Serine racemase deletion protects against cerebral ischemia and excitotoxicity.
D-Serine, formed from L-serine by serine racemase (SR), is a physiologic coagonist at NMDA receptors. Using mice with targeted deletion of SR, we demonstrate a role for D-serine in NMDA receptor-mediated neurotoxicity and stroke. Brain cultures of SR-deleted mice display markedly diminished nitric oxide (NO) formation and neurotoxicity. In intact SR knock-out mice, NO formation and nitrosylation of NO targets are substantially reduced. Infarct volume following middle cerebral artery occlusion is dramatically diminished in several regions of the brains of SR mutant mice despite evidence of increased NMDA receptor number and sensitivity.
Mustafa
Asif K
AK
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Ahmad
Abdullah S
AS
Zeynalov
Emil
E
Gazi
Sadia K
SK
Sikka
Gautam
G
Ehmsen
Jeffrey T
JT
Barrow
Roxanne K
RK
Coyle
Joseph T
JT
Snyder
Solomon H
SH
Doré
Sylvain
S
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology / Q000503:physiopathology; D020520:Brain Infarction / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D002478:Cells, Cultured; D019610:Cytoprotection / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D007536:Isomerism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009498:Neurotoxins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D009574:Nitro Compounds / Q000378:metabolism; D019998:Racemases and Epimerases / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D000099300:Serine Racemase
D009498:Neurotoxins; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D009574:Nitro Compounds; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase