CALCINEURIN INHIBITOR, FK506, PREVENTS REDUCTION IN THE BINDING-CAPACITY OF CYCLIC-AMP-DEPENDENT PROTEIN-KINASE IN ISCHEMIC GERBIL BRAIN

We examined the effects of FK506, a specific inhibitor of calcineurin, on the binding capacity of cyclic AMP-dependent protein kinase (cAMP- DPK) in gerbils subjected to 2-h cerebral hemispheric ischemia. FK506 (0.1 mg/kg) was infused intravenously at 15 min prior to the induction of ischemia by common carotid artery occlusion. The binding capacity of cAMP-DPK was evaluated by autoradiographic analysis of the cAMP bin ding, and cerebral blood flow (CBF) was measured by the [C-14] iodoant ipyrine method. In the sham-operated gerbils, FK506 significantly incr eased mean arterial blood pressure and tended to decrease CBF, suggest ing that FK506 may constrict systemic blood vessels as well as cerebra l blood vessels. On the other hand, cAMP binding was not altered by FK 506 in the sham-operated gerbils. In the ischemia group of gerbils, FK 506 prevented any significant reduction of cAMP binding in the hippoca mpus CA1 and cerebral cortices on the ischemic side, whereas it exerte d no significant influence on the cAMP binding of the nonischemic side , The values of CBF were comparable between the vehicle-treated gerbil s and FK506-treated gerbils in the ischemic regions. Preservation of c AMP binding indicates that intracellular signal transduction via cAMP- DPK can be maintained by FK506 despite ischemia, suggesting that this agent may be beneficial for reducing ischemic tissue damage.