Advertisement

Therapeutic potentials of the Rho kinase inhibitor Fasudil in experimental autoimmune encephalomyelitis and the related mechanisms

  • Yuqing Yan
  • Jiezhong Yu
  • Ye Gao
  • Gajendra Kumar
  • Minfang Guo
  • Yijin Zhao
  • Qingli Fang
  • Huiyu Zhang
  • Jingwen Yu
  • Yuqiang JiangEmail author
  • Han-Ting ZhangEmail author
  • Cun-Gen MaEmail author
Review Article
  • 68 Downloads

Abstract

Multiple sclerosis (MS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurodegenerative diseases of central nervous system (CNS) disorders are serious human health problems. Rho-kinase (ROCK) is emerging as a potentially important therapeutic target relevant to inflammatory neurodegeneration diseases. This is supported by studies showing the beneficial effects of fasudil, a ROCK inhibitor, in inflammatory neurodegeneration diseases. MS is an autoimmune disease resulting from inflammation and demyelination in the white matter of the CNS. It has been postulated that activation of Rho/ROCK causes neuropathological changes accompanied with related clinical symptoms, which are improved by treatment with ROCK inhibitors. Therefore, inhibition of abnormal activation of the Rho/ROCK signaling pathway appears to be a new mechanism for treating CNS diseases. In this review, we extensively discussed the role of ROCK inhibitors, summarized the efficacy of fasudil in the MS conventional animal model of experimental autoimmune encephalomyelitis (EAE), both in vivo and in vitro, and highlighted the mechanism involved. Overall, the findings collected in this review support the role of the ROCK signaling pathway in neurodegenerative diseases. Hence, ROCK inhibitors such as fasudil can be novel, and efficacious treatment for inflammatory neurodegenerative diseases.

Keywords

Rho-kinase Fasudil Experimental autoimmune encephalomyelitis Microglia/macrophages Multiple sclerosis 

Notes

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81272163 to CGM, 81471412 to JZY and 81371414 to CGM), the Department of Science and Technology, Shanxi Province of China (2016ZD0505 to JZY, HQXTCXZX2016-022 to JWY), Datong Municipal Science and Technology Bureau (No.2017134 to YQY), PhD initiation Grant of Datong University (No. 2016-B-01 to YQY, 2017-B-23 to Y G), and Open project of State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China(2018-MDB-KF-07 to YQY).

Author contribution

YY and JY outlined and drafted the manuscript. CGM, HTZ and YJ helped coordinate and draft the manuscript. YG, MG, GK, YZ, QF, HZ, JY were involved in the revisions. HTZ and CGM revised and finalized the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests. None of the authors has any potential financial conflict of interest related to this manuscript.

