Involvement of the brain-derived neurotrophic factor/TrkB pathway in neuroprotecive effect of cyclosporin A in forebrain ischemia

Recent studies have shown that cyclosporin A, a specific antagonist of calc ineurin, a phosphatase, ameliorates neuronal cell death in the CAI sector o f the hippocampus after forebrain ischemia in animal models. The mechanism of this neuroprotective effect, however, has not yet been established. Brai n-derived neurotrophic factor (BDNF), a member of the neurotrophins, is one of the potent survival and developmental factors whose expression is regul ated by cyclic AMP-response element-binding protein (CREB). Activation of C REB is dependent on-its phosphorylation at Ser(133), and calcineurin has be en reported to dephosphorylate CREB via protein phosphatase 1. Based on the se observations, we attempted to investigate how cyclosporin A treatment wo uld affect the changes of phosphorylated CREB (pCREB), BDNF and its recepto r tyrosine kinase B (TrkB) after forebrain ischemia in rats. Phosphorylation of CREB was kept augmented throughout the time course exami ned in cyclosporin A-treated animals, while it ceased without cyclosporin A . Reverse transcription-polymerise chain reaction revealed prolonged mainte nance of BDNF mRNA expression in the CAI sector of cyclosporin A-treated an imals. The protein expression of BDNF and TrkB appeared to be up-regulated in cyclosporin A-treated animals, whereas it was transiently up-regulated b ut decreased to the marginal level of expression without cyclosporin A. From these results we suggest that cyclosporin A induces pCREB by an inhibi tion of calcineurin, resulting in the induction of BDNF. The mechanisms by which cyclosporin A protects the CAI region from neuronal cell death in for ebrain ischemia may involve the interaction of pCREB, BDNF and TrkB. (C) 20 01 IBRO. Published by Elsevier Science Ltd. All rights reserved.