Skip to content
2000
Volume 24, Issue 2
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Objective

Facial nerve injury induces autophagy and apoptosis in facial nerve nucleus motoneurons of the CNS, impairing nerve regeneration and functional recovery. The function of P2Y2R after facial nerve injury remains to be determined. This study hypothesizes that inhibiting P2Y2R may play a protective role in facial nerve injury by modulating the autophagy signaling pathway.

Methods

An mouse model of facial nerve crush injury was utilized in this study. Mice received either a P2Y2R agonist or antagonist through intrathecal injections of 10 μL/daily for 4 weeks. This study measured facial nerve function, examined fibrogenesis, and analyzed expression of autophagy regulatory proteins. In an experiment, NSC34 cells were treated with a P2Y2R agonist or an antagonist, and changes in the levels of phosphorylated PI3K, Akt, and mTOR, as well as autophagy regulatory proteins determined.

Results

Inhibition of P2Y2R significantly increased autophagy levels and enhanced facial nerve function. These protective outcomes were linked to the suppression of phosphorylated PI3K, Akt, and mTOR signaling pathways.

Conclusion

The study suggests that P2Y2R inhibition may improve facial nerve function by improving autophagy, making it a promising therapeutic approach for treating facial nerve injury.

© 2026 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cn/10.2174/011570159X349328250717113503
2025-08-08
2026-03-01

