A novel ROCK inhibitor, Y-39983, promotes regeneration of crushed axons of retinal ganglion cells into the optic nerve of adult cats.
We investigated the effect of a novel ROCK inhibitor, Y-39983, on neurite regeneration in vitro and axonal regeneration in the crushed cat optic nerve in vivo. To determine the effective dose for neurite regeneration, retinal pieces were cultured with ROCK inhibitors, Y-39983 or Y-27632, a well-characterized ROCK inhibitor, and the number and length of TUJ-1-positive neurites were evaluated. The greatest number of neurites protruded at a dose of 3-10 microM Y-39983 and at a dose of 10-100 microM Y-27632, respectively. The neurite number at maximum effect of Y-39983 was greater than that of Y-27632. No significant difference was observed between values of neurite length with the inhibitors. Based on this finding, we examined the effect of Y-39983 on axonal regeneration in the crushed optic nerve in vivo. Immediately after crushing the left optic nerve, Y-39983 was injected into the vitreous and the crushed site. An injection of 10 microM Y-39983 induced the crushed axons to regenerate and pass over the crush site. In contrast, very few axons passed beyond the crush site in the optic nerve with phosphate-buffered saline injection. The second injection of 10 microM Y-39983 on day 7 doubled the number of regenerated axons, suggesting that new axons may have entered into the optic nerve after day 7 and that a continuous supply of the drug may make more axons to regenerate.
Sagawa
Hiroe
H
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Tsuruma-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Terasaki
Hiroko
H
Nakamura
Makoto
M
Ichikawa
Masahiro
M
Yata
Takayuki
T
Tokita
Yoshihito
Y
Watanabe
Masami
M
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects*; D002415:Cats; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007267:Injections; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D009409:Nerve Crush; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects; D009900:Optic Nerve / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D013997:Time Factors; D014822:Vitreous Body; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C520365:Y-39983; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases