Calcineurin and cyclophilin D are differential targets of neuroprotection by immunosuppressants CsA and FK506 in ischemi
The search for an effective treatment for global ischemia following cardiac arrest has proved to be very difficult. However, studies by Uchino et al. [1, 2] show that the immunosuppressant cyclosporin A (CsA), when administered in such a way that the drug
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Calcineurin and cyclophilin D are differential targets of neuroprotection by immunosuppressants CsA and FK506 in ischemic brain damage H. Uchino", N. Ishii l , and F. Shibasaki' 1 2
Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, Tatemachi, Hachioji, Japan Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, Honkomagome, Bunkyo-ku,Tokyo, Japan
Summary The searchfor an effective treatment for global ischemiafollowing cardiac arrest has proved to be very difficult. However, studies by Uchino et al. [I, 2) show that the immunosuppressant cyclosporin A (CsA), whenadministeredin such a waythat the drug can bypassthe blood brain barrier (BBB), dramatically reduces ischemic damage in rat forebrain preparations. An alternative immunosuppressant, FK506, is apparently less efficacious [3, 4). Both CsA and FK506 are specific inhibitors of immunophilins, (CsA inhibits cyclophilins, FK506 inhibits FKBPs), and of calcineurin, a type 2B Ser{Thr phosphatase that is abundant in the central nervous system [5). The superiorityof CsA may be partly attributable to its selective amelioration of mitochondrialdamage, as assayedin vivo and in vitro. Our resultssuggest that pathways involving ca1cineurin and cyclophilins, particularly mitochondrial cyclophilin D, play pivotal roles in the development of ischemic brain damage. The present findings may inform the search for new drugs in the treatment of global ischemic damage to the brain, and in other organs. Keywords: Brain ischemia; cyclosporin A; FK506; ca1cineurin; MRI; cyclophilin D; Mitochondrial Permeability Transition (MPT); bad; and cytochrome c.
Introduction Brief periods of brain ischemia can lead to specific forms of damage at the cellular level that are accompanied by a cascade of biochemical events. The influx of calcium into cells is a key event among several factors in the pathogenesis of ischemic brain damage. The influx is due to the opening of calcium channels on the cell membrane, which in turn is due to presynaptic release of glutamate resulting in membrane depolarization. The rise in free cytosolic calcium concentration triggers a further cascade of reactions. These include lipolysis, proteolysis and phosphorylationj dephosphorylation of regulatory proteins, which include kinases and phosphatases. Transient global is-
chemia may cause severe brain damage with serious social, medical, and economic implications. In the past, the effectiveness of neuroprotective treatment following ischemia has been at best mild to moderate. Recently, interest has focused on the use of selective immunosuppressants for the treatment of ischemia . The neuroprotective effects of immunosuppressants on ischemic brain damage were first reported for Tacrolimus (FK506) in rats subjected to focal ischemia [11]. Pre-treatment with cyclosporin A (CsA) also dramatically reduces forebrain ischemic damage in rats, provided that the drug can be delivered to the brain without being blocked by the blood-brain barrier (BBB) [15-17]. Alt
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