Cyclophilin-D Inhibition in Neuroprotection: Dawn of a New Era of Mitochondrial Medicine
Traumatic brain injury and ischemia can result in marked neuronal degeneration and residual impairment of cerebral function. However, no effective pharmacological treatment directed at tissues of the central nervous system (CNS) for acute intervention has
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Abstract Traumatic brain injury and ischemia can result in marked neuronal degeneration and residual impairment of cerebral function. However, no effective pharmacological treatment directed at tissues of the central nervous system (CNS) for acute intervention has been developed. The detailed pathophysiological cascade leading to neurodegeneration in these conditions has not been elucidated, but cellular calcium overload and mitochondrial dysfunction have been implicated in a wide range of animal models involving degeneration of H. Uchino, MD, PhD (*) and M. Suzuki Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, 160-0023, Tokyo, Japan e-mail: [email protected]
the CNS. In particular, activation of the calcium-induced mitochondrial permeability transition (mPT) is considered to be a major cause of cell death inferred by the broad and potent neuroprotective effects of pharmacological inhibitors of mPT, especially modulators of cyclophilin activity and, more specifically, genetic inactivation of the mitochondrial cyclophilin, cyclophilin D. Reviewed are evidence and challenges that could bring on the dawning of mitochondrial medicine aimed at safeguarding energy supply following acute injury to the CNS. Keywords Mitochondria • Neurodegeneration • Neuroprotection • Permeability transition • Brain • Cyclophilin Cyclosporin
K. Hatakeyama Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, 160-0023, Tokyo, Japan Department of Anesthesiology, Toda Chuo General Hospital, 1-19-3 Honmachi, Toda City, 335-0023, Saitama, Japan
Abbreviations
S. Morota, M.J. Hansson, and E. Elmér Mitochondrial Pathophysiology Unit, Department of Clinical Sciences, Lund University, BMC A13, 221 84 Lund, Sweden e-mail: [email protected]; [email protected]; [email protected]
ANT BBB CRC CsA CypD MCAO mPT PhArs RCR TBI tBOOH
T. Tanoue, D. Usui, C. Taguchi, and T. Nishiyama Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, 160-0023, Tokyo, Japan Department of Anesthesiology, Kimura Hospital, 2-39-10 Chidori, Ohta-ku, 146-0083, Tokyo, Japan e-mail: [email protected]
Adenine nucleotide translocator Blood–brain barrier Calcium retention capacity Cyclosporin A Cyclophilin D Middle cerebral artery occlusion Mitochondrial permeability transition Phenylarsine oxide Respiratory control ratios Traumatic brain injury Tert-butyl hydroperoxide
Y. Katayama et al. (eds.), Brain Edema XV, Acta Neurochirurgica Supplement, Vol. 118, DOI 10.1007/978-3-7091-1434-6_61, © Springer-Verlag Wien 2013
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Mitochondria are central to the maintenance and survival of cells of the CNS and have been proposed to participate both directly and indirectly in the pathogenesis of brain damage. A well-described aspect of neurodegeneration is calcium dysregulation. Following cellular calcium overload, a sudden increase in the permeability of the inner mitochondrial membrane can occur, a phenomenon named the mitochondrial permeab
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