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H2S-RhoA/ROCK Pathway and Glial Cells in Axonal Remyelination After Ischemic Stroke

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Abstract

Ischemic stroke is one of the main reasons of disability and death. Stroke-induced functional deficits are mainly due to the secondary degeneration of the white matter characterized by axonal demyelination and injury of axon-glial integrity. Enhancement of the axonal regeneration and remyelination could promote the neural functional recovery. However, cerebral ischemia-induced activation of RhoA/Rho kinase (ROCK) pathway plays a crucial and harmful role in the process of axonal recovery and regeneration. Inhibition of this pathway could promote the axonal regeneration and remyelination. In addition, hydrogen sulfide (H2S) has the significant neuroprotective role during the recovery of ischemic stroke via inhibiting the inflammatory response and oxidative stress, regulating astrocyte function, promoting the differentiation of endogenous oligodendrocyte precursor cells (OPCs) to mature oligodendrocyte. Among all of these effects, promoting the formation of mature oligodendrocyte is a crucial part of axonal regeneration and remyelination. Furthermore, numerous studies have uncovered the crosstalk between astrocytes and oligodendrocyte, microglial cells and oligodendrocyte in the axonal remyelination following ischemic stroke. The purpose of this review was to discuss the relationship among H2S, RhoA/ROCK pathway, astrocytes, and microglial cells in the axonal remyelination following ischemic stroke to reveal new strategies for preventing and treating this devastating disease.

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References

  1. Powers WJ (2020) Acute ischemic stroke. N Engl J Med 383(3):252–260. https://doi.org/10.1056/NEJMcp1917030

    Article  PubMed  Google Scholar 

  2. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR et al (2020) Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation 141(9):e139–e596. https://doi.org/10.1161/CIR.0000000000000757

    Article  PubMed  Google Scholar 

  3. Gallacher KI, Jani BD, Hanlon P, Nicholl BI, Mair FS (2019) Multimorbidity in stroke. Stroke 50(7):1919–1926. https://doi.org/10.1161/STROKEAHA.118.020376

    Article  PubMed  Google Scholar 

  4. Caprio FZ, Sorond FA (2019) Cerebrovascular disease: primary and secondary stroke prevention. Med Clin North Am 103(2):295–308. https://doi.org/10.1016/j.mcna.2018.10.001

    Article  PubMed  Google Scholar 

  5. Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67(2):181–198. https://doi.org/10.1016/j.neuron.2010.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4(5):399–415. https://doi.org/10.1038/nrn1106

    Article  CAS  PubMed  Google Scholar 

  7. Garcia-Martin G, Alcover-Sanchez B, Wandosell F, Cubelos B (2022) Pathways involved in remyelination after cerebral ischemia. Curr Neuropharmacol 20(4):751–765. https://doi.org/10.2174/1570159X19666210610093658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mattos DJS, Rutlin J, Hong X, Zinn K, Shimony JS, Carter AR (2021) White matter integrity of contralesional and transcallosal tracts may predict response to upper limb task-specific training in chronic stroke. Neuroimage Clin 31:102710. https://doi.org/10.1016/j.nicl.2021.102710

    Article  PubMed  PubMed Central  Google Scholar 

  9. Pierpaoli C, Barnett A, Pajevic S, Chen R, Penix LR, Virta A, Basser P (2001) Water diffusion changes in Wallerian degeneration and their dependence on white matter architecture. Neuroimage 13(6 Pt 1):1174–1185. https://doi.org/10.1006/nimg.2001.0765

    Article  CAS  PubMed  Google Scholar 

  10. Jindahra P, Petrie A, Plant GT (2012) The time course of retrograde trans-synaptic degeneration following occipital lobe damage in humans. Brain 135(Pt 2):534–541. https://doi.org/10.1093/brain/awr324

    Article  PubMed  Google Scholar 

  11. Marin MA, Carmichael ST (2019) Mechanisms of demyelination and remyelination in the young and aged brain following white matter stroke. Neurobiol Dis 126:5–12. https://doi.org/10.1016/j.nbd.2018.07.023

    Article  CAS  PubMed  Google Scholar 

  12. Thomalla G, Glauche V, Koch MA, Beaulieu C, Weiller C, Rother J (2004) Diffusion tensor imaging detects early Wallerian degeneration of the pyramidal tract after ischemic stroke. Neuroimage 22(4):1767–1774. https://doi.org/10.1016/j.neuroimage.2004.03.041

