The role of ras homolog family/ras homolog family kinase signaling pathway and its inhibitors in the optic nerve disease_Chinese Journal of Ocular Fundus Diseases

Authors：

Wang Xiaoling ,  Chen Changzheng

Department of Ophthalmology, Remin Hospital of Wuhan University ,Wuhan 430060, China;

Corresponding author：

Chen Changzheng, Email: whuchenchzh@163.com

Keywords：

Optic nerve diseases/etiology; Optic nerve diseases/therapy; G-protein-coupled receptor kinase 1/antagonists & inhibitors; Review

DOI：

10.3760/cma.j.issn.1005-1015.2017.05.031

Video：

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Ras homolog family (Rho)/ Rho-associated coiled-coil kinase (ROCK) signaling pathway widely exists in human and mammal cells, which is closely related to inhibition of repair after optic nerve damage. The expression level of Rho/ROCK signaling pathway-related proteins is up-regulated in glaucoma, and related with the death of retinal ganglionic cell (RGC) and the axon activity. ROCK inhibitors can protect the surviving RGC and promote axon extension with a dose-dependent manner. ROCK inhibitors also can inhibit glial scar formation, lower intraocular pressure and inhibit inflammatory response to some degrees. Rho/ROCK signaling pathway correlates with the optic nerve disease progression, and ROCK inhibitors hope to become a new therapeutic drug.

Citation： Wang Xiaoling, Chen Changzheng. The role of ras homolog family/ras homolog family kinase signaling pathway and its inhibitors in the optic nerve disease. Chinese Journal of Ocular Fundus Diseases, 2017, 33(5): 548-550. doi: 10.3760/cma.j.issn.1005-1015.2017.05.031 Copy

