SNX-111, A NOVEL, PRESYNAPTIC N-TYPE CALCIUM-CHANNEL ANTAGONIST, IS NEUROPROTECTIVE AGAINST FOCAL CEREBRAL-ISCHEMIA IN RABBITS

Cytosolic Ca2+ overload has been proposed as a main cause of neuronal injury during cerebral ischemia. SNX-111, a synthetic product of the n aturally occurring omega-conotoxin MVIIA, is a novel, presynaptic N-ty pe Ca2+ channel antagonist and has been reported to be neuroprotective against cerebral ischemia. We studied the neuroprotective effects of SNX-111 in a rabbit model of focal cerebral ischemia. New Zealand whit e male rabbits (2.5-3.5 kg) were given 1 mg/kg/h i.v. SNX-111 (n=8) or normal saline (n=8) 10 min after onset of a 2-h period of transient f ocal cerebral ischemia induced by occlusion of the left middle cerebra l, anterior cerebral and internal carotid arteries followed by 4 h rep erfusion. SNX-111 significantly attenuated overall cortical ischemic n euronal damage by 44% (saline, 38.7+/-3.0%; SNX-111, 21.5+/-6.0%, P<0. 05) and regions of hyperintensity on T2-weighted MRI by 30% (saline, 7 0.6+/-4.0%; SNX-111, 49.3+/-11.0%, P<0.05). No significant difference in (regional cerebral blood flow) rCBF or MAP (mean arterial blood pre ssure) was found between SNX-111- and saline-treated rabbits suggestin g that neuroprotection is due to a cellular effect. We conclude that S NX-111 reduces ischemic injury in this model. Its use as a clinical ne uroprotective agent for cerebrovascular surgery or stroke should be in vestigated further. (C) 1997 Elsevier Science B.V.