The critical threshold of 3-nitropropionic acid-induced ischemic tolerance in the rat.
3-Nitropropionic acid (3-NPA) is a suicide inactivator of succinate dehydrogenase (SDH), commonly used as a pharmacological model of Huntington's disease in rodents. Several studies have shown that a single administration of 3-NPA given systemically provides subsequent ischemic tolerance. The present study has tested the hypothesis that 3-NPA is capable of inducing tolerance in a model of permanent focal cerebral ischemia and whether 3-NPA can be truly applicable as a tolerance-inducer to ischemia. Rats given 3-NPA intraperitoneally revealed that the mortality of 3-NPA of 15, 20, and 25 mg/kg groups was 20.5, 38.8, and 83.3%, respectively. All rats survived without behavioral sequelae at smaller doses. Three days after 3-NPA preconditioning, the rats showing no behavioral changes underwent the permanent middle cerebral artery occlusion. The groups treated with 10 and 15 mg/kg of 3-NPA showed significantly reduced neurological deficits and infarction volumes in comparison with the control group, whereas the groups treated with 5 and 20 mg/kg of 3-NPA revealed no tolerance effects. When the regional SDH activity (% of control) was photometrically semi-quantified, it was observed that the activity was reduced to 90.8, 76.1, 67.8, and 64.3% in the outer layers of the cerebral cortex, and to 79.4, 67.5, 63.2, and 62.9% in the striatum 1 h after 3-NPA application (5, 10, 15, 20 mg/kg), respectively. In conclusion, although the preconditioning with 3-NPA is clearly shown in the setting of permanent ischemia, the preconditioning with this mitochondrial toxin demonstrated a rather narrow safety margin (critical threshold).
Hoshi
Akihiko
A
Department of Neurology, Fukushima Medical University, Fukushima 960-1295, Japan.
Nakahara
Toshiki
T
Ogata
Masahiro
M
Yamamoto
Teiji
T
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003292:Convulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D003292:Convulsants; D009574:Nitro Compounds; D011422:Propionates; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid