Amelioration by cyclosporin A of brain damage in transient forebrain ischemia in the rat.
The immunosuppressant drug cyclosporin A (CsA) is considered to be inherently protective in conditions of ischemia, e.g. in hepatic and cardiac tissue. However, investigations of effects of CsA on neuronal tissue have been contradictory, probably because the blood-brain barrier (BBB) is virtually impermeable to CsA. In the present study, we exploited the finding that the insertion of a syringe needle into brain parenchyma obviously disrupts the BBB and allows influx of CsA, and explored whether CsA, given as intraperitoneal injections daily for 1 week before and 1 week after forebrain ischemia of 7 or 10 min duration, ameliorates the damage incurred to the hippocampal CA 1 sector. In other experiments, the needle insertion and the first i.p. injection of CsA were made 30 min after the start of recirculation, with continued daily administration of CsA during the postinsult week. In animals which were injected with CsA in daily doses of 10 mg kg-1, but in which no needle 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 before 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 anti-ischemic effect in forebrain/global ischemia. Injection of tritiated CsA in one animal with BBB disruption lead to detectable radioactivity throughout the ventricular system, suggesting a generalised increase of the entry of CsA across the BBB. The results demonstrate that immunosuppressants of the type represented by CsA markedly ameliorate delayed 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 counteracts a permeability transition of the inner mitochondrial membrane, assumed to occur in response to adverse conditions, e.g. gradual accumulation of Ca2+ in the mitochondria in the postischemic period.
Uchino
H
H
Department of Anesthesiology, Tokyo Medical College, 6-7-1 Nishishinjuku Shinjuku-ku 160, Tokyo, Japan.
Elmér
E
E
Uchino
K
K
Li
P A
PA
He
Q P
QP
Smith
M L
ML
Siesjö
B K
BK
D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016548:Prosencephalon / Q000098:blood supply / Q000187:drug effects*; D051381:Rats; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D016572:Cyclosporine