1.	傅平平, 吴强.视紫红质类及卷曲蛋白受体在糖尿病视网膜病变发生发展中的作用[J]. 中华眼底病杂志, 2014, 30(4): 431-434. DOI: 10.3760/cma.j.issn.1005-1015.2014.04.030.Fu PP, Wu Q. The role of receptors of rhodopsin and Frizzled in diabetic retinopathy[J]. Chin J Ocul Fundus Dis, 2014, 30(4): 431-434. DOI: 10.3760/cma.j.issn.1005-1015.2014.04.030.
2.	Feng Y, LoGrasso PV, Defert O, et al. Rho kinase (ROCK) inhibitors and their therapeutic potential[J]. J Med Chem, 2016, 59(6): 2269-2300. DOI: 10.1021/acs.jmedchem.5b00683.
3.	李洁, 梅妍. 视紫红质在视网膜变性疾病中作用机制的研究进展[J]. 四川解剖学杂志, 2011, 19(4): 46-48. DOI: 10.3969/j.issn.1005-1457.2011.096.Li J, Mei Y. The progress of rhodopsin in light induced retina degeneration[J]. Sichuan Journal of Anatomy, 2011, 19(4): 46-48. DOI: 10.3969/j.issn.1005-1457.2011.096.
4.	Zhang J, Adrian FJ, Jahnke W, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors[J]. Nature, 2010, 463(7280): 501-506. DOI: 10.1038/nature08675.
5.	Fujisawa K, Fujita A, Ishizaki T, et al. Identification of the rho-binding domain of p160ROCK, a rhoassociated coiled-coil containing protein kinase[J]. J Biol Chem, 1996, 271(38): 23022-23028.
6.	Takahashi N, Tuiki H, Saya H, et al. Localization of the gene coding for ROCK Ⅱ/Rho kinase on human chromosome 2p24[J]. Genomics, 1999, 55(2): 235-237. DOI: 10.1006/geno.1998.5344.
7.	Nakagawa O, Fujisawa K, Ishizaki T, et al. ROCK-Ⅰ and ROCK-Ⅱ, two isoforms of rho-associated coiled-coil forming protein serine/threonine kinase in mice[J]. FEBS Lett, 1996, 392(2): 189-193.
8.	Huang S, Huang D, Zhao J, et al. Electroacupuncture promotes axonal regeneration in rats with focal cerebral ischemia through the downregulation of Nogo-A/NgR/RhoA/ROCK signaling [J]. Exp Ther Med, 2017, 14(2): 905-912. DOI: 10.3892/etm.2017.4621.
9.	Palandri A, Salvador VR, Wojnacki J, et al. Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75NTR receptor-mediated activation of RhoA signaling pathways[J/OL]. Cell Death Dis, 2015, 6(9): 1876[2015-09-03]. https://jhu.pure.elsevier.com/en/publications/myelin-associated-glycoprotein-modulates-apoptosis-of-motoneurons-4. DOI: 10.1038/cddis.2015.228.
10.	Kubo T, Yamaguchi A, Iwata N, et al. The therapeutic effects of Rho-ROCK inhibitors on CNS disorders[J]. Ther Clin Risk Manag, 2008, 4 (3): 605-615.
11.	Li Z, Dong X, Wang Z, et al. Regulation of PTEN by Rho small GTPases[J]. Nat Cell Biol, 2005, 7 (4): 399-404. DOI: 10.1038/ncb1236.
12.	Zuo Y, Xiong N, Shen J, et al. MARK2 rescues Nogo-66-induced inhibition of neurite outgrowth via regulating microtubule-associated proteins in neurons in vitro [J]. Neurochem Res, 2016, 41(11): 2958-2968. DOI: 10.1007/s11064-016-2016-8.
13.	McKeon RJ, Schreiber RC, Rudge JS, et al. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes[J]. J Neurosci, 1991, 11(11): 3398-3411.
14.	Yang Z, Wang J, Liu X, et al. Y-39983 downregulates RhoA/Rho-associated kinase expression during its promotion of axonal regeneration[J]. Oncol Rep, 2013, 29(3): 1140-1146. DOI: 10.3892/or.2012.2205.
15.	Olson M. Applications for ROCK kinase inhibition[J]. Curr Opin Cell Biol, 2008, 20(2): 242-248. DOI: 10.1016/j.ceb.2008.01.002.
16.	Roser AE, Tönges L, Lingor P. Modulation of microglial activity by Rho-Kinase (ROCK) inhibition as therapeutic strategy in Parkinson’s disease and amyotrophic lateral sclerosis[J/OL]. Front Aging Neurosci, 2017, 9: 94[2017-04-04]. https://dx.doi.org/10.3389/fnagi.2017.00094. DOI: 10.3389/fnagi.2017.00094.
17.	Ichikawa M, Yoshida J, Saito K, et al. Differential effects of two ROCK inhibitors, Fasudil and Y-27632, on optic nerve regeneration in adult cats[J]. Brain Res, 2008, 27: 23-33. DOI: 10.1016/j.brainres.2008.01.063.
18.	Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review[J]. JAMA, 2014, 311(18): 1901-1911. DOI: 10.1001/jama.2014.3192.
