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C.-J. Dong, Y. Guo, P. Agey, L. Wheeler, W. A. Hare; 2 Adrenergic Modulation of NMDA Receptor Function: A Novel Mechanism of Neuroprotection in Experimental Glaucoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5503.
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© ARVO (1962-2015); The Authors (2016-present)
α2 agonists, such as brimonidine, have been shown to protect retinal ganglion cells (RGCs) in animal models of glaucoma and acute retinal ischemia. However, the mechanism of action is not well understood. In this study, we explored the mechanism that underlies α2 neuroprotection of RGCs.
We used in situ RGCs in the isolated rat retina to characterize α2 regulation of NMDA signaling, and rat glaucoma or rabbit retinal NMDA excitotoxicity models to verify our in vitro findings under in vivo conditions. Ca++ imaging and electrophysiological (patch clamp) recordings were conducted simultaneously in single RGCs. In vivo drug dosing in rat and rabbit was carried out through osmotic pumps and intraocular injections, respectively. RGC injury was evaluated by counting dye labeled RGCs.
Local application of NMDA elicited a robust intracellular Ca++ signal and inward current in individual RGCs voltage clamped at -70 mV. D-AP5 or memantine, a selective NMDA receptor antagonist and channel blocker, respectively, either blocked or attenuated substantially these NMDA-elicited responses. Brimonidine pretreatment also reduced significantly NMDA-elicited whole-cell currents and cytosolic Ca++ signals in RGCs. This suppressive action of brimonidine was blocked by α2 antagonists, cAMP analogs, an adenylate cyclase activator, and a cAMP-specific phosphodiesterase (PDE4) inhibitor, indicating that this brimonidine effect is mediated by the α2 receptor through a reduction of intracellular cAMP production (a Gi coupled mechanism). Brimonidine or NMDA receptor blockers protected RGCs in both rat glaucoma and rabbit retinal NMDA excitotoxicity models. The brimonidine neuroprotective effect was abolished by either an α2 antagonist or a PDE4 inhibitor in both in vivo models.
Our in vitro and in vivo findings demonstrate α2 modulation of NMDA receptor function as an important novel mechanism of neuroprotection. These results provide a new therapeutic approach based on neuromodulation, instead of direct inhibition, of the NMDA receptor for the treatment of CNS disorders associated with NMDA receptor overactivation. They also support a critical role of NMDA receptor overactivation in RGC injury in experimental glaucoma.
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