References

  1. Aihara M, Dobashi K, Iizuka K, Nakazawa T, Mori M (2003) Comparison of effects of Y-27632 and isoproterenol on release of cytokines from human peripheral T cells. Int Immunopharmacol 3(12):1619–1625PubMedCrossRefGoogle Scholar
  2. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K (1996 Aug 23) Phosphorylation and activation of myosin by rho-associated kinase (Rho-kinase). J Biol Chem 271(34):20246–20249PubMedCrossRefGoogle Scholar
  3. Bando Y, Hagiwara Y, Suzuki Y, Yoshida K, Aburakawa Y, Kimura T, Murakami C, Ono M, Tanaka T, Jiang YP, Mitrovi B, Bochimoto H, Yahara O, Yoshida S (2018) Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis. Glia 66(2):359–378PubMedCrossRefGoogle Scholar
  4. Biswas PS, Gupta S, Chang E, Song L, Stirzaker RA, Liao JK, Bhagat G, Pernis AB (2010) Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest 120(9):3280–3295 Pubmed Central PMCID: 2929726PubMedPubMedCentralCrossRefGoogle Scholar
  5. Borrajo A, Rodriguez-Perez AI, Diaz-Ruiz C, Guerra MJ, Labandeira-Garcia JL (2014) Microglial TNF-alpha mediates enhancement of dopaminergic degeneration by brain angiotensin. Glia 62(1):145–157PubMedCrossRefGoogle Scholar
  6. Chen C, Li YH, Zhang Q, Yu JZ, Zhao YF, Ma CG, Xiao BG (2014) Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis. Acta Pharmacol Sin 35(11):1428–1438 Pubmed Central PMCID: 4220072PubMedPubMedCentralCrossRefGoogle Scholar
  7. Chen C, Yu JZ, Zhang Q, Zhao YF, Liu CY, Li YH, Yang WF, Ma CG, Xiao BG (2015) Role of Rho kinase and Fasudil on synaptic plasticity in multiple sclerosis. NeuroMolecular Med 17(4):454–465PubMedCrossRefGoogle Scholar
  8. Chen J, Sun Z, Jin M, Tu Y, Wang S, Yang X, Chen Q, Zhang X, Han Y, Pi R (2017) Inhibition of AGEs/RAGE/rho/ROCK pathway suppresses non-specific neuroinflammation by regulating BV2 microglial M1/M2 polarization through the NF-kappaB pathway. J Neuroimmunol 305:108–114PubMedCrossRefGoogle Scholar
  9. Chiba Y, Kuroda S, Shichinohe H, Hokari M, Osanai T, Maruichi K, Yano S, Hida K, Iwasaki Y (2010) Synergistic effects of bone marrow stromal cells and a Rho kinase (ROCK) inhibitor, fasudil on axon regeneration in rat spinal cord injury. Neuropathology 30(3):241–250PubMedCrossRefGoogle Scholar
  10. Chong CM, Ai N, Lee SM (2017) ROCK in CNS: different roles of isoforms and therapeutic target for neurodegenerative disorders. Curr Drug Targets 18(4):455–462PubMedCrossRefGoogle Scholar
  11. Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9(11):839–855PubMedCrossRefGoogle Scholar
  12. Fujii M, Duris K, Altay O, Soejima Y, Sherchan P, Zhang JH (2012) Inhibition of Rho kinase by hydroxyfasudil attenuates brain edema after subarachnoid hemorrhage in rats. Neurochem Int 60(3):327–333 Pubmed Central PMCID: 3288616PubMedCrossRefGoogle Scholar
  13. Fukata Y, Oshiro N, Kinoshita N, Kawano Y, Matsuoka Y, Bennett V, Matsuura Y, Kaibuchi K (1999) Phosphorylation of adducin by Rho-kinase plays a crucial role in cell motility. J Cell Biol 145(2):347–361 Pubmed Central PMCID: 2133101PubMedPubMedCentralCrossRefGoogle Scholar
  14. Gao S, Zhou J, Liu N, Wang L, Gao Q, Wu Y, Zhao Q, Liu P, Wang S, Liu Y, Guo N, Shen Y, Wu Y, Yuan Z (2015) Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13. J Mol Cell Cardiol 85:131–139PubMedCrossRefGoogle Scholar
  15. Garcia-Rojo G, Fresno C, Vilches N, Diaz-Veliz G, Mora S, Aguayo F et al (2017) The ROCK inhibitor Fasudil prevents chronic restraint stress-induced depressive-like behaviors and dendritic spine loss in rat hippocampus. Int J Neuropsychopharmacol 20(4):336–345 Pubmed Central PMCID: 5409106PubMedGoogle Scholar