    Article  PubMed  Google Scholar 

  13. Tobin MK, Stephen TKL, Lopez KL, Pergande MR, Bartholomew AM, Cologna SM, Lazarov O (2020) Activated mesenchymal stem cells induce recovery following stroke via regulation of inflammation and oligodendrogenesis. J Am Heart Assoc 9(7):e013583. https://doi.org/10.1161/JAHA.119.013583

    Article  PubMed  PubMed Central  Google Scholar 

  14. Blasi F, Wei Y, Balkaya M, Tikka S, Mandeville JB, Waeber C, Ayata C, Moskowitz MA (2014) Recognition memory impairments after subcortical white matter stroke in mice. Stroke 45(5):1468–1473. https://doi.org/10.1161/STROKEAHA.114.005324

    Article  PubMed  Google Scholar 

  15. Symons M, Settleman J (2000) Rho family GTPases: more than simple switches. Trends Cell Biol 10(10):415–419. https://doi.org/10.1016/s0962-8924(00)01832-8

    Article  CAS  PubMed  Google Scholar 

  16. Wen JY, Gao SS, Chen FL, Chen S, Wang M, Chen ZW (2019) Role of CSE-Produced H2S on cerebrovascular relaxation via RhoA-ROCK inhibition and cerebral ischemia-reperfusion injury in mice. ACS Chem Neurosci 10(3):1565–1574. https://doi.org/10.1021/acschemneuro.8b00533

    Article  CAS  PubMed  Google Scholar 

  17. Chen H, Firestein BL (2007) RhoA regulates dendrite branching in hippocampal neurons by decreasing cypin protein levels. J Neurosci 27(31):8378–8386. https://doi.org/10.1523/JNEUROSCI.0872-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang Y, Li K, Wang X, Ding Y, Ren Z, Fang J, Sun T, Guo Y et al (2021) CSE-derived H2S inhibits reactive astrocytes proliferation and promotes neural functional recovery after cerebral ischemia/reperfusion injury in mice via inhibition of RhoA/ROCK2 pathway. ACS Chem Neurosci 12(14):2580–2590. https://doi.org/10.1021/acschemneuro.0c00674

    Article  CAS  PubMed  Google Scholar 

  19. Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E, Fasudil Ischemic Stroke Study G (2005) Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J Neurol Sci 238(1–2):31–39. https://doi.org/10.1016/j.jns.2005.06.003

    Article  CAS  PubMed  Google Scholar 

  20. Li X, Zhang KY, Zhang P, Chen LX, Wang L, Xie M, Wang CY, Tang XQ (2014) Hydrogen sulfide inhibits formaldehyde-induced endoplasmic reticulum stress in PC12 cells by upregulation of SIRT-1. PLoS One 9(2):e89856. https://doi.org/10.1371/journal.pone.0089856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Qu K, Lee SW, Bian JS, Low CM, Wong PT (2008) Hydrogen sulfide: neurochemistry and neurobiology. Neurochem Int 52(1–2):155–165. https://doi.org/10.1016/j.neuint.2007.05.016

    Article  CAS  PubMed  Google Scholar 

  22. Wang R (2002) Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16(13):1792–1798. https://doi.org/10.1096/fj.02-0211hyp

    Article  CAS  PubMed  Google Scholar 

  23. Von Bartheld CS, Bahney J, Herculano-Houzel S (2016) The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comparative Neurol 524(18):3865–3895. https://doi.org/10.1002/cne.24040

    Article  Google Scholar 

  24. Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B (2008) Neocortical glial cell numbers in human brains. Neurobiol Aging 29(11):1754–1762. https://doi.org/10.1016/j.neurobiolaging.2007.04.013

    Article  CAS  PubMed  Google Scholar 

  25. Pekny M, Wilhelmsson U, Tatlisumak T, Pekna M (2019) Astrocyte activation and reactive gliosis-A new target in stroke? Neurosci Lett 689:45–55. https://doi.org/10.1016/j.neulet.2018.07.021

