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Editors Selection IGR 24-1
Basic Science: Neuroprotection in vivo
Comment by Derek Welsbie on:
69373 Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury, Shaw PX; Sang A; Wang Y et al., Experimental Eye Research, 2017; 158: 33-42
Rho-associated protein kinase (ROCK) 1 and 2 are known to play a role in trabecular meshwork physiology and thus pan-ROCK inhibitors like AR-13324 (Rhopressa/netarsudil) are being developed as clinical intraocular pressure (IOP)-lowering agents. In addition, using multiple rodent models of retinal ganglion cell (RGC) axon injury, ROCK1/ROCK2 have been shown to play a role in promoting RGC cell death and limiting the ability of RGC axons to regenerate.
ROCK-inhibition may have multiple beneficial effects as a glaucoma therapy
In this article, Peter Shaw and colleagues, tested the effect of ROCK1/ROCK2 inhibition, using AR-13324, on RGC survival and axon regeneration in the rat model of optic nerve crush. Thrice daily administration of 0.6% AR-13324 eye drops (which can penetrate to the posterior segment in mice and rats) led to ~40% rescue of RGC cell death two weeks after injury. Moreover, unlike vehicle-treated eyes which are devoid of axons extending much beyond the crush site, AR-13324-treated eye showed clear evidence of short-distance (up to 5 mm) axon regeneration. Given that ROCKs are known to modulate the phosphorylation status of cofilin and LIM kinase (LIMK), they assayed retinas and optic nerves for these biochemical markers of ROCK activity and found evidence of ROCK inhibition in RGCs and proximal optic nerve glia.
The availability of conditional ROCK1 and ROCK2 knockout mice should make it possible in future to dissect out whether the neuroprotective/neuroregenerative mechanism of ROCK inhibition is RGC-intrinsic or whether there is a role for cell-cell signaling. Of note, the authors found that unilateral optic nerve crush led to an unexpected increase in IOP, even in the uninjured fellow eye. AR-13324 partially blocked the increase so yet another possible mechanism of action in this model involves the role of IOP-lowering. Taken together, ROCK-inhibition may have multiple beneficial effects as a glaucoma therapy and will certainly warrant further investigation.
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