  16. Ghosh M, Xu Y, Pearse DD (2016) Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines. J Neuroinflammation 13:9 Pubmed Central PMCID: 4711034PubMedPubMedCentralCrossRefGoogle Scholar
  17. Guo MF, Meng J, Li YH, Yu JZ, Liu CY, Feng L, Yang WF, Li JL, Feng QJ, Xiao BG, Ma CG (2014) The inhibition of Rho kinase blocks cell migration and accumulation possibly by challenging inflammatory cytokines and chemokines on astrocytes. J Neurol Sci 343(1–2):69–75PubMedCrossRefGoogle Scholar
  18. Hashimoto R, Nakamura Y, Kosako H, Amano M, Kaibuchi K, Inagaki M, Takeda M (1999) Distribution of Rho-kinase in the bovine brain. Biochem Biophys Res Commun 263(2):575–579PubMedCrossRefGoogle Scholar
  19. Heasman SJ, Ridley AJ (2010) Multiple roles for RhoA during T cell transendothelial migration. Small GTPases 1(3):174–179 Pubmed Central PMCID: 3116607PubMedPubMedCentralCrossRefGoogle Scholar
  20. Hensel N, Rademacher S, Claus P (2015) Chatting with the neighbors: crosstalk between rho-kinase (ROCK) and other signaling pathways for treatment of neurological disorders. Front Neurosci 9:198 Pubmed Central PMCID: 4451340PubMedPubMedCentralCrossRefGoogle Scholar
  21. Higashi Y, Aratake T, Shimizu S, Shimizu T, Nakamura K, Tsuda M, Yawata T, Ueba T, Saito M (2017) Influence of extracellular zinc on M1 microglial activation. Sci Rep 7:43778 Pubmed Central PMCID: 5327400PubMedPubMedCentralCrossRefGoogle Scholar
  22. Hou SW, Liu CY, Li YH, Yu JZ, Feng L, Liu YT, Guo MF, Xie Y, Meng J, Zhang HF, Xiao BG, Ma CG (2012) Fasudil ameliorates disease progression in experimental autoimmune encephalomyelitis, acting possibly through antiinflammatory effect. CNS Neurosci Ther 18(11):909–917PubMedCrossRefGoogle Scholar
  23. Huang XN, Fu J, Wang WZ (2011) The effects of fasudil on the permeability of the rat blood-brain barrier and blood-spinal cord barrier following experimental autoimmune encephalomyelitis. J Neuroimmunol 239(1–2):61–67PubMedCrossRefGoogle Scholar
  24. Julian L, Olson MF (2014) Rho-associated coiled-coil containing kinases (ROCK): structure, regulation, and functions. Small GTPases 5:e29846 Pubmed Central PMCID: 4114931PubMedPubMedCentralCrossRefGoogle Scholar
  25. Kesherwani V, Tarang S, Barnes R, Agrawal SK (2014) Fasudil reduces GFAP expression after hypoxic injury. Neurosci Lett 576:45–50PubMedCrossRefGoogle Scholar
  26. Kim JH, Hossain FM, Patil AM, Choi JY, Kim SB, Uyangaa E et al (2016) Ablation of CD11c(hi) dendritic cells exacerbates Japanese encephalitis by regulating blood-brain barrier permeability and altering tight junction/adhesion molecules. Comp Immunol Microbiol Infect Dis 48:22–32PubMedCrossRefGoogle Scholar
  27. Kubo T, Yamaguchi A, Iwata N, Yamashita T (2008) The therapeutic effects of Rho-ROCK inhibitors on CNS disorders. Ther Clin Risk Manag 4(3):605–615 Pubmed Central PMCID: 2500253PubMedPubMedCentralCrossRefGoogle Scholar
  28. Kushiyama T, Oda T, Yamamoto K, Higashi K, Watanabe A, Takechi H, Uchida T, Oshima N, Sakurai Y, Miura S, Kumagai H (2013) Protective effects of Rho kinase inhibitor fasudil on rats with chronic kidney disease. Am J Physiol Ren Physiol 304(11):F1325–F1334CrossRefGoogle Scholar
  29. Lau CL, O'Shea RD, Broberg BV, Bischof L, Beart PM (2011 Jun) The Rho kinase inhibitor Fasudil up-regulates astrocytic glutamate transport subsequent to actin remodelling in murine cultured astrocytes. Br J Pharmacol 163(3):533–545 Pubmed Central PMCID: 3101616Google Scholar
  30. Lau CL, Perreau VM, Chen MJ, Cate HS, Merlo D, Cheung NS, O'Shea RD, Beart PM (2012) Transcriptomic profiling of astrocytes treated with the rho kinase inhibitor fasudil reveals cytoskeletal and pro-survival responses. J Cell Physiol 227(3):1199–1211PubMedCrossRefGoogle Scholar