19.	Toft-Kehler AK, Skytt DM, Poulsen KA, et al. Limited energy supply in Müller cells alters glutamate uptake[J]. Neurochem Res, 2014, 39(5): 941-949. DOI: 10.1007/s11064-014-1289-z.
20.	Van de Velde S, De Groef L, Stalmans I, et al. Towards axonal regeneration and neuroprotection in glaucoma: Rho kinase inhibitors as promising therapeutics[J]. Prog Neurobiol, 2015, 131: 105-119. DOI: 10.1016/j.pneurobio.2015.06.002.
21.	Yamamoto K, Maruyama K, Himori N, et al. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma[J]. Invest Ophthalmol Vis Sci, 2014, 55(11): 7126-7136. DOI: 10.1167/iovs.13-13842.
22.	Vranka JA, Kelley MJ, Acott TS, et al. Extracellular matrix in the trabecular meshwork: intraocular pressure regulation and dysregulation in glaucoma[J]. Exp Eye Res, 2015, 133: 112-125. DOI: 10.1016/j.exer.2014.07.014.
23.	Kaneko Y, Ohta M, Inoue T, et al. Effects of K-115 (Ripasudil), a novel ROCK inhibitor, on trabecular meshwork and Schlemm’s canal endothelial cells[J/OL]. Sci Rep, 2016, 6: 19640[2016-01-19]. http://dx.doi.org/10.1038/srep19640. DOI: 10.1038/srep19640.
24.	Meyer-ter-Vehn T, Sieprath S, Katzenberger B, et al. Contractility as a prerequisite for TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts[J]. Invest Ophthalmol Vis Sci, 2006, 47(11): 4895-4904. DOI: 10.1167/iovs.06-0118.
25.	Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrois[J]. J Clin Invest, 2013, 123(3): 1096-1108. DOI: 10.1172/JCI66700.
26.	Koch JC, Lingor P. The role of autophagy in axonal degeneration of the optic nerve[J]. Exp Eye Res, 2016, 144: 81-89. DOI: 10.1016/j.exer.2015.08.016.
27.	Chang EE, Goldberg JL. Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement[J]. Ophthalmology, 2012, 119(5): 979-986. DOI: 10.1016/j.ophtha.2011.11.003.
28.	Steinsapir KD, Goldberg RA. Traumatic optic neuropathy: an evolving understanding[J]. Am J Ophthalmol, 2011, 151(6): 928-933. DOI: 10.1016/j.ajo.2011.02.007.
29.	Koch JC, Tönges L, Barski E, et al. ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS[J/OL]. Cell Death Dis, 2014, 5: 1225[2014-05-15]. http://dx.doi.org/10.1038/cddis.2014.191. DOI: 10.1038/cddis.2014.191.
30.	Sagawa H, Terasaki H, Nakamura M, et al. A novel ROCK inhibitor, Y-39983, promotes regeneration of crushed axons of retinal ganglion cells into the optic nerve of adult cats[J]. Exp Neurol, 2007, 205(1): 230-240. DOI: 10.1016/j.expneurol.2007.02.002.
31.	Zhang C, Guo Y, Slater BJ, et al. Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION) [J]. Exp Eye Res, 2010, 91(2): 286-292. DOI: 10.1016/j.exer.2010.05.021.
32.	Biousse V, Newman NJ. Ischemic optic neuropathies[J]. N Engl J Med, 2015, 372(25): 2428-2436. DOI: 10.1056/NEJMra1413352.
33.	Salgado C, Vilson F, Miller NR, et al. Cellular inflammation in nonarteritic anterior ischemic optic neuropathy and its primate model[J]. Arch Ophthalmol, 2011, 129(12): 1583-1591. DOI: 10.1001/archophthalmol.2011.351.
34.	Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: natural history of visual outcome[J]. Ophthalmology, 2008, 115(2): 298-305. DOI: 10.1016/j.ophtha.2007.05.027.
35.	Sanjari N, Pakravan M, Nourinia R, et al. Intravitreal injection of a Rho-kinase inhibitor (fasudil) for recent-onset nonarteritic anterior ischemic optic neuropathy[J]. J Clin Pharmacol, 2016, 56(6): 749-753. DOI: 10.1002/jcph.655.
36.	Watabe H, Abe S, Yoshitomi T. Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries[J]. Jpn J Ophthalmol, 2011, 55(4): 411-417. DOI: 10.1007/s10384-011-0048-9.
37.	Jung CH, Lee WJ, Hwang JY, et al. The role of Rho/Rho-kinase pathway in the expression of ICAM-1 by linoleic acid in human aortic endothelial cells[J]. Inflammation, 2012, 35(3): 1041-1048. DOI: 10.1007/s10753-011-9409-2.