    Article  CAS  PubMed  Google Scholar 

  26. Mifsud G, Zammit C, Muscat R, Di Giovanni G, Valentino M (2014) Oligodendrocyte pathophysiology and treatment strategies in cerebral ischemia. CNS Neurosci Ther 20(7):603–612. https://doi.org/10.1111/cns.12263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Amantea D, Micieli G, Tassorelli C, Cuartero MI, Ballesteros I, Certo M, Moro MA, Lizasoain I et al (2015) Rational modulation of the innate immune system for neuroprotection in ischemic stroke. Front Neurosci 9:147. https://doi.org/10.3389/fnins.2015.00147

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shibahara T,Ago T,Nakamura K,Tachibana M,Yoshikawa Y,Komori M,Yamanaka K,Wakisaka Y et al (2020) Pericyte-mediated tissue repair through PDGFRbeta promotes peri-infarct astrogliosis, oligodendrogenesis, and functional recovery after acute ischemic stroke. eNeuro 7(2). https://doi.org/10.1523/ENEURO.0474-19.2020

  29. Raffaele S, Fumagalli M (2022) Dynamics of microglia activation in the ischemic brain: implications for myelin repair and functional recovery. Front Cell Neurosci 16:950819. https://doi.org/10.3389/fncel.2022.950819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Regenold WT, Phatak P, Marano CM, Gearhart L, Viens CH, Hisley KC (2007) Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression. Psychiatry Res 151(3):179–188. https://doi.org/10.1016/j.psychres.2006.12.019

    Article  CAS  PubMed  Google Scholar 

  31. Chang KJ, Redmond SA, Chan JR (2016) Remodeling myelination: implications for mechanisms of neural plasticity. Nat Neurosci 19(2):190–197. https://doi.org/10.1038/nn.4200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Saab AS, Tzvetanova ID, Nave KA (2013) The role of myelin and oligodendrocytes in axonal energy metabolism. Curr Opin Neurobiol 23(6):1065–1072. https://doi.org/10.1016/j.conb.2013.09.008

    Article  CAS  PubMed  Google Scholar 

  33. Mecha M, Yanguas-Casas N, Feliu A, Mestre L, Carrillo-Salinas F, Azcoitia I, Yong VW, Guaza C (2019) The endocannabinoid 2-AG enhances spontaneous remyelination by targeting microglia. Brain Behav Immun 77:110–126. https://doi.org/10.1016/j.bbi.2018.12.013

    Article  CAS  PubMed  Google Scholar 

  34. Jian Z, Liu R, Zhu X, Smerin D, Zhong Y, Gu L, Fang W, Xiong X (2019) The involvement and therapy target of immune cells after ischemic stroke. Front Immunol 10:2167. https://doi.org/10.3389/fimmu.2019.02167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eldahshan W, Fagan SC, Ergul A (2019) Inflammation within the neurovascular unit: focus on microglia for stroke injury and recovery. Pharmacol Res 147:104349. https://doi.org/10.1016/j.phrs.2019.104349

    Article  PubMed  PubMed Central  Google Scholar 

  36. Koch JC, Tonges L, Barski E, Michel U, Bahr M, Lingor P (2014) ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS. Cell Death Dis 5:e1225. https://doi.org/10.1038/cddis.2014.191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Khoshnam SE, Winlow W, Farzaneh M, Farbood Y, Moghaddam HF (2017) Pathogenic mechanisms following ischemic stroke. Neurol Sci 38(7):1167–1186. https://doi.org/10.1007/s10072-017-2938-1

    Article  PubMed  Google Scholar 

  38. Orellana-Urzua S, Rojas I, Libano L, Rodrigo R (2020) Pathophysiology of ischemic stroke: role of oxidative stress. Curr Pharm Des 26(34):4246–4260. https://doi.org/10.2174/1381612826666200708133912

    Article  CAS  PubMed  Google Scholar 

  39. Radak D, Katsiki N, Resanovic I, Jovanovic A, Sudar-Milovanovic E, Zafirovic S, Mousad SA, Isenovic ER (2017) Apoptosis and acute brain ischemia in ischemic stroke. Curr Vasc Pharmacol 15(2):115–122. https://doi.org/10.2174/1570161115666161104095522

    Article  CAS  PubMed  Google Scholar 

  40. Shi K, Tian DC, Li ZG, Ducruet AF, Lawton MT, Shi FD (2019) Global brain inflammation in stroke. Lancet Neurol 18(11):1058–1066. https://doi.org/10.1016/S1474-4422(19)30078-X