  31. Li YH, Liu CY, Zhang PJ, Yu JZ, Ji N, Yan YY et al (2012) Effect of Fasudil on miroglia and astrocytes in experimental autoimmune encephalomyelitis mice. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 28(12):1242–1245PubMedGoogle Scholar
  32. Li Y, Yang X, Zhang H, Yu J, Liu C, Feng L et al (2014) Inhibition of Fasudil on lipopolysaccharide-induced TNF-alpha and IL-1beta expressions through TLR4 pathway in murine BV-2 cells in vitro. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 30(1):11–14PubMedGoogle Scholar
  33. Li YH, Xie C, Zhang Y, Li X, Zhang HF, Wang Q, Chai Z, Xiao BG, Thome R, Zhang GX, Ma CG (2017) FSD-C10, a Fasudil derivative, promotes neuroregeneration through indirect and direct mechanisms. Sci Rep 7:41227 Pubmed Central PMCID: 5255566PubMedPubMedCentralCrossRefGoogle Scholar
  34. Lisi L, Ciotti GM, Braun D, Kalinin S, Curro D, Dello Russo C et al (2017) Expression of iNOS, CD163 and ARG-1 taken as M1 and M2 markers of microglial polarization in human glioblastoma and the surrounding normal parenchyma. Neurosci Lett 645:106–112PubMedCrossRefGoogle Scholar
  35. Liu K, Li Z, Wu T, Ding S (2011) Role of rho kinase in microvascular damage following cerebral ischemia reperfusion in rats. Int J Mol Sci 12(2):1222–1231 Pubmed Central PMCID: 3083701PubMedPubMedCentralCrossRefGoogle Scholar
  36. Liu C, Li Y, Yu J, Feng L, Hou S, Liu Y, Guo M, Xie Y, Meng J, Zhang H, Xiao B, Ma C (2013) Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil. PLoS One 8(2):e54841 Pubmed Central PMCID: 3572131PubMedPubMedCentralCrossRefGoogle Scholar
  37. Liu H, Chen X, Han Y, Li C, Chen P, Su S et al (2014) Rho kinase inhibition by fasudil suppresses lipopolysaccharide-induced apoptosis of rat pulmonary microvascular endothelial cells via JNK and p38 MAPK pathway. Biomedicine & pharmacotherapy = Biomedecine & Pharmacotherapie 68(3):267–275CrossRefGoogle Scholar
  38. Liu C, Guo S, Zhang N, Yu J, Xiao B, Ma C (2016) Immunoregulative effect of Fasudil on encephalomyelitic T cells in experimental autoimmune encephalomyelitis mice. Zhong Nan Da Xue Xue Bao Yi Xue Ban 41(3):225–232PubMedGoogle Scholar
  39. Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J 15(9):2208–2216 Pubmed Central PMCID: 450144PubMedPubMedCentralCrossRefGoogle Scholar
  40. McRae M, LaFratta LM, Nguyen BM, Paris JJ, Hauser KF, Conway DE (2018) Characterization of cell-cell junction changes associated with the formation of a strong endothelial barrier. Tissue Barriers 6(1):e1405774PubMedCrossRefGoogle Scholar
  41. Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S (1996 Aug 26) ROCK-I and ROCK-II, two isoforms of rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 392(2):189–193PubMedCrossRefGoogle Scholar
  42. Niego B, Freeman R, Puschmann TB, Turnley AM, Medcalf RL (2012) t-PA-specific modulation of a human blood-brain barrier model involves plasmin-mediated activation of the Rho kinase pathway in astrocytes. Blood 119(20):4752–4761PubMedCrossRefGoogle Scholar
  43. Niego B, Lee N, Larsson P, De Silva TM, Au AE, McCutcheon F et al (2017) Selective inhibition of brain endothelial Rho-kinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin. PLoS One 12(5):e0177332 Pubmed Central PMCID: 5433693PubMedPubMedCentralCrossRefGoogle Scholar
  44. O'Shea RD, Lau CL, Zulaziz N, Maclean FL, Nisbet DR, Horne MK et al (2015) Transcriptomic analysis and 3D bioengineering of astrocytes indicate ROCK inhibition produces cytotrophic astrogliosis. Front Neurosci 9:50 Pubmed Central PMCID: 4335181PubMedPubMedCentralCrossRefGoogle Scholar
