Neuroprotective effects of the neuronal Ca2+ channel blockers, LY042826 and LY393615 in vivo

In the present studies, we have examined the effects of two new Ca2+ channe l blockers, LY042826 (N-{2[(2-methylphenyl)(phenyl)methoxy]ethyl}-1-butanam ine hydrochloride) and LY393615 (N-{[5,5-bis(4-fluorophenyl)tetrahydro-2-fu ranyl]methyl}-1-butanamine hydrochloride) in the gerbil model of global and the endothelin-1 rat model of focal cerebral ischaemia in vivo. Results in dicated that both LY042826 (P < 0.01) and LY393615 (P < 0.001) provided sig nificant protection against ischaemia-induced hippocampal damage in global cerebral ischaemia when dosed at 15 mg/kg i.p. 30 min before and 2 h 30 min after occlusion. In further studies, LY042826 (P < 0.05) and LY393615 (P < 0.01) were also protective when administered at 15 mg/kg i.p. immediately after and 3 h post-occlusion. Both compounds also provided a significant re duction in the infarct volume following endothelin-l middle cerebral artery occlusion in the rat when administered at 15 mg/kg i.p, immediately (P < 0 .05) after occlusion. This protection was similar to that observed with the NMDA receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine), MK-801 in this model. In conclusion and as a res ult of the present studies, we report that the novel Ca2+ channel blockers, LY042826 and LY393615 protect against ischaemia-induced brain injury in ge rbils and rats. The compounds were neuroprotective when administered post-o cclusion and may therefore be useful anti-ischaemic agents. (C) 2000 Elsevi er Science B.V. All rights reserved.