ARL 17477 dihydrochloride is a selective and potent neuronal nitrogen oxide synthase (nNOS) inhibitor with IC50 values of 1 and 17μM for nNOS and endothelial NOS, respectively [1].
Neuronal NOS (nNOS) plays an important role in the development of ischaemic brain necrosis while endothelial NOS (eNOS) protects brain tissue through increasing ischaemic regional cerebral blood flow [1].
In rats after transient MCA occlusion, ARL 17477 (1mg/kg, 3mg/kg and 10mg/kg) reduced ischemic infarct volume by 53%, 23% and 6.5% respectively in a dose-dependent way. ARL 17477 (10 mg/kg) significantly reduced regional cerebral blood flow (rCBF) by 27±5.3% and 24±14.08%. Also, it reduced cortical NOS activity by 86±14.9% and 91±8.9% at 10 min or 3 h, respectively [2]. In the global cerebral ischaemia gerbil model, the combination of MK-801 with ARL 17477 provided 44% greater protection than the total protection or either alone. Likewise, the combination of LY293558 with ARL 17477 provided 35% greater protection than total protection of either compound alone [3].
References:
[1]. O'Neill MJ, Murray TK, McCarty DR, et al. ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia. Brain Res, 2000, 871(2): 234-244.
[2]. Zhang ZG, Reif D, Macdonald J, et al. ARL 17477, a potent and selective neuronal NOS inhibitor decreases infarct volume after transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab, 1996, 16(4): 599-604.
[3]. Hicks CA, Ward MA, Swettenham JB, et al. Synergistic neuroprotective effects by combining an NMDA or AMPA receptor antagonist with nitric oxide synthase inhibitors in global cerebral ischaemia. Eur J Pharmacol, 1999, 381(2-3): 113-119.