  45. Paintlia AS, Paintlia MK, Singh AK, Singh I (2013) Modulation of Rho-Rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR-alpha-dependent mechanism. Glia 61(9):1500–1517 Pubmed Central PMCID: 3919553PubMedPubMedCentralCrossRefGoogle Scholar
  46. Pernis AB, Ricker E, Weng CH, Rozo C, Yi W (2016) Rho kinases in autoimmune diseases. Annu Rev Med 67:355–374PubMedCrossRefGoogle Scholar
  47. Ricker E, Chowdhury L, Yi W, Pernis AB (2016) The RhoA-ROCK pathway in the regulation of T and B cell responses. F1000Research 5 Pubmed Central PMCID: 5022701Google Scholar
  48. Riento K, Ridley AJ (2003) Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4(6):446–456Google Scholar
  49. Schinzari F, Tesauro M, Rovella V, Di Daniele N, Gentileschi P, Mores N et al (2012) Rho-kinase inhibition improves vasodilator responsiveness during hyperinsulinemia in the metabolic syndrome. Am J Physiol Endocrinol Metab 303(6):E806–E811 Pubmed Central PMCID: 3468433PubMedPubMedCentralCrossRefGoogle Scholar
  50. Sellers KJ, Elliott C, Jackson J, Ghosh A, Ribe E, Rojo AI, Jarosz-Griffiths HH, Watson IA, Xia W, Semenov M, Morin P, Hooper NM, Porter R, Preston J, al-Shawi R, Baillie G, Lovestone S, Cuadrado A, Harte M, Simons P, Srivastava DP, Killick R (2018) Amyloid beta synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. Alzheimer’s & Dementia 14(3):306–317.CrossRefGoogle Scholar
  51. Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA et al (2011) TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease. J Neuroinflammation 8:92 Pubmed Central PMCID: 3169468PubMedPubMedCentralCrossRefGoogle Scholar
  52. Tharaux PL, Bukoski RC, Rocha PN, Crowley SD, Ruiz P, Nataraj C et al (2003) Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells. J Immunol 171(1):96–105PubMedCrossRefGoogle Scholar
  53. Thumkeo D, Watanabe S, Narumiya S (2013 Oct-Nov) Physiological roles of Rho and Rho effectors in mammals. Eur J Cell Biol 92(10–11):303–315PubMedCrossRefGoogle Scholar
  54. Vicente-Manzanares M, Cabrero JR, Rey M, Perez-Martinez M, Ursa A, Itoh K, Sanchez-Madrid F (2002) A role for the Rho-p160 Rho coiled-coil kinase axis in the chemokine stromal cell-derived factor-1alpha-induced lymphocyte actomyosin and microtubular organization and chemotaxis. J Immunol 168(1):400–410PubMedCrossRefGoogle Scholar
  55. Wu J, Li J, Hu H, Liu P, Fang Y, Wu D (2012) Rho-kinase inhibitor, fasudil, prevents neuronal apoptosis via the Akt activation and PTEN inactivation in the ischemic penumbra of rat brain. Cell Mol Neurobiol 32(7):1187–1197PubMedCrossRefGoogle Scholar
  56. Yan J, Zhou X, Guo JJ, Mao L, Wang YJ, Sun J, Sun LX, Zhang LY, Zhou XF, Liao H (2012) Nogo-66 inhibits adhesion and migration of microglia via GTPase Rho pathway in vitro. J Neurochem 120(5):721–731PubMedCrossRefGoogle Scholar
  57. Yang XW, Li YH, Zhang H, Zhao YF, Ding ZB, Yu JZ, Liu CY, Liu JC, Jiang WJ, Feng QJ, Xiao BG, Ma CG (2016) Safflower yellow regulates microglial polarization and inhibits inflammatory response in LPS-stimulated Bv2 cells. Int J Immunopathol Pharmacol 29(1):54–64 Pubmed Central PMCID: 5806736PubMedCrossRefGoogle Scholar
  58. Yu JZ, Ding J, Ma CG, Sun CH, Sun YF, Lu CZ, Xiao BG (2010) Therapeutic potential of experimental autoimmune encephalomyelitis by Fasudil, a Rho kinase inhibitor. J Neurosci Res 88(8):1664–1672PubMedGoogle Scholar