1. 傅平平, 吴强.视紫红质类及卷曲蛋白受体在糖尿病视网膜病变发生发展中的作用[J]. 中华眼底病杂志, 2014, 30(4): 431-434. DOI: 10.3760/cma.j.issn.1005-1015.2014.04.030.Fu PP, Wu Q. The role of receptors of rhodopsin and Frizzled in diabetic retinopathy[J]. Chin J Ocul Fundus Dis, 2014, 30(4): 431-434. DOI: 10.3760/cma.j.issn.1005-1015.2014.04.030.
2. Feng Y, LoGrasso PV, Defert O, et al. Rho kinase (ROCK) inhibitors and their therapeutic potential[J]. J Med Chem, 2016, 59(6): 2269-2300. DOI: 10.1021/acs.jmedchem.5b00683.
3. 李洁, 梅妍. 视紫红质在视网膜变性疾病中作用机制的研究进展[J]. 四川解剖学杂志, 2011, 19(4): 46-48. DOI: 10.3969/j.issn.1005-1457.2011.096.Li J, Mei Y. The progress of rhodopsin in light induced retina degeneration[J]. Sichuan Journal of Anatomy, 2011, 19(4): 46-48. DOI: 10.3969/j.issn.1005-1457.2011.096.
4. Zhang J, Adrian FJ, Jahnke W, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors[J]. Nature, 2010, 463(7280): 501-506. DOI: 10.1038/nature08675.
5. Fujisawa K, Fujita A, Ishizaki T, et al. Identification of the rho-binding domain of p160ROCK, a rhoassociated coiled-coil containing protein kinase[J]. J Biol Chem, 1996, 271(38): 23022-23028.
6. Takahashi N, Tuiki H, Saya H, et al. Localization of the gene coding for ROCK Ⅱ/Rho kinase on human chromosome 2p24[J]. Genomics, 1999, 55(2): 235-237. DOI: 10.1006/geno.1998.5344.
7. Nakagawa O, Fujisawa K, Ishizaki T, et al. ROCK-Ⅰ and ROCK-Ⅱ, two isoforms of rho-associated coiled-coil forming protein serine/threonine kinase in mice[J]. FEBS Lett, 1996, 392(2): 189-193.
8. Huang S, Huang D, Zhao J, et al. Electroacupuncture promotes axonal regeneration in rats with focal cerebral ischemia through the downregulation of Nogo-A/NgR/RhoA/ROCK signaling [J]. Exp Ther Med, 2017, 14(2): 905-912. DOI: 10.3892/etm.2017.4621.
9. Palandri A, Salvador VR, Wojnacki J, et al. Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75NTR receptor-mediated activation of RhoA signaling pathways[J/OL]. Cell Death Dis, 2015, 6(9): 1876[2015-09-03]. https://jhu.pure.elsevier.com/en/publications/myelin-associated-glycoprotein-modulates-apoptosis-of-motoneurons-4. DOI: 10.1038/cddis.2015.228.
10. Kubo T, Yamaguchi A, Iwata N, et al. The therapeutic effects of Rho-ROCK inhibitors on CNS disorders[J]. Ther Clin Risk Manag, 2008, 4 (3): 605-615.
11. Li Z, Dong X, Wang Z, et al. Regulation of PTEN by Rho small GTPases[J]. Nat Cell Biol, 2005, 7 (4): 399-404. DOI: 10.1038/ncb1236.
12. Zuo Y, Xiong N, Shen J, et al. MARK2 rescues Nogo-66-induced inhibition of neurite outgrowth via regulating microtubule-associated proteins in neurons in vitro [J]. Neurochem Res, 2016, 41(11): 2958-2968. DOI: 10.1007/s11064-016-2016-8.
13. McKeon RJ, Schreiber RC, Rudge JS, et al. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes[J]. J Neurosci, 1991, 11(11): 3398-3411.
14. Yang Z, Wang J, Liu X, et al. Y-39983 downregulates RhoA/Rho-associated kinase expression during its promotion of axonal regeneration[J]. Oncol Rep, 2013, 29(3): 1140-1146. DOI: 10.3892/or.2012.2205.
15. Olson M. Applications for ROCK kinase inhibition[J]. Curr Opin Cell Biol, 2008, 20(2): 242-248. DOI: 10.1016/j.ceb.2008.01.002.
16. Roser AE, Tönges L, Lingor P. Modulation of microglial activity by Rho-Kinase (ROCK) inhibition as therapeutic strategy in Parkinson’s disease and amyotrophic lateral sclerosis[J/OL]. Front Aging Neurosci, 2017, 9: 94[2017-04-04]. https://dx.doi.org/10.3389/fnagi.2017.00094. DOI: 10.3389/fnagi.2017.00094.
17. Ichikawa M, Yoshida J, Saito K, et al. Differential effects of two ROCK inhibitors, Fasudil and Y-27632, on optic nerve regeneration in adult cats[J]. Brain Res, 2008, 27: 23-33. DOI: 10.1016/j.brainres.2008.01.063.
18. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review[J]. JAMA, 2014, 311(18): 1901-1911. DOI: 10.1001/jama.2014.3192.
19. Toft-Kehler AK, Skytt DM, Poulsen KA, et al. Limited energy supply in Müller cells alters glutamate uptake[J]. Neurochem Res, 2014, 39(5): 941-949. DOI: 10.1007/s11064-014-1289-z.
