AMELIORATION BY CYCLOSPORINE-A OF BRAIN-DAMAGE IN TRANSIENT FOREBRAINISCHEMIA IN THE RAT

The immunosuppressant drug cyclosporin A (CsA) is considered to be inh erently protective in conditions of ischemia, e.g. in hepatic and card iac tissue. However, investigations of effects of CsA on neuronal tiss ue have been contradictory, probably because the blood-brain barrier ( BBB) is virtually impermeable to CsA. In the present study, we exploit ed the finding that the insertion of a syringe needle into brain paren chyma obviously disrupts the BBB and allows influx of CsA, and explore d whether CsA, given as intraperitoneal injections daily for 1 week be fore and 1 week after forebrain ischemia of 7 or 10 min duration, amel iorates the damage incurred to the hippocampal CA 1 sector. In other e xperiments, the needle insertion and the first i.p. injection of CsA w ere made 30 min after the start of recirculation, with continued daily administration of CsA during the postinsult week. In animals which we re injected with CsA in daily doses of 10 mg kg(-1), but in which no n eedle was inserted, the drug failed to ameliorate CA1 damage, whether the ischemia had a duration of 7 or 10 min. Likewise, needle insertion had no effect on CA1 damage if CsA was not administered. In contrast, when CsA was given to animals with a needle insertion, CA1 damage was dramatically ameliorated, whether treatment was initiated 1 week befo re ischemia, or 30 min after the start of recirculation. The effect of CsA seemed larger than that of any other drug proposed to have an ant i-ischemic effect in forebrain/global ischemia. Injection of tritiated CsA in one animal with BBB disruption lead to detectable radioactivit y throughout the ventricular system, suggesting a generalised increase of the entry of CsA across the BBB. The results demonstrate that immu nosuppressants of the type represented by CsA markedly ameliorate dela yed neuronal damage after transient forebrain ischemia, provided that they can pass the BBB. It is discussed whether the effect of the drug is one involving calcineurin, a protein phosphatase, or if CsA counter acts a permeability transition of the inner mitochondrial membrane, as sumed to occur in response to adverse conditions, e.g. gradual accumul ation of Ca2+ in the mitochondria in the postischemic period. (C) 1998 Elsevier Science B.V. All rights reserved.