Effect of D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid on ischemic brain damage induced by four-vessel occlusion in rats.
The effect of the new competitive N-methyl-D-aspartate (NMDA) antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CAS 137424-81-8, CGP 40116) was evaluated in a rat four-vessel occlusion model and compared to the effect of another NMDA antagonist (+/-)-cis-4-phosphonomethyl-piperadine-2-carboxylic acid (CAS 110347-85-8, CGS 19755) under the same conditions. Drugs were administered intravenously immediately following occlusion. At 72 h after the ischemia, latency in the passive avoidance test was significantly shorter in ischemic control rats in comparison with sham-operated rats. CGP 40116 at the dose of 10 mg/kg and CGS 19755 at the doses of 10 and 30 mg/kg significantly lengthened the latency. At 2 weeks after ischemia, ischemic control rats showed no differences in latency compared to sham-operated rats. The number of survived neurons of control rats was significantly less than that of sham-operated rats at 72 h and 2 weeks after ischemia. CGP 40116 at the doses of 3 and 10 mg/kg and CGS 19755 at the doses of 10 and 30 mg/kg significantly increased the number of survived neurons. Adenosine triphosphate (ATP) level in striatum of control rats was significantly lower than that of sham-operated rats at 24 h after ischemia when an acquisition trial was performed in the passive avoidance test. CGP 40116 at the dose of 10 mg/kg and CGS 19755 at the dose of 30 mg/kg ameliorated the decrease. These results suggest that CGP 40116 might have an ameliorative effect on the memory deficits in the passive avoidance test after ischemic injuries through the suppression of changes in brain energy metabolism.
Okada
M
M
Drug Discovery Research Unit, Ciba-Geigy Japan Ltd., Takarazuka, Japan.
Fujimura
Y
Y
Ueda
H
H
Kometani
M
M
Nakao
K
K
Inukai
T
T
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D051381:Rats; D011916:Rats, Inbred F344
D018691:Excitatory Amino Acid Antagonists; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D000255:Adenosine Triphosphate