    Article  PubMed  Google Scholar 

  41. Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA (2019) Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation 16(1):142. https://doi.org/10.1186/s12974-019-1516-2

    Article  PubMed  PubMed Central  Google Scholar 

  42. Gomes-Leal W (2019) Why microglia kill neurons after neural disorders? The friendly fire hypothesis. Neural Regen Res 14(9):1499–1502. https://doi.org/10.4103/1673-5374.255359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miyanohara J, Kakae M, Nagayasu K, Nakagawa T, Mori Y, Arai K, Shirakawa H, Kaneko S (2018) TRPM2 channel aggravates CNS inflammation and cognitive impairment via activation of microglia in chronic cerebral hypoperfusion. J Neurosci 38(14):3520–3533. https://doi.org/10.1523/JNEUROSCI.2451-17.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kalakh S, Mouihate A (2017) Demyelination-induced inflammation attracts newly born neurons to the white matter. Mol Neurobiol 54(8):5905–5918. https://doi.org/10.1007/s12035-016-0127-5

    Article  CAS  PubMed  Google Scholar 

  45. Cunha MI,Su M,Cantuti-Castelvetri L,Muller SA,Schifferer M,Djannatian M,Alexopoulos I,Van Der Meer F et al (2020) Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis. Journal of Experimental Medicine 217(5). https://doi.org/10.1084/jem.20191390

  46. Tonges L,Koch JC,Bahr M,Lingor P (2011) ROCKing regeneration: Rho kinase inhibition as molecular target for neurorestoration. Frontiers in Molecular Neuroscience 4(39. https://doi.org/10.3389/fnmol.2011.00039

  47. Wang QM, Liao JK (2012) ROCKs as immunomodulators of stroke. Expert Opin Ther Targets 16(10):1013–1025. https://doi.org/10.1517/14728222.2012.715149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bruzzone B,De Leo P,Sticchi L,Canepa P,Rappazzo E,Anselmo M,Icardi G (2017) Diagnostic and therapeutic implications in a case of mixed hepatitis C virus (HCV) infection. Hepat Mon 17(3). https://doi.org/10.5812/hepatmon.44774

  49. Zhang Y, Miao L, Peng Q, Fan X, Song W, Yang B, Zhang P, Liu G et al (2022) Parthenolide modulates cerebral ischemia-induced microglial polarization and alleviates neuroinflammatory injury via the RhoA/ROCK pathway. Phytomedicine 105:154373. https://doi.org/10.1016/j.phymed.2022.154373

    Article  CAS  PubMed  Google Scholar 

  50. Sladojevic N, Yu B, Liao JK (2017) ROCK as a therapeutic target for ischemic stroke. Expert Rev Neurother 17(12):1167–1177. https://doi.org/10.1080/14737175.2017.1395700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fujita Y, Yamashita T (2014) Axon growth inhibition by RhoA/ROCK in the central nervous system. Front Neurosci 8:338. https://doi.org/10.3389/fnins.2014.00338

    Article  PubMed  PubMed Central  Google Scholar 

  52. Jeon BT, Jeong EA, Park SY, Son H, Shin HJ, Lee DH, Kim HJ, Kang SS et al (2013) The Rho-kinase (ROCK) inhibitor Y-27632 protects against excitotoxicity-induced neuronal death in vivo and in vitro. Neurotox Res 23(3):238–248. https://doi.org/10.1007/s12640-012-9339-2

    Article  CAS  PubMed  Google Scholar 

  53. Cen LP, Liang JJ, Chen JH, Harvey AR, Ng TK, Zhang M, Pang CP, Cui Q et al (2017) AAV-mediated transfer of RhoA shRNA and CNTF promotes retinal ganglion cell survival and axon regeneration. Neuroscience 343:472–482. https://doi.org/10.1016/j.neuroscience.2016.12.027

    Article  CAS  PubMed  Google Scholar 

  54. Liu C, Han S, Zheng J, Wang H, Li S, Li J (2022) EphA4 regulates white matter remyelination after ischemic stroke through Ephexin-1/RhoA/ROCK signaling pathway. Glia 70(10):1971–1991. https://doi.org/10.1002/glia.24232

