Neuroprotective effects of the neuronal Ca(2+) channel blockers, LY042826 and LY393615 in vivo.

Abstract

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.

• Authors: C A Hicks, M A Ward, M J O'Neill
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 408 Issue 3 Pg. 241-8 (Nov 24 2000) ISSN: 0014-2999 [Print] Netherlands
• PMID: 11090640 (Publication Type: Journal Article)

Chemical References

• Biphenyl Compounds
• Butylamines
• CNS 1237
• Calcium Channel Blockers
• Endothelin-1
• Furans
• Guanidines
• Neuroprotective Agents
• Piperidines
• NNC 09-0026
• SB 201823-A
• Dizocilpine Maleate
• LY 393615
• LY 042826

Topics

• Animals
• Biphenyl Compounds (pharmacology)
• Butylamines (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Cell Count
• Dizocilpine Maleate (pharmacology)
• Endothelin-1 (pharmacology)
• Furans (pharmacology)
• Gerbillinae
• Guanidines (pharmacology)
• Hippocampus (drug effects, pathology)
• Ischemic Attack, Transient (prevention & control)
• Male
• Neurons (chemistry, cytology, drug effects)
• Neuroprotective Agents (pharmacology)
• Piperidines (pharmacology)