Protective effect of N-(3-(aminomethyl)benzyl) acetamidine, an inducible nitric oxide synthase inhibitor, in brain slices exposed to oxygen-glucose deprivation.
It has been suggested that large amounts of nitric oxide (NO) produced by inducible NO synthase are involved in the mechanisms of neurotoxicity after cerebral ischaemia. We have recently demonstrated that inducible NO synthase was expressed within hours after rat forebrain slices were exposed to oxygen-glucose deprivation. Therefore, we sought to determine whether NO produced by inducible NO synthase contributes to tissue damage in this model, by using a new, highly selective, inhibitor of inducible NO synthase, N-(3-(aminomethyl)benzyl)acetamidine (1400W). We found that incubation with 1400W from the start of the oxygen-glucose deprivation period until the end of the experiment decreases tissue damage determined as lactate dehydrogenase (LDH) efflux 4 h after the oxygen-glucose deprivation period, the time at which inducible NO synthase expression is maximal in this model. This effect may be a result of direct inhibition of inducible NO synthase activity, raising the possibility of a clinical use of selective inhibitors of this NO synthase isoform in the management of cerebral ischaemia.
Cárdenas
A
A
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Spain.
De Alba
J
J
Moro
M A
MA
Leza
J C
JC
Lorenzo
P
P
Lizasoain
I
I
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D016548:Prosencephalon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D020011:Protective Agents; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005947:Glucose