The neuroprotective effects of the decahydroisoquinoline, LY 215490; a novel AMPA antagonist in focal ischaemia.
LY 215490 (3RS,4aRS,6RS,8aRS)-6-[2-(1(2)H-tetrazole-5- yl)ethyl]decahydroisoquinoline-3-carboxylic acid), a novel, selective, competitive and systemically active AMPA receptor antagonist was tested as a neuroprotective agent against focal ischaemia in a model of permanent MCA occlusion in the rat. LY 215490 was administered at a dose of 10, 30 or 100 mg/kg 30 min prior to and post-MCA occlusion. The animals were allowed to survive for 24 hr, following which time the brains were processed for volumetric analysis of the infarct size. The low dose of LY 215490 was not effective against the infarct volume in the hemisphere, cortex or caudate. The 2 x 30 mg/kg dose of LY 215490 resulted in 25 and 31% protection against the volume of hemispheric and cortical ischaemic damage, respectively. The highest dose of LY 215490 resulted in a reduced neuroprotective effect with 23 and 27% protection against the volume of hemispheric and cortical ischaemic damage, respectively. The slightly reduced neuroprotective effect of the highest dosing regimen may be due to the respiratory problems seen with this dose. Neither of the two neuroprotective doses of LY 215490 produced any reduction in the volume of caudate damage which represents the core of the infarct.
Gill
R
R
Royal Veterinary College, Department of Veterinary Basic Sciences, London, U.K.
Lodge
D
D
D000704:Analysis of Variance; D000818:Animals; D002546:Ischemic Attack, Transient / Q000517:prevention & control*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009410:Nerve Degeneration / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013777:Tetrazoles / Q000494:pharmacology*
D007546:Isoquinolines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; C082309:tezampanel