    Article  CAS  PubMed  Google Scholar 

  55. Zheng J, Zhang T, Han S, Liu C, Liu M, Li S, Li J (2021) Activin A improves the neurological outcome after ischemic stroke in mice by promoting oligodendroglial ACVR1B-mediated white matter remyelination. Exp Neurol 337:113574. https://doi.org/10.1016/j.expneurol.2020.113574

    Article  CAS  PubMed  Google Scholar 

  56. Moyon S, Ma D, Huynh JL, Coutts DJC, Zhao C, Casaccia P, Franklin RJM (2017) Efficient Remyelination Requires DNA Methylation. eNeuro 4(2). https://doi.org/10.1523/ENEURO.0336-16.2017

  57. Fernandez-Enright F, Andrews JL, Newell KA, Pantelis C, Huang XF (2014) Novel implications of Lingo-1 and its signaling partners in schizophrenia. Transl Psychiatry 4:e348. https://doi.org/10.1038/tp.2013.121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bove RM, Green AJ (2017) Remyelinating pharmacotherapies in multiple sclerosis. Neurotherapeutics 14(4):894–904. https://doi.org/10.1007/s13311-017-0577-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mi S, Sandrock A, Miller RH (2008) LINGO-1 and its role in CNS repair. Int J Biochem Cell Biol 40(10):1971–1978. https://doi.org/10.1016/j.biocel.2008.03.018

    Article  CAS  PubMed  Google Scholar 

  60. Zhu J, Zhu Z, Ren Y, Dong Y, Li Y, Yang X (2021) LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-kappaB and JAK2/STAT3. Hum Cell 34(4):1114–1122. https://doi.org/10.1007/s13577-021-00527-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Foale S, Berry M, Logan A, Fulton D, Ahmed Z (2017) LINGO-1 and AMIGO3, potential therapeutic targets for neurological and dysmyelinating disorders? Neural Regen Res 12(8):1247–1251. https://doi.org/10.4103/1673-5374.213538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Meabon JS, De Laat R, Ieguchi K, Serbzhinsky D, Hudson MP, Huber BR, Wiley JC, Bothwell M (2016) Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling. Mol Cell Neurosci 70:1–10. https://doi.org/10.1016/j.mcn.2015.11.002

    Article  CAS  PubMed  Google Scholar 

  63. Li B, Xu Y, Quan Y, Cai Q, Le Y, Ma T, Liu Z, Wu G et al (2020) Inhibition of RhoA/ROCK pathway in the early stage of hypoxia ameliorates depression in mice via protecting myelin sheath. ACS Chem Neurosci 11(17):2705–2716. https://doi.org/10.1021/acschemneuro.0c00352

    Article  CAS  PubMed  Google Scholar 

  64. Staugaitis SM, Chang A, Trapp BD (2012) Cortical pathology in multiple sclerosis: experimental approaches to studies on the mechanisms of demyelination and remyelination. Acta Neurologica Scandinavica. Supplementum 195:97–102. https://doi.org/10.1111/ane.12041

    Article  Google Scholar 

  65. Chang A, Staugaitis SM, Dutta R, Batt CE, Easley KE, Chomyk AM, Yong VW, Fox RJ et al (2012) Cortical remyelination: a new target for repair therapies in multiple sclerosis. Ann Neurol 72(6):918–926. https://doi.org/10.1002/ana.23693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kirby L, Jin J, Cardona JG, Smith MD, Martin KA, Wang J, Strasburger H, Herbst L et al (2019) Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination. Nat Commun 10(1):3887. https://doi.org/10.1038/s41467-019-11638-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Song J, Goetz BD, Baas PW, Duncan ID (2001) Cytoskeletal reorganization during the formation of oligodendrocyte processes and branches. Mol Cell Neurosci 17(4):624–636. https://doi.org/10.1006/mcne.2001.0974

    Article  CAS  PubMed  Google Scholar 

  68. Wang H, Rusielewicz T, Tewari A, Leitman EM, Einheber S, Melendez-Vasquez CV (2012) Myosin II is a negative regulator of oligodendrocyte morphological differentiation. J Neurosci Res 90(8):1547–1556. https://doi.org/10.1002/jnr.23036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Xu S, Lu J, Shao A, Zhang JH, Zhang J (2020) Glial cells: role of the immune response in ischemic stroke. Front Immunol 11:294. https://doi.org/10.3389/fimmu.2020.00294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Li L, Harms KM, Ventura PB, Lagace DC, Eisch AJ, Cunningham LA (2010) Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic. Glia 58(13):1610–1619. https://doi.org/10.1002/glia.21033

