IOVS Archives of Disease in Childhood
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Originally published In Press as doi:10.1167/iovs.08-2078 on June 19, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4515-4522.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-2078
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{alpha}2 Adrenergic Modulation of NMDA Receptor Function as a Major Mechanism of RGC Protection in Experimental Glaucoma and Retinal Excitotoxicity

Cun-Jian Dong, Yuanxing Guo, Peter Agey, Larry Wheeler, and William A. Hare

From the Department of Biological Sciences, Allergan Pharmaceuticals, Irvine, California.

PURPOSE. {alpha}2 Agonists, such as brimonidine, have been shown to protect retinal ganglion cells (RGCs) in animal models of glaucoma and acute retinal ischemia. In this study, the authors investigated the neural mechanism that may underlie {alpha}2 neuroprotection of RGCs.

METHODS. The authors used in situ RGCs in the isolated rat retina to investigate possible interactions between {alpha}2 and N-methyl-D-aspartate (NMDA) receptors and rat glaucoma or rabbit retinal NMDA excitotoxicity models to verify in vitro findings under in vivo conditions.

RESULTS. Application of NMDA elicited a robust intracellular Ca2+ signal and inward current in individual in situ RGCs voltage clamped at –70 mV. NMDA-elicited responses were blocked by D-AP5 (D-2-amino-5-phosphonopentanoic acid), a selective NMDA receptor antagonist. Brimonidine pretreatment also significantly reduced NMDA-elicited whole-cell currents and cytosolic Ca2+ signals in RGCs. This suppressive action of brimonidine was blocked by {alpha}2 antagonists, cAMP analogs, an adenylate cyclase activator, and a cAMP-specific phosphodiesterase (PDE4) inhibitor, indicating that this brimonidine effect is mediated by the {alpha}2 receptor through a reduction of intracellular cAMP production. Brimonidine or NMDA receptor blockers protected RGCs in rat glaucoma and rabbit retinal NMDA excitotoxicity models. The brimonidine neuroprotective effect was abolished by an {alpha}2 antagonist or a PDE4 inhibitor in both in vivo models.

CONCLUSIONS. The results demonstrate {alpha}2 modulation of NMDA receptor function as an important mechanism for neuroprotection. These results suggest a new therapeutic approach based on neuromodulation, instead of direct inhibition, of the NMDA receptor for the treatment of glaucoma and other CNS disorders associated with NMDA receptor overactivation.






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