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 calcineurin, a phosphatase, ameliorates neuronal cell death in the CA1 sector of the hippocampus after forebrain ischemia in animal models. The mechanism of this neuroprotective effect, however, has not yet been established. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophins, is one of the potent survival and developmental factors whose expression is regulated by cyclic AMP-response element-binding protein (CREB). Activation of CREB is dependent on its phosphorylation at Ser(133), and calcineurin has been reported to dephosphorylate CREB via protein phosphatase 1. Based on these observations, we attempted to investigate how cyclosporin A treatment would affect the changes of phosphorylated CREB (pCREB), BDNF and its receptor tyrosine kinase B (TrkB) after forebrain ischemia in rats. Phosphorylation of CREB was kept augmented throughout the time course examined in cyclosporin A-treated animals, while it ceased without cyclosporin A. Reverse transcription-polymerase chain reaction revealed prolonged maintenance of BDNF mRNA expression in the CA1 sector of cyclosporin A-treated animals. The protein expression of BDNF and TrkB appeared to be up-regulated in cyclosporin A-treated animals, whereas it was transiently up-regulated but decreased to the marginal level of expression without cyclosporin A.From these results we suggest that cyclosporin A induces pCREB by an inhibition of calcineurin, resulting in the induction of BDNF. The mechanisms by which cyclosporin A protects the CA1 region from neuronal cell death in forebrain ischemia may involve the interaction of pCREB, BDNF and TrkB.
Miyata
K
K
Department of Anesthesiology, Tokyo Medical University, Japan. kmiyata@ops.dti.ne.jp
Omori
N
N
Uchino
H
H
Yamaguchi
T
T
Isshiki
A
A
Shibasaki
F
F
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D016572:Cyclosporine; D020813:Receptor, trkB