    Article  PubMed  PubMed Central  Google Scholar 

  71. Pantoni L, Garcia JH, Gutierrez JA (1996) Cerebral white matter is highly vulnerable to ischemia. Stroke 27(9):1641–1646; discussion 1647. https://doi.org/10.1161/01.str.27.9.1641

  72. Dyck SM, Alizadeh A, Santhosh KT, Proulx EH, Wu CL, Karimi-Abdolrezaee S (2015) Chondroitin sulfate proteoglycans negatively modulate spinal cord neural precursor cells by signaling through LAR and RPTPsigma and modulation of the Rho/ROCK pathway. Stem Cells 33(8):2550–2563. https://doi.org/10.1002/stem.1979

    Article  CAS  PubMed  Google Scholar 

  73. Dyck S, Kataria H, Akbari-Kelachayeh K, Silver J, Karimi-Abdolrezaee S (2019) LAR and PTPsigma receptors are negative regulators of oligodendrogenesis and oligodendrocyte integrity in spinal cord injury. Glia 67(1):125–145. https://doi.org/10.1002/glia.23533

    Article  PubMed  Google Scholar 

  74. Pedraza CE, Taylor C, Pereira A, Seng M, Tham CS, Izrael M, Webb M (2014) Induction of oligodendrocyte differentiation and in vitro myelination by inhibition of rho-associated kinase. ASN Neuro 6(4). https://doi.org/10.1177/1759091414538134

  75. Ding Y, Liu B, Zhang Y, Fang F, Li X, Wang S, Wen J (2022) Hydrogen sulphide protects mice against the mutual aggravation of cerebral ischaemia/reperfusion injury and colitis. Eur J Pharmacol 914:174682. https://doi.org/10.1016/j.ejphar.2021.174682

    Article  CAS  PubMed  Google Scholar 

  76. Kimura Y, Shibuya N, Kimura H (2019) Sulfite protects neurons from oxidative stress. Br J Pharmacol 176(4):571–582. https://doi.org/10.1111/bph.14373

    Article  CAS  PubMed  Google Scholar 

  77. Jiang WW, Huang BS, Han Y, Deng LH, Wu LX (2017) Sodium hydrosulfide attenuates cerebral ischemia/reperfusion injury by suppressing overactivated autophagy in rats. FEBS Open Bio 7(11):1686–1695. https://doi.org/10.1002/2211-5463.12301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhou X, Cao Y, Ao G, Hu L, Liu H, Wu J, Wang X, Jin M et al (2014) CaMKKbeta-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation. Antioxid Redox Signal 21(12):1741–1758. https://doi.org/10.1089/ars.2013.5587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hu LF, Wong PT, Moore PK, Bian JS (2007) Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia. J Neurochem 100(4):1121–1128. https://doi.org/10.1111/j.1471-4159.2006.04283.x

    Article  CAS  PubMed  Google Scholar 

  80. Chen Y, Wen J, Chen Z (2021) H2S protects hippocampal neurons against hypoxia-reoxygenation injury by promoting RhoA phosphorylation at Ser188. Cell Death Discov 7(1):132. https://doi.org/10.1038/s41420-021-00514-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tarui T, Fukami K, Nagasawa K, Yoshida S, Sekiguchi F, Kawabata A (2010) Involvement of Src kinase in T-type calcium channel-dependent neuronal differentiation of NG108-15 cells by hydrogen sulfide. J Neurochem 114(2):512–519. https://doi.org/10.1111/j.1471-4159.2010.06774.x

    Article  CAS  PubMed  Google Scholar 

  82. Wang Z, Liu DX, Wang FW, Zhang Q, Du ZX, Zhan JM, Yuan QH, Ling EA et al (2013) L-Cysteine promotes the proliferation and differentiation of neural stem cells via the CBS/H(2)S pathway. Neuroscience 237:106–117. https://doi.org/10.1016/j.neuroscience.2012.12.057

