tacrolimus and Arterial-Occlusive-Diseases

The neuroprotective properties of drugs binding to FKBP12, with and without subsequent inhibition of calcineurin, were investigated in rat models of ischemic embolic stroke. Drug effects on brain infarct volumes evoked by transient middle cerebral artery occlusion (MCAO) and by permanent MCAO were determined 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 dependently reduced the infarct volumes, determined 48 h after MCAO by both magnetic resonance imaging and triphenyltetrazolium chloride staining but only in the transient MCAO model. In vivo potencies to reduce brain infarcts paralleled the in vitro potencies to inhibit calcineurin. Histological staining after 6 days of survival showed that the neuroprotective effects were permanent. Rapamycin, known to bind with similar affinity to FKBP12 but not to inhibit calcineurin, was not neuroprotective but abolished the neuroprotective effects of FK506 when coadministered. In the permanent MCAO models, FK506 showed no effect when injected before and little effect when injected after MCAO. Measurements of core temperatures after MCAO in controls and drug-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 permanent ischemia models, possibly by preventing reperfusion injury.

Topics: Animals; Arterial Occlusive Diseases; Calcineurin Inhibitors; Cerebral Arteries; Cerebral Infarction; Dose-Response Relationship, Drug; Enzyme Inhibitors; Immunosuppressive Agents; Ischemic Attack, Transient; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Rats; Rats, Inbred SHR; Reperfusion Injury; Tacrolimus

In the present experiments, we compared the anti-ischemic effects of the immunosuppressants cyclosporin A (CsA) and FK506 in hyperglycemic animals subjected to 30 min of middle cerebral artery (MCA) occlusion. Both immunosuppressants were given as pre-treatment, the effect of treatment being evaluated by 2,3, 5-triphenyltetrazolium (TTC) staining after 3 days of recovery. Both FK506 and CsA reduced the infarct volume to less than 1/3 of control. In spite of CsA's known effect as a blocker of the mitochondrial transition (MPT) pore, it failed to give a more robust effect than FK506. If anything, FK506, which lacks an effect on the MPT pore, had a more pronounced anti-ischemic effect. We conclude that, in this model of infarction, an MPT may not play a major pathogenetic role.

Topics: Analysis of Variance; Animals; Arterial Occlusive Diseases; Cerebral Infarction; Cyclosporine; Hyperglycemia; Immunosuppressive Agents; Ischemic Attack, Transient; Male; Neuroprotective Agents; Rats; Rats, Wistar; Tacrolimus; Treatment Outcome

Topics: Animals; Arterial Occlusive Diseases; Cyclosporine; Disease Models, Animal; Male; Platelet Aggregation; Rats; Rats, Wistar; Tacrolimus; Thrombin; Thrombosis