Antisense oligodeoxynucleotides to NMDA-R1 receptor channel protect cortical neurons from excitotoxicity and reduce focal ischaemic infarctions

Abstract

The excitatory amino acid, L-glutamate, acting through its N-methyl-D-aspartate (NMDA) receptor, may contribute to neuronal death following cerebral vascular occlusion1-3. In support of this hypothesis, NMDA receptor antagonists reduce the volume of infarction produced by occlusion of the middle cerebral artery in vivo4,5 and attenuate Ca2+ influx and neuronal death elicited by L-glutamate or NMDA in vitro3,6. A complementary DNA coding for a major component of the NMDA receptor channel complex, a single protein of Mr 105.5K (NMDA-R1), has been isolated from rat brain7. Here we demonstrate that inhibition of the synthesis of NMDA-R1 by treatment with antisense oligodeoxy-nucleotides selectively reduces the expression of NMDA receptors, prevents the neurotoxicity elicited by NMDA in vitro and reduces the volume of the focal ischaemic infarction produced by occlusion of the middle cerebral artery in the rat.