.ejmech.2017.09.001 28923363
    [Google Scholar]
  33. Ghafouri-FardS. GholipourM. AbakA. MazdehM. TaheriM. SayadA. Expression analysis of NF-κB-related lncRNAs in Parkinson’s Disease.Front. Immunol.20211275524610.3389/fimmu.2021.755246
    [Google Scholar]
  34. SuF. BaiF. ZhouH. ZhangZ. Reprint of: Microglial toll-like receptors and Alzheimer’s disease.Brain Behav. Immun.20165516617810.1016/j.bbi.2016.05.016 27255539
    [Google Scholar]
  35. YangY.L. LiuM. ChengX. LiW.H. ZhangS.S. WangY.H. DuG.H. Myricitrin blocks activation of NF-κB and MAPK signaling pathways to protect nigrostriatum neuron in LPS-stimulated mice.J. Neuroimmunol.201933757704910.1016/j.jneuroim.2019.577049 31526918
    [Google Scholar]
  36. ShababT. KhanabdaliR. MoghadamtousiS.Z. KadirH.A. MohanG. Neuroinflammation pathways: A general review.Int. J. Neurosci.2017127762463310.1080/00207454.2016.1212854 27412492
    [Google Scholar]
  37. 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]
  38. LiuT. Zhang, L.; Joo, D.; Sun, S.C. NF-κB signaling in inflammation.Curr. Signal Transduct. Ther.2017219
    [Google Scholar]
  39. LeeE. ParkH.R. JiS.T. LeeY. LeeJ. Baicalein attenuates astroglial activation in the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson’s disease model by downregulating the activations of nuclear factor-κB, ERK, and JNK.J. Neurosci. Res.201492113013910.1002/jnr.23307 24166733
    [Google Scholar]
  40. HunotS. BruggB. RicardD. MichelP.P. MurielM.P. RubergM. FaucheuxB.A. AgidY. HirschE.C. Nuclear translocation of NF-κB is increased in dopaminergic neurons of patients with Parkinson disease.Proc. Natl. Acad. Sci. USA199794147531753610.1073/pnas.94.14.7531 9207126
    [Google Scholar]
  41. WangP. LiC. LiaoG. HuangY. LvX. LiuX. ChenW. ZhangL. Vanillin attenuates proinflammatory factors in a tMCAO mouse model via inhibition of TLR4/NF-kB signaling pathway.Neuroscience2022491657410.1016/j.neuroscience.2022.03.003 35276304
    [Google Scholar]
  42. BohushA. NiewiadomskaG. FilipekA. Role of mitogen activated protein kinase signaling in Parkinson’s disease.Int. J. Mol. Sci.20181910297310.3390/ijms19102973 30274251
    [Google Scholar]
  43. JhaS.K. JhaN.K. KarR. AmbastaR.K. KumarP. p38 MAPK and PI3K/AKT signalling cascades inParkinson’s disease.Int. J. Mol. Cell. Med.2015426786 26261796
    [Google Scholar]
  44. CargnelloM. RouxP.P. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.Microbiol. Mol. Biol. Rev.2011751508310.1128/MMBR.00031‑10 21372320
    [Google Scholar]
  45. HeY. SheH. ZhangT. XuH. ChengL. YepesM. ZhaoY. MaoZ. p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1.J. Cell Biol.2018217131532810.1083/jcb.201701049 29196462
    [Google Scholar]
  46. KimE.H. ShimY.Y. LeeH.I. LeeS. ReaneyM.J. ChungM.J. Astragalin and isoquercitrin isolated from aster scaber suppress LPS-induced neuroinflammatory responses in microglia and mice.Foods202211101505
    [Google Scholar]
  47. MichelsJ. KeppO. SenovillaL. LissaD. CastedoM. KroemerG. GalluzziL. Functions of BCL-XL at the interface between cell death and metabolism.Int. J. Cell Biol.20132013705294
    [Google Scholar]
  48. WuF. WangZ. GuJ.H. GeJ.B. LiangZ.Q. QinZ.H. p38MAPK/p53-Mediated bax induction contributes to neurons degeneration in rotenone-induced cellular and rat models of Parkinson’s disease.Neurochem. Int.201363313314010.1016/j.neuint.2013.05.006 23714208
    [Google Scholar]
  49. NaseerM.I. UllahN. UllahI. KohP.O. LeeH.Y. ParkM.S. KimM.O. Vitamin C protects against ethanol and PTZ-induced apoptotic neurodegeneration in prenatal rat hippocampal neurons.Synapse201165756257110.1002/syn.20875 20963815
    [Google Scholar]
  50. LiuJ. LiuW. YangH. Balancing apoptosis and autophagy for Parkinson’s disease therapy: Targeting BCL-2.ACS Chem. Neurosci.201910279280210.1021/acschemneuro.8b00356 30400738
    [Google Scholar]
  51. DaiY. ZhangH. ZhangJ. YanM. Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB pathway.Chem. Biol. Interact.2018284324010.1016/j.cbi.2018.02.017 29454613
    [Google Scholar]
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