Rho-kinase (ROCK) Inhibitors - A Neuroprotective Therapeutic Paradigm with a Focus on Ocular Utility

Abstract

Background: Glaucoma is a progressive optic neuropathy causing visual impairment and Retinal Ganglionic Cells (RGCs) death gradually posing a need for neuroprotective strategies to minimize the loss of RGCs and visual field. It is recognized as a multifactorial disease, Intraocular Pressure (IOP) being the foremost risk factor. ROCK inhibitors have been probed for various possible indications, such as myocardial ischemia, hypertension, kidney diseases. Their role in neuroprotection and neuronal regeneration has been suggested to be of value in the treatment of neurological diseases, like spinal-cord injury, Alzheimer’s disease and multiple sclerosis but recently Rho-associated Kinase inhibitors have been recognized as potential antiglaucoma agents. Evidence Synthesis: Rho-Kinase is a serine/threonine kinase with a kinase domain which is constitutively active and is involved in the regulation of smooth muscle contraction and stress fibre formation. Two isoforms of Rho-Kinase, ROCK-I (ROCK .) and ROCK-II (ROCK .) have been identified. ROCK II plays a pathophysiological role in glaucoma and hence the inhibitors of ROCK may be beneficial to ameliorate the vision loss. These inhibitors decrease the intraocular pressure in the glaucomatous eye by increasing the aqueous humour outflow through the trabecular meshwork pathway. They also act as anti-scarring agents and hence prevent post-operative scarring after the glaucoma filtration surgery. Their major role involves axon regeneration by increasing the optic nerve blood flow which may be useful in treating the damaged optic neurons. These drugs act directly on the neurons in the central visual pathway, interrupting the RGC apoptosis and therefore serve as a novel pharmacological approach for glaucoma neuroprotection. Conclusion: Based on the results of high-throughput screening, several Rho kinase inhibitors have been designed and developed comprising of diverse scaffolds exhibiting Rho kinase inhibitory activity from micromolar to subnanomolar ranges. This diversity in the scaffolds with inhibitory potential against the kinase and their SAR development will be intricated in the present review. Ripasudil is the only Rho kinase inhibitor marketed to date for the treatment of glaucoma. Another ROCK inhibitor AR-13324 has recently passed the clinical trials whereas AMA0076, K115, PG324, Y39983 and RKI-983 are still under trials. In view of this, a detailed and updated account of ROCK II inhibitors as the next generation therapeutic agents for glaucoma will be discussed in this review.

Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

“…In addition, hyperglycaemia has been shown to increase the expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and VEGF by vascular endothelial cells and in the vitreous samples from patients with DR [119,120]. It has been reported that the inhibition of RhoA/ROCK1 may attenuate the hypertonicity of endothelial cell caused by high glucose microenvironment, partly block inflammation and prevented considerably the apoptosis of endothelial cells aroused by high glucose [111,112,115,116]. ROCKs involvement in the mechanisms underlying DMO according to the results of preclinical studies.…”

“…ROCK1, is highly expressed in lung, liver, spleen, and kidney [ 106 , 107 , 108 , 109 ]. Both ROCK isomers are also present in ocular tissues and aberrant regulation of ROCK levels plays a role in the pathogenesis of corneal wound healing, glaucoma, diabetic retinopathy, and AMD [ 110 , 111 , 112 ].…”

“…In addition, the activation of the Rho/ROCK signalling pathway regulates the NF-κB signalling pathway, which upregulates inflammatory genes, fibronectin and transcription factor AP-1 activation and accumulation of glomerular matrix proteins. Upregulation of Rho/ROCK pathway also results in the dephosphorylation of endothelial nitric oxide synthase (eNOS), which induces endothelial cell apoptosis and vasoconstriction [ 110 , 111 , 112 , 114 ].…”

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

“…Several ROCK inhibitors have been developed in the past few decades that are predominantly ATP-competitive type 1 inhibitors exemplified by fasudil, the closely related ripasudil/K-115 and the chemically divergent Y-27632 (Yamamoto et al, 2014 and reviewed in Abbhi and Piplani, 2018). However, selectivity is a challenge for these and other molecules.…”

<p>The Latest Drugs in Development That Reduce Intraocular Pressure in Ocular Hypertension and Glaucoma</p>

“…Rho kinase (ROCK) inhibitors have great potential in glaucoma, as they not only lower IOP through an increase in conventional aqueous outflow, but they also display neuroprotective effects, thought to have potential benefit in other neurodegenerative conditions such as Alzheimer's disease. 43…”