LY393615, a novel neuronal Ca2+ and Na+ channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia

In the present studies we have examined the effects of a new calcium channe l blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl ]methylamine hydrochloride, NCC1048) in a model of hypoxia-hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cereb ral ischaemia in vivo. Results indicated that LY393615 protected against hy poxia-hypoglycaemic insults in brain slices and also provided significant p rotection against ischaemia-induced hippocampal damage in gerbil global cer ebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 3 0 min before and 2 h 30 min after occlusion. The compound penetrated the br ain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In furthe r studies LY393615 was protective 1 h post-occlusion when administered at 1 5 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615 dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume follo wing Endothelin-l (Et-l) middle cerebral artery occlusion in the rat when a dministration was initiated immediately (P<0.01) or I h (P<0.05) after occl usion. The compound was also evaluated in the intraluminal monofilament mod el of focal ischaemia. The animals had the middle cerebral artery occluded for 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction i n infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, wi th good bioavailability protects against neuronal damage caused by hypoxia- hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo . The compound is neuroprotective when administered post-occlusion and may therefore be a useful anti-ischaemic agent. (C) 2001 Elsevier Science B.V. All rights reserved.