  • From This Site

    /content/journals/cn/10.2174/011570159X349328250717113503
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. DeumensR. BozkurtA. MeekM.F. MarcusM.A.E. JoostenE.A.J. WeisJ. BrookG.A. Repairing injured peripheral nerves: Bridging the gap.Prog. Neurobiol.201092324527610.1016/j.pneurobio.2010.10.002 20950667
     [Google Scholar]
  2. WangS. LiuX. WangY. Evaluation of platelet-rich plasma therapy for peripheral nerve regeneration: A critical review of literature.Front. Bioeng. Biotechnol.20221080824810.3389/fbioe.2022.808248 35299637
     [Google Scholar]
  3. AoQ. WenL-L. YuT-H. MaY-Z. MaoX-Y. AoT-R. JavedR. TenH. MatsunoA. Sequential expression of miR-221-3p and miR-338-3p in Schwann cells as a therapeutic strategy to promote nerve regeneration and functional recovery.Neural Regen. Res.202318367168210.4103/1673‑5374.350214 36018193
     [Google Scholar]
  4. KoS.H. GonzalezG. LiuZ. ChenL. Axon injury-induced autophagy activation is impaired in a C. elegans model of tauopathy.Int. J. Mol. Sci.20202122855910.3390/ijms21228559 33202845
     [Google Scholar]
  5. LipinskiM.M. WuJ. FadenA.I. SarkarC. Function and mechanisms of autophagy in brain and spinal cord trauma.Antioxid. Redox Signal.201523656557710.1089/ars.2015.6306 25808205
     [Google Scholar]
  6. HeM. DingY. ChuC. TangJ. XiaoQ. LuoZ.G. Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury.Proc. Natl. Acad. Sci. USA201611340113241132910.1073/pnas.1611282113 27638205
     [Google Scholar]
  7. Saraswat OhriS. BankstonA.N. MullinsS.A. LiuY. AndresK.R. BeareJ.E. HowardR.M. BurkeD.A. RieglerA.S. SmithA.E. HetmanM. WhittemoreS.R. Blocking autophagy in oligodendrocytes limits functional recovery after spinal cord injury.J. Neurosci.201838265900591210.1523/JNEUROSCI.0679‑17.2018 29793971
     [Google Scholar]
  8. ShaoS.M. ParkK.H. YuanY. ZhangZ. YouY. ZhangZ. HaoL. Electroacupuncture attenuates learning and memory impairment via PI3K/Akt pathway in an amyloid β25-35-induced Alzheimer’s disease mouse model.Evid. Based Complement. Alternat. Med.2022202211010.1155/2022/3849441 35463064
     [Google Scholar]
  9. Muñoz-GaldeanoT. ReigadaD. del ÁguilaÁ. VelezI. Caballero-LópezM.J. MazaR.M. Nieto-DíazM. Cell specific changes of autophagy in a mouse model of contusive spinal cord injury.Front. Cell. Neurosci.20181216410.3389/fncel.2018.00164 29946241
     [Google Scholar]
  10. ZhouZ. NiuY. HuangG. LuJ. ChenA. ZhuL. Silencing of circRNA.2837 plays a protective role in sciatic nerve injury by sponging the mir-34 family via regulating neuronal autophagy.Mol. Ther. Nucleic Acids20181271872910.1016/j.omtn.2018.07.011 30098504
     [Google Scholar]
  11. ZhaoS. WangS. CaoL. ZengH. LinS. LinZ. ChenM. ZhuM. PangZ. ZhangY. Acupuncture promotes nerve repair through the benign regulation of mTOR-mediated neuronal autophagy in traumatic brain injury rats.CNS Neurosci. Ther.202329145847010.1111/cns.14018 36422883
     [Google Scholar]
  12. HaraT. NakamuraK. MatsuiM. YamamotoA. NakaharaY. Suzuki-MigishimaR. YokoyamaM. MishimaK. SaitoI. OkanoH. MizushimaN. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.Nature2006441709588588910.1038/nature04724 16625204
     [Google Scholar]
  13. KomatsuM. WaguriS. ChibaT. MurataS. IwataJ. TanidaI. UenoT. KoikeM. UchiyamaY. KominamiE. TanakaK. Loss of autophagy in the central nervous system causes neurodegeneration in mice.Nature2006441709588088410.1038/nature04723 16625205
     [Google Scholar]
  14. LingorP. KochJ.C. TöngesL. BährM. Axonal degeneration as a therapeutic target in the CNS.Cell Tissue Res.2012349128931110.1007/s00441‑012‑1362‑3 22392734
     [Google Scholar]
  15. ZarrinmayehH. TerritoP.R. Purinergic receptors of the central nervous system: biology, pet ligands, and their applications.Mol. Imaging202019153601212092760910.1177/1536012120927609 32539522
     [Google Scholar]
  16. XiangZ. Enhanced expression of P2X4 purinoceptors in pyramidal neurons of the rat hippocampal CA1 region may be involved ischemia-reperfusion injury.Purinerg. Signal.2021173425438
     [Google Scholar]
  17. WoodsL.T. AjitD. CamdenJ.M. ErbL. WeismanG.A. Purinergic receptors as potential therapeutic targets in Alzheimer’s disease.Neuropharmacology201610416917910.1016/j.neuropharm.2015.10.031 26519903
