Blocking the glycine-binding site of NMDA receptors prevents the progression of ischemic pathology induced by bilateral carotid artery occlusion in spontaneously hypertensive rats.
This study was designed to investigate the participation of N-methyl-D-aspartate (NMDA) receptors in the progression of the pathology induced by bilateral carotid artery occlusion (BCAo) in spontaneously hypertensive rats (SHRs). We examined the effects of the selective NMDA receptor glycine-binding site antagonist SM-18400 on the mortality rate, deterioration of neurological signs, and formation of brain edema in the SHR-BCAo model. SM-18400 (15 or 30 mg/kg) was administered via the tail vein immediately and 2 h after BCAo. Neurological signs were monitored continuously for 8 h after BCAo, and the mortality rates were followed for 5 days. All SM-18400-treated animals were still alive 5 h after BCAo, whereas 38% of the animals died in the vehicle-treated group. The mortality rates of the SM-18400-treated groups were still lower than those of the vehicle-treated group 5 days after BCAo. In addition, SM-18400 markedly prevented the deterioration of neurological signs. The water content of the telencephalon and diencephalon/mesencephalon in the vehicle-treated group, measured 3 h after BCAo, was significantly higher than in the sham-operated group. SM-18400 significantly inhibited the increase in water content in both regions in a dose-dependent manner. These findings suggest that NMDA receptors participate in the increase in the mortality rate, deterioration of neurological signs, and formation of brain edema following ischemic brain damage in the SHR-BCAo model, and that SM-18400 can prevent ischemic insults.
Ohtani
K
K
Research Center, Sumitomo Pharmaceuticals Co., Ltd., 3-1-98 Kasugadenaka, Konohana-ku, 554-0022, Osaka, Japan. ohtani@sumitomopharm.co.jp
Tanaka
H
H
Yasuda
H
H
Maruoka
Y
Y
Kawabe
A
A
Nakamura
M
M
D000818:Animals; D001665:Binding Sites / Q000187:drug effects* / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001834:Body Water / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D002341:Carotid Artery Thrombosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005998:Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D015996:Survival Rate
D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C113033:SM 18400; D005998:Glycine