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VF Roche, CA Opere, SE Ohia; Effect of a Bicyclic Hexahydroaporphine on Ischemia-Induced [3H]D-Aspartate Release From Bovine Isolated Retinae . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3266.
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Purpose: We have shown that bicyclic hexahydroaporphines (HHAs), including nor-HHA (1) and its N-methyl congener (3,11c-ethano-10-methoxy-1,2,3,3a,11b,11c-hexahydroaporphine, 2), lower intraocular pressure in normotensive rabbits in a dose-dependent fashion (Saha et al. J. Ocul. Pharmacol. Ther. 497, 1997). As part of studies to elucidate their mechanism of action, we found that 1: 1) significantly increased outflow facility in normotensive rabbits, 2) had no effect on aqueous inflow in the same animal model, and 3) did not directly stimulate PGF2α production or produce direct contractile or relaxant effects in bovine isolated iris. In the present study, we investigated the effect of 2 on ischemia-induced [3H]D-aspartate release from bovine retinae. Methods: Isolated neural retinae were incubated in oxygenated Krebs solution containing 200 nM of [3H]D-aspartate for 60 minutes and then prepared for studies of neurotransmitter release using the superfusion method. Release of [3H]D-aspartate was evoked by K+(50 mM) stimuli applied at 90 minutes (S1) and ischemia (induced by exposure of tissues to glucose-deficient Krebs buffer solution gassed with 95% N2:5% CO2) at 108 minutes (S2) after the onset of superfusion. Compound 2 was added to the buffer solution 20 minutes before and during S2. Results: Exposure of bovine retinal tissues to ischemic buffer solution increased the spontaneous efflux of [3H]D-aspartate by 22%. In the concentration range, 10 nM to 3 µM, compound 2 caused inhibition of ischemia-induced [3H]D-aspartate overflow without affecting basal tritium efflux. For instance, at 1µM, 2 caused a 58.7 11.6% (n = 6) inhibition of ischemia-induced [3H]D-aspartate release. Conclusion: We conclude that bicyclic hexahydroaporphines can inhibit ischemia-induced [3H]D-aspartate release from bovine retinae. These results indicate that bicyclic hexahydroaporphines may have a neuroprotective action against glutamate excitotoxicity in the neural retinae.
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