20. Van de Velde S, De Groef L, Stalmans I, et al. Towards axonal regeneration and neuroprotection in glaucoma: Rho kinase inhibitors as promising therapeutics[J]. Prog Neurobiol, 2015, 131: 105-119. DOI: 10.1016/j.pneurobio.2015.06.002.
21. Yamamoto K, Maruyama K, Himori N, et al. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma[J]. Invest Ophthalmol Vis Sci, 2014, 55(11): 7126-7136. DOI: 10.1167/iovs.13-13842.
22. Vranka JA, Kelley MJ, Acott TS, et al. Extracellular matrix in the trabecular meshwork: intraocular pressure regulation and dysregulation in glaucoma[J]. Exp Eye Res, 2015, 133: 112-125. DOI: 10.1016/j.exer.2014.07.014.
23. Kaneko Y, Ohta M, Inoue T, et al. Effects of K-115 (Ripasudil), a novel ROCK inhibitor, on trabecular meshwork and Schlemm’s canal endothelial cells[J/OL]. Sci Rep, 2016, 6: 19640[2016-01-19]. http://dx.doi.org/10.1038/srep19640. DOI: 10.1038/srep19640.
24. Meyer-ter-Vehn T, Sieprath S, Katzenberger B, et al. Contractility as a prerequisite for TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts[J]. Invest Ophthalmol Vis Sci, 2006, 47(11): 4895-4904. DOI: 10.1167/iovs.06-0118.
25. Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrois[J]. J Clin Invest, 2013, 123(3): 1096-1108. DOI: 10.1172/JCI66700.
26. Koch JC, Lingor P. The role of autophagy in axonal degeneration of the optic nerve[J]. Exp Eye Res, 2016, 144: 81-89. DOI: 10.1016/j.exer.2015.08.016.
27. Chang EE, Goldberg JL. Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement[J]. Ophthalmology, 2012, 119(5): 979-986. DOI: 10.1016/j.ophtha.2011.11.003.
28. Steinsapir KD, Goldberg RA. Traumatic optic neuropathy: an evolving understanding[J]. Am J Ophthalmol, 2011, 151(6): 928-933. DOI: 10.1016/j.ajo.2011.02.007.
29. Koch JC, Tönges L, Barski E, et al. ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS[J/OL]. Cell Death Dis, 2014, 5: 1225[2014-05-15]. http://dx.doi.org/10.1038/cddis.2014.191. DOI: 10.1038/cddis.2014.191.
30. Sagawa H, Terasaki H, Nakamura M, et al. A novel ROCK inhibitor, Y-39983, promotes regeneration of crushed axons of retinal ganglion cells into the optic nerve of adult cats[J]. Exp Neurol, 2007, 205(1): 230-240. DOI: 10.1016/j.expneurol.2007.02.002.
31. Zhang C, Guo Y, Slater BJ, et al. Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION) [J]. Exp Eye Res, 2010, 91(2): 286-292. DOI: 10.1016/j.exer.2010.05.021.
32. Biousse V, Newman NJ. Ischemic optic neuropathies[J]. N Engl J Med, 2015, 372(25): 2428-2436. DOI: 10.1056/NEJMra1413352.
33. Salgado C, Vilson F, Miller NR, et al. Cellular inflammation in nonarteritic anterior ischemic optic neuropathy and its primate model[J]. Arch Ophthalmol, 2011, 129(12): 1583-1591. DOI: 10.1001/archophthalmol.2011.351.
34. Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: natural history of visual outcome[J]. Ophthalmology, 2008, 115(2): 298-305. DOI: 10.1016/j.ophtha.2007.05.027.
35. Sanjari N, Pakravan M, Nourinia R, et al. Intravitreal injection of a Rho-kinase inhibitor (fasudil) for recent-onset nonarteritic anterior ischemic optic neuropathy[J]. J Clin Pharmacol, 2016, 56(6): 749-753. DOI: 10.1002/jcph.655.
36. Watabe H, Abe S, Yoshitomi T. Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries[J]. Jpn J Ophthalmol, 2011, 55(4): 411-417. DOI: 10.1007/s10384-011-0048-9.
37. Jung CH, Lee WJ, Hwang JY, et al. The role of Rho/Rho-kinase pathway in the expression of ICAM-1 by linoleic acid in human aortic endothelial cells[J]. Inflammation, 2012, 35(3): 1041-1048. DOI: 10.1007/s10753-011-9409-2.

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The role of ras homolog family/ras homolog family kinase signaling pathway and its inhibitors in the optic nerve disease

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