    Article  CAS  PubMed  Google Scholar 

  83. Liu H, Wang Y, Xiao Y, Hua Z, Cheng J, Jia J (2016) Hydrogen sulfide attenuates tissue plasminogen activator-induced cerebral hemorrhage following experimental stroke. Transl Stroke Res 7(3):209–219. https://doi.org/10.1007/s12975-016-0459-5

    Article  CAS  PubMed  Google Scholar 

  84. Wei SW, Zou MM, Huan J, Li D, Zhang PF, Lu MH, Xiong J, Ma YX (2022) Role of the hydrogen sulfide-releasing donor ADT-OH in the regulation of mammal neural precursor cells. J Cell Physiol 237(7):2877–2887. https://doi.org/10.1002/jcp.30726

    Article  CAS  PubMed  Google Scholar 

  85. Anrather J, Iadecola C (2016) Inflammation and stroke: an overview. Neurotherapeutics 13(4):661–670. https://doi.org/10.1007/s13311-016-0483-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ben Haim L, Rowitch DH (2017) Functional diversity of astrocytes in neural circuit regulation. Nat Rev Neurosci 18(1):31–41. https://doi.org/10.1038/nrn.2016.159

    Article  CAS  PubMed  Google Scholar 

  87. Hara M, Kobayakawa K, Ohkawa Y, Kumamaru H, Yokota K, Saito T, Kijima K, Yoshizaki S et al (2017) Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. Nat Med 23(7):818–828. https://doi.org/10.1038/nm.4354

    Article  CAS  PubMed  Google Scholar 

  88. Mukherjee N, Nandi S, Garg S, Ghosh S, Ghosh S, Samat R, Ghosh S (2020) Targeting chondroitin sulfate proteoglycans: an emerging therapeutic strategy to treat CNS injury. ACS Chem Neurosci 11(3):231–232. https://doi.org/10.1021/acschemneuro.0c00004

    Article  CAS  PubMed  Google Scholar 

  89. Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015) Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 11(1):56–64. https://doi.org/10.1038/nrneurol.2014.207

    Article  PubMed  Google Scholar 

  90. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487. https://doi.org/10.1038/nature21029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jiang T, Luo J, Pan X, Zheng H, Yang H, Zhang L, Hu X (2021) Physical exercise modulates the astrocytes polarization, promotes myelin debris clearance and remyelination in chronic cerebral hypoperfusion rats. Life Sci 278:119526. https://doi.org/10.1016/j.lfs.2021.119526

    Article  CAS  PubMed  Google Scholar 

  92. Jia J, Yang L, Chen Y, Zheng L, Chen Y, Xu Y, Zhang M (2021) The role of microglial phagocytosis in ischemic stroke. Frontiers in Immunology 12:790201. https://doi.org/10.3389/fimmu.2021.790201

    Article  CAS  PubMed  Google Scholar 

  93. De Waard DM, Bugiani M (2020) Astrocyte-oligodendrocyte-microglia crosstalk in astrocytopathies. Front Cell Neurosci 14:608073. https://doi.org/10.3389/fncel.2020.608073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Badimon A, Strasburger HJ, Ayata P, Chen X, Nair A, Ikegami A, Hwang P, Chan AT et al (2020) Negative feedback control of neuronal activity by microglia. Nature 586(7829):417–423. https://doi.org/10.1038/s41586-020-2777-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Li T, Liu T, Chen X, Li L, Feng M, Zhang Y, Wan L, Zhang C et al (2020) Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain. J Neuroinflammation 17(1):211. https://doi.org/10.1186/s12974-020-01891-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shindo A, Liang AC, Maki T, Miyamoto N, Tomimoto H, Lo EH, Arai K (2016) Subcortical ischemic vascular disease: roles of oligodendrocyte function in experimental models of subcortical white-matter injury. J Cereb Blood Flow Metab 36(1):187–198. https://doi.org/10.1038/jcbfm.2015.80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Miyamoto N, Magami S, Inaba T, Ueno Y, Hira K, Kijima C, Nakajima S, Yamashiro K et al (2020) The effects of A1/A2 astrocytes on oligodendrocyte linage cells against white matter injury under prolonged cerebral hypoperfusion. Glia 68(9):1910–1924. https://doi.org/10.1002/glia.23814

