LY393615, a novel neuronal Ca(2+) and Na(+) channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia.

Abstract

In the present studies we have examined the effects of a new calcium channel 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 cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia-hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 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 following Endothelin-1 (Et-1) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or 1 h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model 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 in infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, with 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.

• Authors: M J O'Neill, C A Hicks, M A Ward, D J Osborne, G Wishart, K S Mathews, D P McLaughlin, J A Stamford, D R McCarty, K E Patrick, C Roman, J H Fleisch, J Gilmore, J R Boot
• Journal: Brain research (Brain Res) Vol. 888 Issue 1 Pg. 138-149 (Jan 05 2001) ISSN: 0006-8993 [Print] Netherlands
• PMID: 11146060 (Publication Type: Journal Article)

Chemical References

• Butylamines
• Calcium Channel Blockers
• Furans
• Neuroprotective Agents
• Sodium Channel Blockers
• LY 393615

Topics

• Animals
• Brain Ischemia (drug therapy, pathology)
• Butylamines (chemistry, pharmacology)
• Calcium Channel Blockers (chemistry, pharmacology)
• Cell Survival (drug effects)
• Disease Models, Animal
• Furans (chemistry, pharmacology)
• Gerbillinae
• Hippocampus (blood supply, pathology)
• In Vitro Techniques
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• Male
• Neuroprotective Agents (chemistry, pharmacology)
• Purkinje Cells (drug effects, pathology)
• Rats
• Rats, Wistar
• Sodium Channel Blockers