Neuroprotective effects of the neuronal Ca(2+) channel blockers, LY042826 and LY393615 in vivo.
In the present studies, we have examined the effects of two new Ca(2+) channel blockers, LY042826 (N-[2-[(2-methylphenyl)(phenyl)methoxy]ethyl]-1-butanamine hydrochloride) and LY393615 (N-[[5, 5-bis(4-fluorophenyl)tetrahydro-2-furanyl]methyl]-1-butanamine hydrochloride) in the gerbil model of global and the endothelin-1 rat model of focal cerebral ischaemia in vivo. Results indicated that both LY042826 (P<0.01) and LY393615 (P<0.001) provided significant 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 reduction in the infarct volume following endothelin-1 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 result of the present studies, we report that the novel Ca(2+) channel blockers, LY042826 and LY393615 protect against ischaemia-induced brain injury in gerbils and rats. The compounds were neuroprotective when administered post-occlusion and may therefore be useful anti-ischaemic agents.
Hicks
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CA
Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Surrey GU20 6PH, Windlesham, UK.
Ward
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MA
O'Neill
M J
MJ
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002082:Butylamines / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002452:Cell Count; D016291:Dizocilpine Maleate / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology*; D005849:Gerbillinae; D006146:Guanidines / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000517:prevention & control*; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology
D001713:Biphenyl Compounds; D002082:Butylamines; C096441:CNS 1237; D002121:Calcium Channel Blockers; D019332:Endothelin-1; D005663:Furans; D006146:Guanidines; D018696:Neuroprotective Agents; D010880:Piperidines; C088314:NNC 09-0026; C085883:SB 201823-A; D016291:Dizocilpine Maleate; C420105:LY 393615; C420104:LY 042826