Experimental glutamatergic excitotoxicity in rabbit retinal ganglion cells: block by memantine.
OBJECTIVE
Excessive activity of NMDA-type (N-methyl-d-aspartate) glutamatergic channels has been implicated as a mechanism for neuronal injury in neurologic disorders, including glaucoma, and retinal disease. This study was designed to characterize the retinal response to experimental manipulations that mimic features of glutamatergic excitotoxic insult and also to determine whether memantine, an NMDA-type glutamatergic channel blocker, is effective in reversing experimental excitotoxicity.


METHODS
Recordings of the electroretinogram (ERG) and spiking activity of single retinal ganglion cells (RGCs) were made from rabbit retinas. Excitotoxic insult was induced by either (1) application of NMDA, a selective NMDA receptor agonist; (2) application of TBOA (dl-threo-beta-benzyloxyaspartic acid), a selective inhibitor of glutamate transporters, or (3) perfusion with magnesium-free medium. For each condition, memantine was coapplied to determine its efficacy for reversal of experimental excitotoxicity. Memantine was also applied in isolation to characterize any effect on retinal responses to light stimuli.


RESULTS
All three experimental manipulations were associated with an increase in the tonic level of RGC spiking activity, a reduction in RGC spike amplitude, and, in some cells, block of spike generation. Experimental excitotoxicity had little or no effect on ERG responses. Coapplication of memantine was associated with recovery of RGC tonic spiking activity and spike amplitude toward control levels. Application of memantine in isolation was associated with a dose-dependent effect on the timing of ERG and RGC-OFF responses.


CONCLUSIONS
Memantine was effective in reversing acute experimental excitotoxicity at concentrations that have little effect on retinal light signaling.
Hare
William A
WA
Department of Biological Sciences, Allergan, Inc, Irvine, California 92612, USA. hare_william@allergan.com
Wheeler
Larry
L
D000200:Action Potentials; D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D004596:Electroretinography / Q000187:drug effects*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008559:Memantine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D010775:Photic Stimulation; D011817:Rabbits; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects
D027322:Amino Acid Transport System X-AG; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D016202:N-Methylaspartate; D008559:Memantine