Calcineurin inhibitors as neuroprotectants - Focus of tacrolimus and cyclosporin

Tacrolimus (FK506) and cyclosporin (cyclosporin-A) are potent immunosuppressants which are presently in clinical use for the treatment of allograft rejection. Recent studies suggest that tacrolimus and cyclosporin may also be of therapeutic benefit for the treatment of neurodegenerative disorders, in particular those associated with acute brain ischaemia. At immunosuppressive doses, tacrolimus is a powerful neuroprotectant in many experimental models of cerebral ischaemia: reducing infarct volume and improving neurological outcome. In rat focal ischaemia models neuroprotection can be elicited by a single injection of tacrolimus given up to 72 hours before or up to 2 hours after the insult. A similar postocclusion window of efficacy has been reported in the gerbil forebrain ischaemia model. These neuroprotective properties are also shared by cyclosporin, although the poor penetration of cyclosporin across the blood-brain barrier necessitates the use of high doses (20 mg/kg) of this drug to achieve neuroprotection. The observation that sirolimus (rapamycin) is not neuroprotective in models of focal cerebral ischaemia, but can effectively inhibit the neuroprotective effects of tacrolimus, supports the view that the protective effects of tacrolimus are mediated via the inhibition of calcineurin.