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K.D. Rittenhouse, D.W. Rickman, P. Saloupis, B. Jessen, M.R. Niesman; The Pan–Cyclin–Dependent Kinase Antagonist, AG–012986, Protects Photoreceptors From Light–Induced Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1692.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: CDK5 has homology to other CDKs that regulate the cell cycle, but its activity is largely confined to postmitotic neurons. Developmentally, CDK5 appears to have roles in neuronal migration, cell positioning and synaptogenesis. In the mature retina it may be important in "resetting" photoreceptors (PR), as demonstrated by its ability to turn off GTP–transducin α–activated PDE. Here, we investigated the corollary that inhibition of CDK5 activity would protect PR following constant light exposure. Methods: Adult Sprague Dawley rats were exposed to constant light (700 lux) for 7 days, then returned to conventional housing. After 24 hr, rats received a single intraocular injection of AG–012986 (3 µl of 10 ng/ml – 1 µg/ml). Some rats received a second injection 1 wk later, and all were allowed to survive for 1–6 wk. Retinas were then processed for histological and immunohistochemical analyses using antibodies to cell type–specific markers. Results: In normal retinas the outer nuclear layer (ONL) contained ∼10 rows of cells. Two wk after constant light exposure, this was reduced to 3–5 rows; after 6 wk, 2–3 rows. At all time points, PR had shorter outer segments and concomitant reductions in rhodopsin immunoreactivity in PR somata in the ONL and synaptophysin (SYN)–immunoreactive PR terminals in the outer plexiform layer (OPL). Also there was an up–regulation of GFAP in Muller cells and a disruption of inner retinal circuitry, as evidenced by aberrant patterns of PKC–α, recoverin and parvalbumin immunostaining. In rats receiving a single injection of AG–012986 (10 ng/ml), the ONL was slightly increased in thickness (5–6 rows) at two wk. Also there was a substantial increase in the number of rhodopsin positive cells in the ONL, and outer segments appeared longer. At higher concentrations the thickness of the ONL was similarly preserved. However, the number of rhodopsin–positive cells in the ONL was only modestly increased, as was the number of SYN–positive terminals in the OPL. Conclusions: CDK5 likely plays a role in PR maintenance. Following constant light exposure, inhibition of CDK5 activity enhances PR survival. This protection is likely mediated through deactivation of normal PR functioning. In contrast, when normal mice received i.v. AG–012986, outer segment toxicities were observed. These may be due to non–CDK5 related activity of the molecule, dose or route of delivery.
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