  59. Yu JW, Li YH, Song GB, Yu JZ, Liu CY, Liu JC, Zhang HF, Yang WF, Wang Q, Yan YP, Xiao BG, Ma CG (2016a) Synergistic and superimposed effect of bone marrow-derived mesenchymal stem cells combined with Fasudil in experimental autoimmune encephalomyelitis. Journal of Molecular Neuroscience: MN 60(4):486–497PubMedCrossRefGoogle Scholar
  60. Yu JZ, Chen C, Zhang Q, Zhao YF, Feng L, Zhang HF et al (2016b) Changes of synapses in experimental autoimmune encephalomyelitis by using Fasudil. Wound Repair Regen 24(2):317–327.PubMedCrossRefGoogle Scholar
  61. Yu J, Gu Q, Yan Y, Yu H, Guo M, Liu C et al (2017) Fasudil improves cognition of APP/PS1 transgenic mice via inhibiting the activation of microglia and shifting microglia phenotypes from M1 to M2. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 33(12):1585–1593PubMedGoogle Scholar
  62. Yu J, Yan Y, Gu Q, Kumar G, Yu H, Zhao Y, Liu C, Gao Y, Chai Z, Chumber J, Xiao BG, Zhang GX, Zhang HT, Jiang Y, Ma CG (2018) Fasudil in combination with bone marrow stromal cells (BMSCs) attenuates Alzheimer's disease-related changes through the regulation of the peripheral immune system. Front Aging Neurosci 10:216 PubMed PMID: 30061826; PubMed Central PMCID: PMC6054996PubMedPubMedCentralCrossRefGoogle Scholar
  63. Zhang HF, Guo MF, Meng J, Liu CY, Li YH, Yu JZ et al (2012) Effect of Fasudil on the phenotype conversion of LPS-stimulated BV-2 microglia. Xi bao yu fen zi mian yi xue za zhi = Chinese Journal of Cellular and Molecular Immunology 28(8):818–821PubMedGoogle Scholar
  64. Zhang H, Li Y, Yu J, Guo M, Meng J, Liu C, Xie Y, Feng L, Xiao B, Ma C (2013) Rho kinase inhibitor fasudil regulates microglia polarization and function. Neuroimmunomodulation 20(6):313–322PubMedCrossRefGoogle Scholar
  65. Zhang X, Zhou M, Guo Y, Song Z, Liu B (2015) 1,25-Dihydroxyvitamin D(3) promotes high glucose-induced M1 macrophage switching to M2 via the VDR-PPARgamma signaling pathway. Biomed Res Int 2015:157834 Pubmed Central PMCID: 4417570PubMedPubMedCentralGoogle Scholar
  66. Zhang H, Guo M, Zhang L, Xue H, Chai Z, Yan Y, Xing Y, Xiao B, Zhang P, Ma C (2017) Anti-inflammatory effect and mechanisms of Huangqi glycoprotein in treating experimental autoimmune encephalomyelitis. Folia Neuropathol 55(4):308–316PubMedCrossRefGoogle Scholar
  67. Zhao Y, Zhang Q, Xi J, Xiao B, Li Y, Ma C (2015) Neuroprotective effect of fasudil on inflammation through PI3K/Akt and Wnt/beta-catenin dependent pathways in a mice model of Parkinson's disease. Int J Clin Exp Pathol 8(3):2354–2364 Pubmed Central PMCID: 4440051PubMedPubMedCentralGoogle Scholar
  68. Zhao C, Su M, Wang Y, Li X, Zhang Y, Du X et al (2017) Selective modulation of K(+) channel Kv7.4 significantly affects the excitability of DRN 5-HT neurons. Front Cell Neurosci 11:405 Pubmed Central PMCID: 5735115PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yuqing Yan
    • 1
  • Jiezhong Yu
    • 1
    • 2
  • Ye Gao
    • 1
  • Gajendra Kumar
    • 3
  • Minfang Guo
    • 1
  • Yijin Zhao
    • 1
  • Qingli Fang
    • 1
  • Huiyu Zhang
    • 1
  • Jingwen Yu
    • 1
  • Yuqiang Jiang
    • 2
    Email author
  • Han-Ting Zhang
    • 1
    • 4
    Email author
  • Cun-Gen Ma
    • 1
    • 5
    Email author
  1. 1.Institute of Brain ScienceShanxi Datong UniversityDatongChina
  2. 2.State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
  3. 3.Department of Biomedical SciencesCity University of Hong KongTat Chee AvenueHong Kong
  4. 4.Departments of Behavioral Medicine & Psychiatry, Physiology & Pharmacology, and Neuroscience, the Rockefeller Neurosciences InstituteWest Virginia University Health Sciences CenterMorgantownUSA
  5. 5.“2011” Collaborative Innovation Center/Research Center of NeurobiologyTaiyuanChina

Personalised recommendations