     [Google Scholar]
  18. JacobsonK.A. GiancottiL.A. LauroF. MuftiF. SalveminiD. Treatment of chronic neuropathic pain: purine receptor modulation.Pain202016171425144110.1097/j.pain.0000000000001857 32187120
     [Google Scholar]
  19. BurnstockG. Physiology and pathophysiology of purinergic neurotransmission.Physiol. Rev.200787265979710.1152/physrev.00043.2006 17429044
     [Google Scholar]
  20. WeismanG.A. WoodsL.T. ErbL. SeyeC.I. P2Y receptors in the mammalian nervous system: Pharmacology, ligands and therapeutic potential.CNS Neurol. Disord. Drug Targets201211672273810.2174/187152712803581047 22963441
     [Google Scholar]
  21. ChengR. ZhuG. NiC. WangR. SunP. TianL. ZhangL. ZhangJ. YeX. LuoB. P2Y2 receptor mediated neuronal regeneration and angiogenesis to affect functional recovery in rats with spinal cord injury.Neural Plast.2022202211010.1155/2022/2191011 35154311
     [Google Scholar]
  22. SongS. WangQ. QuY. GaoW. LiD. XuX. YueS. Pregabalin inhibits purinergic P2Y2 receptor and TRPV4 to suppress astrocyte activation and to relieve neuropathic pain.Eur. J. Pharmacol.202396017614010.1016/j.ejphar.2023.176140 37925132
     [Google Scholar]
  23. FrankeH. IllesP.J.P. Involvement of P2 receptors in the growth and survival of neurons in the CNS.Pharmacol. Ther.2006109329732410.1016/j.pharmthera.2005.06.002
     [Google Scholar]
  24. Rodríguez-ZayasA.E. TorradoA.I. RosasO.R. SantiagoJ.M. FigueroaJ.D. MirandaJ.D. Blockade of P2 nucleotide receptors after spinal cord injury reduced the gliotic response and spared tissue.J. Mol. Neurosci.201246116717610.1007/s12031‑011‑9567‑6 21647706
     [Google Scholar]
  25. D’AmbrosiN. MurraB. CavaliereF. AmadioS. BernardiG. BurnstockG. VolontéC. Interaction between ATP and nerve growth factor signalling in the survival and neuritic outgrowth from PC12 cells.Neuroscience2001108352753410.1016/S0306‑4522(01)00431‑6 11738265
     [Google Scholar]
  26. D’AmbrosiN. CavaliereF. MerloD. MilazzoL. MercantiD. VolontéC. Antagonists of P2 receptor prevent NGF-dependent neuritogenesis in PC12 cells.Neuropharmacology20003961083109410.1016/S0028‑3908(99)00213‑0 10727719
     [Google Scholar]
  27. PoolerA.M. GuezD.H. BenedictusR. WurtmanR.J. Uridine enhances neurite outgrowth in nerve growth factor-differentiated pheochromocytoma cells.Neuroscience2005134120721410.1016/j.neuroscience.2005.03.050 15939540
     [Google Scholar]
  28. DolovcakS. WaldropS.L. FitzJ.G. KilicG. Copper inhibits P2Y2-dependent Ca2+ signaling through the effects on thapsigargin-sensitive Ca2+ stores in HTC hepatoma cells.Biochem. Biophys. Res. Commun.2010397349349810.1016/j.bbrc.2010.05.141 20515656
     [Google Scholar]
  29. ZhouQ. LiuS. KouY. YangP. LiuH. HasegawaT. SuR. ZhuG. LiM. ATP promotes oral squamous cell carcinoma cell invasion and migration by activating the PI3K/AKT pathway via the P2Y2-Src-EGFR axis.ACS Omega2022744397603977110.1021/acsomega.2c03727 36385800
     [Google Scholar]
  30. SophocleousR.A. MilesN.A. OoiL. SluyterR. P2Y2 and P2X4 receptors mediate Ca2+ mobilization in DH82 canine macrophage cells.Int. J. Mol. Sci.20202122857210.3390/ijms21228572 33202978
     [Google Scholar]
  31. WeismanG.A. AjitD. GarradR. PetersonT.S. WoodsL.T. ThebeauC. CamdenJ.M. ErbL. Neuroprotective roles of the P2Y2 receptor.Purinergic Signal.20128355957810.1007/s11302‑012‑9307‑6 22528682
     [Google Scholar]
  32. ChornaN.E. Santiago-PérezL.I. ErbL. SeyeC.I. NearyJ.T. SunG.Y. WeismanG.A. GonzálezF.A. P2Y 2 receptors activate neuroprotective mechanisms in astrocytic cells.J. Neurochem.200491111913210.1111/j.1471‑4159.2004.02699.x 15379893
     [Google Scholar]
  33. MagniG. MerliD. VerderioC. AbbracchioM.P. CerutiS. P2Y2 receptor antagonists as anti-allodynic agents in acute and sub-chronic trigeminal sensitization: Role of satellite glial cells.Glia20156371256126910.1002/glia.22819 25779655
     [Google Scholar]
  34. AjitD. WoodsL.T. CamdenJ.M. ThebeauC.N. El-SayedF.G. GreesonG.W. ErbL. PetrisM.J. MillerD.C. SunG.Y. WeismanG.A. Loss of P2Y2 nucleotide receptors enhances early pathology in the TgCRND8 mouse model of Alzheimer’s disease.Mol. Neurobiol.20144921031104210.1007/s12035‑013‑8577‑5 24193664
     [Google Scholar]
  35. PetersonT.S. CamdenJ.M. WangY. SeyeC.I. WoodW.G. SunG.Y. ErbL. PetrisM.J. WeismanG.A. P2Y2 nucleotide receptor-mediated responses in brain cells.Mol. Neurobiol.2010412-335636610.1007/s12035‑010‑8115‑7 20387013
     [Google Scholar]
  36. Rodríguez-ZayasA.E. TorradoA.I. MirandaJ.D. P2Y 2 receptor expression is altered in rats after spinal cord injury.Int. J. Dev. Neurosci.201028641342110.1016/j.ijdevneu.2010.07.001 20619335
     [Google Scholar]
  37. YuF. WangY. StetlerA.R. LeakR.K. Phagocytic microglia and macrophages in brain injury and repair.CNS Neurosci. Ther.20222891279129310.1111/cns.13899
     [Google Scholar]
  38. MaR.D. ZhouG.J. QuM. YiJ.H. TangY.L. Corticosterone induces neurotoxicity in PC12 cells via disrupting autophagy flux mediated by AMPK/mTOR signaling.CNS Neurosci. Ther.202026216717610.1111/cns.13212
     [Google Scholar]
  39. WangJ. RongY. JiC. LvC. JiangD. GeX. GongF. TangP. CaiW. LiuW. FanJ. MicroRNA-421-3p-abundant small extracellular vesicles derived from M2 bone marrow-derived macrophages attenuate apoptosis and promote motor function recovery via inhibition of mTOR in spinal cord injury.J. Nanobiotechnology20201817210.1186/s12951‑020‑00630‑5 32404105
     [Google Scholar]
  40. MengW. GengX. DanduC. PatelR. DingY. Normobaric Oxygen (NBO) therapy reduces cerebral ischemia/reperfusion injury through inhibition of early autophagy. Evid. Based Complement Alternat. Med.,20212021704129010.1155/2021/7041290.
     [Google Scholar]
  41. Romeo-GuitartD. Marcos-DeJuanaC. Marmolejo-Martínez-ArteseroS. NavarroX. CasasC. Novel neuroprotective therapy with NeuroHeal by autophagy induction for damaged neonatal motoneurons.Theranostics202010115154516810.7150/thno.43765 32308774
     [Google Scholar]
  42. LongT. ChenX. ZhangY. ZhouY.J. HeY.N. ZhuY.F. FuH.J. YuL. YuC.L. LawB.Y.K. WuJ.M. QinD.L. WuA.G. ZhouX.G. Protective effects of Radix stellariae extract against Alzheimer’s disease via autophagy activation in Caenorhabditis elegans and cellular models.Biomed. Pharmacother.202316511526110.1016/j.biopha.2023.115261 37549461
     [Google Scholar]
  43. ChenY. ChenJ. XingZ. PengC. Autophagy in neuroinflammation: A focus on epigenetic regulation.Aging Dis.,202315273975410.14336/AD.2023.0718‑1
     [Google Scholar]
  44. GaoY. XuX. ZhangX. Targeting different phenotypes of macrophages: A potential strategy for natural products to treat inflammatory bone and joint diseases.Phytomedicine202311815495210.1016/j.phymed.2023.154952 37506402
     [Google Scholar]
  45. GaoD. TangT. ZhuJ. TangY. SunH. CXCL12 has therapeutic value in facial nerve injury and promotes Schwann cells autophagy and migration via PI3K-AKT-mTOR signal pathway.Int. J. Biol. Macromol.201912446046810.1016/j.ijbiomac.2018.10.212
     [Google Scholar]
  46. WuY. ShiH. ZhengJ. YangY. LeiX. QianX. ZhuJ. Overexpression of FSP1 Ameliorates ferroptosis via PI3K/AKT/GSK3β pathway in PC12 cells with oxygen-glucose deprivation/] reoxygenation.Heliyon202398e1844910.1016/j.heliyon.2023.e18449 37529339
     [Google Scholar]
  47. WengZ. LinT.H. ChangK.H. ChiuY.J. Lee-ChenG.J. Using ΔK280 Tau folding reporter cells to screen TRKB agonists as Alzheimer’s disease treatment strategy. Biomolecules,202313221910.3390/biom13020219
     [Google Scholar]
  48. DusabimanaT. KimS.R. ParkE.J. JeJ. JeongK. YunS.P. KimH.J. KimH. ParkS.W. P2Y2R contributes to the development of diabetic nephropathy by inhibiting autophagy response.Mol. Metab.20204210108910.1016/j.molmet.2020.101089 32987187
     [Google Scholar]
/content/journals/cn/10.2174/011570159X349328250717113503
Loading
Inhibition of the P2Y2 Receptor Promotes Facial Nerve Function by Enhancing Neuron Autophagy
Curr. Neuropharmacol. 24, 230 (2026); https://doi.org/10.2174/011570159X349328250717113503
/content/journals/cn/10.2174/011570159X349328250717113503
/content/journals/cn/10.2174/011570159X349328250717113503
Loading

Data & Media loading...

Supplements

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

file format download Download

  • Article Type:     Research Article
Keyword(s): autophagy; facial nerve injury; mTOR; nerve regeneration; P2Y2R; signaling pathways

Most Cited Most Cited RSS feed

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