The Role of the Immunophilin FKBP12 in Cerebral Ischemia

Abstract

An immunosuppressant FK506 has been reported to protect the brain from global and focal cerebral ischemia. The actions of FK506 occur through its binding to an immunophilin FK506-binding protein-12 (FKBP12), inhibiting calcineurin and nitric oxide synthase. The major physiological role of FKBP12, on the other hand, is a modulation of intracellular calcium flux. The purpose of this study was to investigate the changes in FKBP12 following global cerebral ischemia (10 min) and focal cerebral ischemia (1 h) in the rat. The animals were killed at 4 h to 7 days after ischemia, and immunohistochemistry was performed using a monoclonal antibody raised against recombinant FKBP12. In normal rats, FKBP12 immunoreactivity was the highest in the CA1 subfield of the hippocampus and the striatum, and the localization was almost exclusively neuronal. Following global ischemia, FKBP12 immunoreactivity in CA1 neurons decreased after 1 day, and then it was lost between 2 days and 7 days. Many CA1 neurons showed a transient increase in FKBP12 at 2 days. Following focal ischemia, FKBP12 immunoreactivity decreased rapidly in the ischemic core, but increased in surviving neurons in the penumbra. Invading leukocytes and macrophages in the infarct exhibited FKBP12 immunoreactivity. No FKBP12 immunoreactivity was observed in reactive glia in both paradigms. Thus, FKBP12 declined in severely damaged neurons, whereas FKBP12 was up regulated in less injured neurons. The findings suggest that FKBP12 plays a pivotal role in the process of neuronal survival and death following cerebral ischemia, and that FKBP12 is involved in inflammatory reactions that occur in the infarction.