title: Cyclosporin A enhances survival, ameliorates brain damage, and prevents secondary mitochondrial dysfunction after a 30-minute period of transient cerebral ischemia.
abstract: Cyclosporin A (CsA) has been shown to be efficacious in protecting against ischemic injury after short periods (5 to 10 min) of forebrain ischemia. The present experiments were undertaken to study if a long period of forebrain ischemia (30 min), induced at a brain temperature of 37 degrees C, is compatible with survival and if the brain damage incurred can be ameliorated by CsA. The results showed that animals subjected to 30 min of forebrain ischemia at a brain temperature of 37 degrees C failed to survive after the first 24 h of recovery and showed extensive neuronal necrosis in all selectively vulnerable regions after 1 day of survival. CsA, when injected in combination with an intracerebral lesion to open the blood-brain barrier, markedly prolonged the survival time. CsA-injected animals also showed amelioration of histological lesions, an effect that was sustained for at least 4 days. Experiments with mitochondria isolated from the neocortex and hippocampus showed that state 3 respiratory rates decreased during ischemia, recovered after 1 and 3 h of recirculation, and then showed a secondary decline at 6 h. Administration of CsA prevented this secondary decline. Measurements of neocortical cerebral blood flow showed that there was no secondary hypoperfusion prior to secondary mitochondrial dysfunction, implying that changes in blood flow may not be responsible for the rapidly developing, secondary brain damage. The results thus demonstrate that if brain temperature is upheld at 37 degrees C, a 30-min period of ischemia is not compatible with survival after the first day of recovery, and gross histopathological damage develops within that period. CsA was efficacious in prolonging animal survival, ameliorating brain damage, and preventing the secondary mitochondrial dysfunction. Since CsA blocks the mitochondrial permeability transition pore its action may, at least in part, be on mitochondrial integrity and function.
authors.affiliation: Center for the Study of Neurological Disease, The Queen's Medical Center, Honolulu, Hawaii 96813, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Li
authors.forename: T
authors.initials: T
authors.lastname: Kristián
authors.forename: Q P
authors.initials: QP
authors.lastname: He
authors.forename: B K
authors.initials: BK
authors.lastname: Siesjö
mesh_terms: D000818:Animals; D001925:Brain Damage, Chronic / Q000401:mortality* / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000150:complications* / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D016572:Cyclosporine