SM-20220, a Na(+)/H(+) exchanger inhibitor: effects on ischemic brain damage through edema and neutrophil accumulation in a rat middle cerebral artery occlusion model.
The Na(+)/H(+) exchanger (NHE) is activated during ischemia-reperfusion in an effort to restore intracellular pH to normal levels. The NHE is recognized to exist as a distinct protein in the plasma membranes of a variety of cells. We investigated the pharmacological effects of a Na(+)/H(+) exchanger inhibitor, SM-20220 (N-(aminoiminomethyl)-1-methyl-1-H-indole-2-carboxamide methanesulfonate), on ischemic brain damage, edema and neutrophil accumulation at 72 h after middle cerebral artery (MCA) occlusion in a rat MCA occlusion model. SM-20220 was intravenously administered as a bolus injection immediately after occlusion, followed by a continuous infusion over 2.5 h. At 72 h after occlusion, the infract area was measured using hematoxylin-eosin staining and, using the same slices, neutrophils in the brain were immuno-stained with anti-myeloperoxidase (n=11). In a separate study, rat behavior was scored and scaled, and brains removed for the determination of water content by the dry-weight method. SM-20220 significantly (P<0.05) attenuated cerebral infarct volume, water content, and the neutrophil accumulation at 72 h after the MCA occlusion, and ameliorated neurological deficits. SM-20220, an NHE inhibitor prevented the progress of cerebral ischemic damage and edema following MCA occlusion in rats though a possible mechanism that may be due to the inhibition of neutrophil accumulation. The NHE in neutrophils may enhance the progress of cerebral damage following cerebral ischemia-reperfusion.
Department of Pharmacology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. yapplel@hama-med.ac.jp
Yasuhiro
Y
Suzuki
Yuji
Y
Matsumoto
Yasuhiko
Y
Ikeda
Kazunao
K
Kondo
Naohito
N
Ohashi
Kazuo
K
Umemura
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology* / Q000523:psychology; D002560:Cerebrovascular Circulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
D000577:Amides; D004791:Enzyme Inhibitors; D007211:Indoles; C401341:SM 20220; D017923:Sodium-Hydrogen Exchangers