Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury

The neuroprotective properties of drugs binding to FKBP12, with and without subsequent inhibition of calcineurin, were investigated in rat models of i schemic embolic stroke. Drug effects on brain infarct Volumes evoked by tra nsient middle cerebral artery occlusion (MCAO) and by permanent MCAO were d etermined in vivo by T2-weighted magnetic resonance imaging and post mortem by triphenyltetrazolium chloride staining and histology. Drugs binding to FKBP12 and inhibiting calcineurin, such as FK506 and SDZ ASM 981, dose depe ndently reduced the infarct volumes, determined 48 h after MCAO by both mag netic resonance imaging and triphenyltetrazolium chloride staining but only in the transient MCAO model. In vivo potencies to reduce brain infarcts pa ralleled the in vitro potencies to inhibit calcineurin, Histological staini ng after 6 days of survival showed that the neuroprotective effects were pe rmanent, Rapamycin, known to bind with similar affinity to FKBP12 but not t o inhibit calcineurin, was not neuroprotective but abolished the neuroprote ctive effects of FK506 when coadministered. In the permanent MCAO models, F K506 showed no effect when injected before and little effect when injected after MCAO. Measurements of core temperatures after MCAO in controls and dr ug-treated rats do not support hypothermia being the mechanism responsible for neuroprotection. We conclude that drugs inhibiting calcineurin activity are neuroprotective in focal cerebral ischemia/reperfusion but not in perm anent ischemia models, possibly by preventing reperfusion injury.