Rho GTPase/Rho kinase inhibition as a novel target for the treatment of glaucoma.
Rho kinase (ROCK1 and ROCK2) is a serine/threonine kinase that serves as an important downstream effector of Rho GTPase, and plays a critical role in regulating the contractile tone of smooth muscle tissues in a calcium-independent manner. Several lines of experimental evidence indicate that modulating ROCK activity within the aqueous humor outflow pathway using selective inhibitors could achieve very significant benefits for the treatment of increased intraocular pressure in patients with glaucoma. The rationale for such an approach stems from experimental data suggesting that both ROCK and Rho GTPase inhibitors can increase aqueous humor drainage through the trabecular meshwork, leading to a decrease in intraocular pressure. In addition to their ocular hypotensive properties, inhibitors of both ROCK and Rho GTPase have been shown to enhance ocular blood flow, retinal ganglion cell survival and axon regeneration. These properties of the ROCK and Rho GTPase inhibitors indicate that targeting the Rho GTPase/ROCK pathway with selective inhibitors represents a novel therapeutic approach aimed at lowering increased intraocular pressure in glaucoma patients.
Rao
Vasantha P
VP
Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA. rao00011@mc.duke.edu
Epstein
David L
DL
D000818:Animals; D001082:Aqueous Humor / Q000502:physiology; D001369:Axons / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005123:Eye / Q000098:blood supply; D005724:Ganglia / Q000166:cytology / Q000187:drug effects; D005901:Glaucoma / Q000188:drug therapy*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000502:physiology; D014129:Trabecular Meshwork / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D054460:rho-Associated Kinases
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins