The neuroprotective effect of a potent and selective inhibitor of type I NOS (L-MIN) in a rat model of focal cerebral ischaemia.
Our newly synthesized delta-(S-methylisothioureido)-L-norvaline (L-MIN) was shown to have potent inhibitory effects on Ca(2+)-dependent and constitutively expressed neuronal nitric oxide synthase (type I NOS) when compared to other commonly recognized NOS inhibitors and produced an IC50 value of 5.7 nM. By contrast, this compound exhibited more than 40-fold weaker inhibitory effects on the other NOS isoforms. Administration of L-MIN (0.1, 0.3 and 1 mg kg-1, i.p.) to rats immediately after 2 h middle cerebral artery occlusion and 2 h reperfusion reduced infarct size in a dose-dependent manner. These results suggest that type I NOS activation has a crucial role in the pathogenic cellular mechanisms underlying cerebral ischaemia.
Nagafuji
T
T
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Company, Ltd., Shizuoka, Japan.
Sugiyama
M
M
Muto
A
A
Makino
T
T
Miyauchi
T
T
Nabata
H
H
D000704:Analysis of Variance; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D002536:Cerebral Arteries; D002956:Citrulline / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005069:Evaluation Studies as Topic; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D018696:Neuroprotective Agents; D002956:Citrulline; D019001:Nitric Oxide Synthase; D013890:Thiourea; C086717:S-methylthiocitrulline