Posttreatment with the immunosuppressant cyclosporin A in transient focal ischemia.
Cyclosporin A (CsA) reduces ischemic brain damage when administered in such a way that its penetration across the blood-brain barrier is enhanced. Since only pretreatment has previously been used in focal ischemia, the objective of the present study was to establish whether posttreatment is efficacious and to assess the window of therapeutic opportunity for CsA. To that end, CsA was given 5 min to 6 h after the start of reperfusion following 2 h transient ischemia, and infarct volume was assessed after 48 h by triphenyltetrazolium chloride staining. Attempts were made to circumvent the BBB to CsA by an intracerebral needle lesion, by an increase in the intravenous CsA dose, or by osmotic opening with intracarotid mannitol. The results were compared to those obtained with FK506. Intravenous CsA in a dose of 10 mg/kg failed to reduce infarct volume, unless preceded by a needle lesion. That procedure, and an increase in CsA dose to 50 mg/kg, reduced infarct volume to about 50% of control, but the higher dose had toxic side effects. The coupled intracarotid infusion of mannitol and CsA (10 mg/kg) was more efficacious, without overt side effects. However, mannitol proved dispensable since CsA alone reduced infarct volume to 30% of control, with a therapeutic window of 3-6 h. When given after 5 min of reflow, CsA reduced infarct volume to 10% of control and was clearly more neuroprotective than FK506. Possibly, this is because CsA blocks the mitochondrial permeability transition pore which is opened under adverse conditions.
Yoshimoto
T
T
Center for the Study of Neurological Disease, Queen's Medical Center, Honolulu, HI 96813, USA. tyoshimoto@cns.queens.org
Siesjö
B K
BK
D000818:Animals; D001786:Blood Glucose; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001831:Body Temperature; D001930:Brain Injuries / Q000188:drug therapy; D002245:Carbon Dioxide / Q000097:blood; D002339:Carotid Arteries; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004234:Diuretics, Osmotic / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D007269:Injections, Intra-Arterial; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D009995:Osmosis; D010100:Oxygen / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D012965:Sodium Chloride; D016559:Tacrolimus / Q000494:pharmacology; D014951:Wounds, Stab / Q000188:drug therapy
D001786:Blood Glucose; D004234:Diuretics, Osmotic; D007166:Immunosuppressive Agents; D002245:Carbon Dioxide; D008353:Mannitol; D012965:Sodium Chloride; D016572:Cyclosporine; D010100:Oxygen; D016559:Tacrolimus