Selective protection against AMPA- and kainate-evoked neurotoxicity by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahyd roisoquinoline- 3-carboxylic acid (LY293558) and its racemate (LY215490).
Glutamate receptor-mediated excitotoxicity is linked to the activation of multiple receptors including those activated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate. In this study, the novel glutamate receptor antagonist, as its active isomer (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahyd roisoquinoline-3- carboxylic acid ((-)LY293558) and it's +/- racemate (LY215490), was examined for neuroprotectant effects against excitotoxic injury in vitro and in vivo. This agent selectively protected against AMPA and kainate injury in cultured primary rat hippocampal neurons, an in vivo rat striatal neurotoxicity model, and against agonist-evoked seizures in mice. Thus, (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydr -oisguino-line-3-carboxylic acid represents a novel receptor selective and potent systemically active AMPA/kainate receptor antagonist for exploring neuroprotection via non-NMDA receptor mechanisms.
Schoepp
D D
DD
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
Salhoff
C R
CR
Fuson
K S
KS
Sacaan
A I
AI
Tizzano
J P
JP
Ornstein
P L
PL
May
P C
PC
D000818:Animals; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013237:Stereoisomerism; D013777:Tetrazoles / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D007608:Kainic Acid; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D013777:Tetrazoles; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C082309:tezampanel