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.