    Article  PubMed  Google Scholar 

  98. Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570(7761):332–337. https://doi.org/10.1038/s41586-019-1195-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Escartin C, Galea E, Lakatos A, O’callaghan JP, Petzold GC, Serrano-Pozo A, Steinhauser C, Volterra A et al (2021) Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci 24(3):312–325. https://doi.org/10.1038/s41593-020-00783-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lambertsen KL, Finsen B, Clausen BH (2019) Post-stroke inflammation-target or tool for therapy? Acta Neuropathol 137(5):693–714. https://doi.org/10.1007/s00401-018-1930-z

    Article  PubMed  Google Scholar 

  101. Clausen BH, Lambertsen KL, Babcock AA, Holm TH, Dagnaes-Hansen F, Finsen B (2008) Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J Neuroinflammation 5:46. https://doi.org/10.1186/1742-2094-5-46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tsuyama J, Nakamura A, Ooboshi H, Yoshimura A, Shichita T (2018) Pivotal role of innate myeloid cells in cerebral post-ischemic sterile inflammation. Seminars in Immunopathology 40(6):523–538. https://doi.org/10.1007/s00281-018-0707-8

    Article  CAS  PubMed  Google Scholar 

  103. Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19(8):987–991. https://doi.org/10.1038/nn.4338

    Article  CAS  PubMed  Google Scholar 

  104. Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43(11):3063–3070. https://doi.org/10.1161/STROKEAHA.112.659656

    Article  CAS  PubMed  Google Scholar 

  105. Ma Y, Wang J, Wang Y, Yang GY (2017) The biphasic function of microglia in ischemic stroke. Prog Neurobiol 157:247–272. https://doi.org/10.1016/j.pneurobio.2016.01.005

    Article  CAS  PubMed  Google Scholar 

  106. Bain JM, Moore L, Ren Z, Simonishvili S, Levison SW (2013) Vascular endothelial growth factors A and C are induced in the SVZ following neonatal hypoxia-ischemia and exert different effects on neonatal glial progenitors. Transl Stroke Res 4(2):158–170. https://doi.org/10.1007/s12975-012-0213-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gelosa P, Bonfanti E, Castiglioni L, Delgado-Garcia JM, Gruart A, Fontana L, Gotti M, Tremoli E et al (2019) Improvement of fiber connectivity and functional recovery after stroke by montelukast, an available and safe anti-asthmatic drug. Pharmacol Res 142:223–236. https://doi.org/10.1016/j.phrs.2019.02.025

    Article  CAS  PubMed  Google Scholar 

  108. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, Van Wijngaarden P, Wagers AJ et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16(9):1211–1218. https://doi.org/10.1038/nn.3469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hagemeyer N, Hanft KM, Akriditou MA, Unger N, Park ES, Stanley ER, Staszewski O, Dimou L et al (2017) Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol 134(3):441–458. https://doi.org/10.1007/s00401-017-1747-1

    Article  PubMed  PubMed Central  Google Scholar 

  110. Bernhart E, Kollroser M, Rechberger G, Reicher H, Heinemann A, Schratl P, Hallstrom S, Wintersperger A et al (2010) Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture. Proteomics 10(1):141–158. https://doi.org/10.1002/pmic.200900195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Barcia C, Ros CM, Annese V, Carrillo-De Sauvage MA, Ros-Bernal F, Gomez A, Yuste JE, Campuzano CM et al (2012) ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo. Sci Rep 2:809. https://doi.org/10.1038/srep00809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Paolicelli RC, Sierra A, Stevens B, Tremblay ME, Aguzzi A, Ajami B, Amit I, Audinat E et al (2022) Microglia states and nomenclature: a field at its crossroads. Neuron 110(21):3458–3483. https://doi.org/10.1016/j.neuron.2022.10.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The authors acknowledge operating grant support from the Natural Science Foundation of Colleges and Universities in Anhui Province in 2020 (No. KJ2020A0976 and KJ2020A0144).

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  1. Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China

    Jiyue Wen

  2. Medical Branch, Hefei Technology College, Hefei, China

    Weizhuo Lu

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Lu, W., Wen, J. H2S-RhoA/ROCK Pathway and Glial Cells in Axonal Remyelination After Ischemic Stroke. Mol Neurobiol 60, 5493–5504 (2023). https://doi.org/10.1007/s12035-023-03422-8

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