Alpha2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity.
OBJECTIVE
alpha2 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 alpha2 neuroprotection of RGCs.


METHODS
The authors used in situ RGCs in the isolated rat retina to investigate possible interactions between alpha2 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 Ca(2+) 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 Ca(2+) signals in RGCs. This suppressive action of brimonidine was blocked by alpha2 antagonists, cAMP analogs, an adenylate cyclase activator, and a cAMP-specific phosphodiesterase (PDE4) inhibitor, indicating that this brimonidine effect is mediated by the alpha2 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 alpha2 antagonist or a PDE4 inhibitor in both in vivo models.


CONCLUSIONS
The results demonstrate alpha2 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.
Department of Biological Sciences, Allergan Pharmaceuticals, Irvine, California 92612, USA. dong_james@allergan.com
Cun-Jian
CJ
Dong
Yuanxing
Y
Guo
Peter
P
Agey
Larry
L
Wheeler
William A
WA
Hare
D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology
D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D010726:Phosphodiesterase Inhibitors; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D016194:Receptors, N-Methyl-D-Aspartate; D000068438:Brimonidine Tartrate; D016202:N-Methylaspartate; D020889:Rolipram; D002118:Calcium