Restricted clinical efficacy of cyclosporin A on rat transient middle cerebral artery occlusion.
The immunosuppressant cyclosporin A (CsA) has been shown to have neuroprotective action. The inhibition of both calcineurin activation and mitochondrial permeability transition pore (mtPTP) opening are considered the primary neuroprotective mechanisms of CsA. Here we have evaluated the effect of CsA on significantly reducing infarct size induced by transient middle cerebral artery occlusion (MCAO) in rats, and examined variable therapeutic applications for brain infarction. Experimental rats were divided into 12 groups according to: CsA administration time (immediately after occlusion or immediately after reperfusion); dosage (between 10 and 50 mg/kg); route (i.v. or i.p.); and with or without needle insertion, which hypothetically disrupts the blood brain barrier (BBB). Neuroprotective effects of CsA were hardly noticeable when administered immediately after occlusion or by i.v. injection. By needle insertion, CsA administration significantly reduced infarct size, although vehicle treatment also reduced infarct size compared with nontreatment animals, i.e. no needle insertion. These results suggest that needle insertion allows endogenous neuroprotective substances to pass into the brain. Furthermore, single dosages over 30 mg/kg CsA were excessive and negated potential neuroprotective effects. However, two i.p. administrations of 20 mg/kg CsA immediately and 24 hrs after reperfusion significantly ameliorated the infarct size compared to the vehicle-treated group. We conclude that CsA exhibits significant neuroprotective activity, although its therapeutic application for stroke may be limited by very strict and precise management requirements.
Matsumoto
Shohei
S
Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan. Shohei@tokyo-med-ac.jp
Isshiki
Atsushi
A
Watanabe
Yasuo
Y
Wieloch
Tadeusz
T
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy*; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology; D004396:Coloring Agents; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D007274:Injections, Intraperitoneal; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D020768:Middle Cerebral Artery; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013778:Tetrazolium Salts
D004396:Coloring Agents; D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D016572:Cyclosporine