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C.-J. Dong, Y.-X. Guo, P. Agey, L. Wheeler, W. A. Hare; Nimodipine Enhances 2 Adrenergic Modulation of NMDA Receptor: A Novel Mechanism of RGC Neuroprotection. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4328.
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© ARVO (1962-2015); The Authors (2016-present)
To demonstrate a novel neural mechanism by which nimodipine protects RGCs from NMDA receptor mediated excitotoxicity in vivo.
We used in situ retinal ganglion cells (RGCs) in the isolated rat retina to characterize 2 modulation of NMDA receptor function and 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 rabbits was achieved by intravitreal injections. RGC injury was evaluated by counting dye labeled RGCs in the isolated retina.
Local application of NMDA elicited a robust intracellular Ca++ signal and inward current in individual RGCs voltage clamped at -70 mV. These NMDA responses were sensitive to specific NMDA receptor blockers, confirming that they are mediated by the NMDA receptor. Pretreatment with brimonidine, a selective 2 agonist, reduced significantly NMDA-elicited whole-cell currents and cytosolic Ca++ signals. This suppressive action of brimonidine was blocked by a specific 2 antagonist, cAMP analogs, an adenylate cyclase activator, and a cAMP-specific phosphodiesterase (PDE4) inhibitor, indicating that it’s mediated by the 2 receptor through a Gi coupled mechanism. Background addition of nimodipine significantly enhanced the suppressive effect of brimonidine on NMDA responses. This nimodipine effect is not related to its Ca++ channel blocking action, since it can be blocked by 2 antagonists and since the control NMDA responses were recorded in the presence of nimodipine. Intravitreal application of brimonidine protected RGCs in the rabbit retinal NMDA excitotoxicity model. The brimonidine neuroprotective effect was enhanced significantly by nimodipine and also blocked by 2 antagonists, indicating that this effect of nimodipine is dependent on 2 receptor activation.
Our in vitro and in vivo findings demonstrate a novel neuroprotective mechanism involving nimodipine enhancing 2 signaling. These findings also demonstrate that nimodipine is neuroprotective by acting directly at the neural retina.
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