Ocular Hypotensive and Neuroprotective Effects of K-115, a Novel Rho-Kinase Inhibitor

Abstract

Purpose:: In this study, we evaluated the kinase inhibition property in vitro, ocular hypotensive effect, distribution pattern, and neuroprotective effect in vivo of K-115.

Methods:: This study was conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Reserach. Inhibition potency of K-115 on several serine/threonine kinases including Rho-kinase were assayed. Ocular hypotensive effect of K-115 was evaluated by the topical instillation into normal rabbit (0.0625% to 0.5%, n=10) and monkey (0.1% to 0.4%, n=8) eyes. In addition, the effect of K-115 was compared with 0.005% Xalatan in monkey. The distribution pattern of K-115 was performed by the whole head autoradiography with [¹⁴C]K-115 in rabbits. The neuroprotective effect of K-115 (10^-9 to 10^-6 M, 5 µL injection into the vitreous) was assayed by using the survival ratio of retinal ganglion cells (GCs) in rat retinal ischemia-reperfusion model (n=5~7).

Results:: K-115 inhibited Rho-kinase (IC₅₀=0.031 µM) with a competitive manner, which was highly selective and approximately 8 times more potent than Y-27632 (0.23 µM). Topical instillation of K-115 showed dose-dependent ocular hypotensive effect in rabbit (p<0.001) and monkey (p<0.001) eyes. In the monkey, the maximal reduction was obtained at 2 hour after the instillation, and the values were 2.3±0.3, 3.3±0.3, and 4.4±0.3 mmHg for 0.1%, 0.2%, and 0.4% of K-115, respectively. The ocular hypotensive effect of 0.4% K-115 was more potent than that of 0.005% Xalatan (2.5±0.2 mmHg, p<0.01). Whole head autoradiography revealed that the topical instillation of K-115 penetrated into the posterior part of the eye including the retina or choroid on the ipsilateral side. Ischemia-reperfusion injury reduced GC numbers to the 57.3±3.9% of control. The intravitreal injection of K-115 significantly inhibited the reduction of GCs at 10^-9 M (77.7±5.6%, p=0.001) and over, and 10^-6 M K-115 almost abolished the reduction of GCs (96.9±1.3% of control, p<0.001).

Conclusions:: These results suggest that K-115 has a potent ocular hypotensive and neuroprotective effects, and may be a useful therapeutic agent for the treatment of glaucoma.

Keywords: drug toxicity/drug effects • intraocular pressure • neuroprotection