Effect of AMPA receptor antagonist YM872 on cerebral hematoma size and neurological recovery in the intracerebral hemorrhage rat model.
[2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate (YM872 or zonampanel), an AMPA receptor antagonist, is in clinical development for acute ischemic cerebral infarction. Stroke patients are prone to have subsequent intracerebral hemorrhages. In order to predict potential adverse effects, YM872 was tested in a rat model with collagenase-induced intracerebral hemorrhage. The morphologically determined hematoma volumes after 24 h were compared between animal groups intravenously infused with 3600 U/kg/h heparin for 30 min, or with 20 or 40 mg/kg/h of YM872, or placebo for 4 h. Heparin enlarged hematoma volume, but neither dose of YM872 affected hematoma size. In a separate study, neurological deficits were scored at various days after intracerebral hemorrhage induction in animals with intravenous infusion for 24 h of 10 or 20 mg/kg/h YM872, or saline. The YM872 groups scored significantly better than the saline group at 14 days. These data suggest that YM872 does not exacerbate intracerebral hemorrhage and might accelerate recovery.
Terai
Kazuhiro
K
Applied Pharmacology Research, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Ibaraki, Tsukuba 305-8585, Japan. terai.kazuuhiro@yamanouchi.co.jp
Suzuki
Masanori
M
Sasamata
Masao
M
Yatsugi
Shin ichi
Si
Yamaguchi
Tokio
T
Miyata
Keiji
K
D000818:Animals; D001284:Atrophy / Q000139:chemically induced / Q000473:pathology; D001929:Brain Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D020520:Brain Infarction / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017364:Collagenases; D004305:Dose-Response Relationship, Drug; D006406:Hematoma / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D006493:Heparin / Q000009:adverse effects; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D011810:Quinoxalines / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D011810:Quinoxalines; D018091:Receptors, AMPA; C110629:YM 872; D006493:Heparin; D017364:Collagenases