Antisense oligodeoxynucleotides to NMDA-R1 receptor channel protect cortical neurons from excitotoxicity and reduce focal ischaemic infarctions.
The excitatory amino acid, L-glutamate, acting through its N-methyl-D-aspartate (NMDA) receptor, may contribute to neuronal death following cerebral vascular occlusion. In support of this hypothesis, NMDA receptor antagonists reduce the volume of infarction produced by occlusion of the middle cerebral artery in vivo and attenuate Ca2+ influx and neuronal death elicited by L-glutamate or NMDA in vitro. A complementary DNA coding for a major component of the NMDA receptor channel complex, a single protein of M(r) 105.5K (NMDA-R1), has been isolated from rat brain. Here we demonstrate that inhibition of the synthesis of NMDA-R1 by treatment with antisense oligodeoxynucleotides 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.
Wahlestedt
C
C
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021.
Golanov
E
E
Yamamoto
S
S
Yee
F
F
Ericson
H
H
Yoo
H
H
Inturrisi
C E
CE
Reis
D J
DJ
D000818:Animals; D001483:Base Sequence; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002536:Cerebral Arteries; D002540:Cerebral Cortex / Q000166:cytology; D002544:Cerebral Infarction / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D015536:Down-Regulation; D008297:Male; D008969:Molecular Sequence Data; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D002118:Calcium