Blockade of both NMDA and non-NMDA receptors is required for optimal protection against ischemic neuronal degeneration in the in vivo adult mammalian retina.
Under ischemic conditions, the excitatory amino acids (EAA), glutamate and aspartate, accumulate in the extracellular compartment of brain and, by excessive stimulation of EAA receptors, trigger excitotoxic degeneration of CNS neurons. Since glutamate and aspartate exert excitotoxic activity through both of the generally recognized classes of EAA receptors [N-methyl-D-aspartate (NMDA) and non-NMDA], it follows that both receptor classes may play a role in ischemic neuronal degeneration. Although several laboratories have reported that NMDA receptor antagonists confer protection in vivo against ischemic neuronal degeneration, very little is known about the ability of non-NMDA antagonists to confer such protection, a major reason being that non-NMDA antagonists that penetrate blood-brain barriers have not been available. In the present study, we examined the ability of NMDA or non-NMDA antagonists, either individually or in combination, to prevent neuronal degeneration in vivo in the adult rat retina rendered ischemic by dye/photothrombotic occlusion of retinal blood vessels. In this model, delivery of drugs to the ischemic tissue is assured by intravitreal administration. Intravitreal administration of the NMDA antagonist, MK-801, reduced the severity of ischemic damage approximately 50% (a ceiling effect that could not be increased by administering higher doses). The predominantly non-NMDA antagonist, CNQX, when administered in the highest dose permitted by its solubility limitations, provided equivocal (statistically nonsignificant) protection, but the two drugs combined provided greater than 80% protection.(ABSTRACT TRUNCATED AT 250 WORDS)
Mosinger
J L
JL
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110.
Price
M T
MT
Bai
H Y
HY
Xiao
H
H
Wozniak
D F
DF
Olney
J W
JW
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007511:Ischemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008027:Light / Q000009:adverse effects; D009410:Nerve Degeneration / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012170:Retinal Vein Occlusion / Q000150:complications / Q000209:etiology; D012171:Retinal Vessels
D016194:Receptors, N-Methyl-D-Aspartate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid