Relationship between the neuroprotective effect of Na+/H+ exchanger inhibitor SM-20220 and the timing of its administration in a transient middle cerebral artery occlusion model of rats.
The aim of this study was to determine the relationship between the neuroprotective effect of SM-20220 (N(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate) and the timing of its administration in an experimental stroke model. Two hours of occlusion followed by 22 h of perfusion of the left middle cerebral artery (MCA) was performed by inserting a nylon thread into the MCA to occlude it, and pulling the thread to initiate reperfusion. Intravenous infusion of SM-20220 for 1 h reduced the infarct volume at doses of 0.2-0.8 mg/kg in a dose-dependent manner without causing changes in the systemic arterial blood pressure or blood gases, when SM-20220 administration was started 1 h after the onset of occlusion. Administration of SM-20220 at a dose of 0.4 mg/kg also reduced the edema formation induced by ischemia. In contrast, SM-20220 failed to reduce the infarction, even at 1.6 mg/kg, when administration was started 2 h after the onset of occlusion. Thus, the therapeutic time window of SM-20220 for this transient MCA occlusion model is 1 h. Daily administration of SM-20220 (0.4 mg/kg) for the 7 d following 1.5 h of middle cerebral artery occlusion reduced the infarct volume with statistical significance (p<0.05), showing that SM-20220 did not merely delay but prevented ischemic damage.
Horikawa
N
N
Research Division, Sumitomo Pharmaceuticals Co, Ltd, Osaka, Japan. horikawa@sumitomopharm.co.jp
Kuribayashi
Y
Y
Matsui
K
K
Ohashi
N
N
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000502:physiology; D001834:Body Water / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013997:Time Factors
D000577:Amides; D004791:Enzyme Inhibitors; D007211:Indoles; D018696:Neuroprotective Agents; C401341:SM 20220; D017923:Sodium-Hydrogen Exchangers