title: Probing the molecular mechanisms of neuronal degeneration: importance of mitochondrial dysfunction and calcineurin activation.
abstract: Cerebral injury is a critical aspect of the management of patients in intensive care. Pathological conditions induced by cerebral ischemia, hypoxia, head trauma, and seizure activity can result in marked residual impairment of cerebral function. We have investigated the potential mechanisms leading to neuronal cell death in pathological conditions, with the aim of discovering therapeutic targets and methods to minimize neuronal damage resulting from insults directed at the central nervous system (CNS). Over the years, deeper understanding of the mechanisms of neuronal cell death has indeed evolved, enabling clinical critical care management to salvage neurons that are at the brink of degeneration and to support recovery of brain function. However, no substantial breakthrough has been achieved in the quest to develop effective pharmacological neuroprotective therapy directed at tissues of the CNS. The current situation is unacceptable, and preservation of function and protection of the brain from terminal impairment will be a vital medical issue in the twenty-first century. To achieve this goal, it is critical to clarify the key mechanisms leading to neuronal cell death. Here, we discuss the importance of the calcineurin/immunophilin signal transduction pathway and mitochondrial involvement in the detrimental chain of events leading to neuronal degeneration.
authors.affiliation: Department of Anesthesiology, Hachioji Medical Center, Tokyo Medical University, 1163 Tate-machi, Hachioji, Tokyo 193-0998, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchino
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Saori
authors.initials: S
authors.lastname: Morota
authors.forename: Go
authors.initials: G
authors.lastname: Hirabayashi
authors.forename: Nagao
authors.initials: N
authors.lastname: Ishii
authors.forename: Futoshi
authors.initials: F
authors.lastname: Shibasaki
authors.forename: Yukiho
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmér
mesh_terms: D001930:Brain Injuries / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D028361:Mitochondrial Diseases / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009410:Nerve Degeneration / Q000378:metabolism*; D015398:Signal Transduction; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D050994:Voltage-Dependent Anion Channels; D019703:Calcineurin; D021983:Cyclophilins; D002118:Calcium