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.

Blockade of acid-sensing ion channels protects articular chondrocytes from acid-induced apoptotic injury

“…Calcineurin is a Ca 2? /calmodulindependent protein phosphatase, and is involved in the pathogenesis of several important calcium-dependent disorders and plays a critical role in the process of apoptosis [25][26][27][28][29][30]. Calpain is a Ca 2?…”

Effect of the calcineurin inhibitor FK506 on K+–Cl− cotransporter 2 expression in the mouse hippocampus after kainic acid-induced status epilepticus

“…This Ca 2? overload induces mitochondrial failure, leading to impaired ATP production and subsequent apoptotic neuronal cell death (Wang et al 1994;Duchen 1999;Uchino et al 2008). CaN provides a critical association between Ca 2?…”

Effect of mild and moderate hypothermia on hypoxic injury in nearly pure neuronal culture

“…However, all clinical pharmacological approaches targeting this cascade have resulted in failure [11]. Meanwhile, the cell death-signaling pathway related to mitochondrial injury leading to apoptosis has recently been demonstrated in the ischemic/hypoxic brain [12].…”

“…Overloading of mitochondrial Ca 2? induces mitochondrial permeability transition, which leads to cytochrome c release and caspase activation [11,13]. Accordingly, we also examined the mechanism of the effect of mild and moderate hypothermia with reference to these two aspects.…”

“…As a mechanism of ischemic/hypoxic cerebral injury, the glutamate-calcium theory, called excitotoxic neuronal cell death, is well known [11]. However, all clinical pharmacological approaches targeting this cascade have resulted in failure [11].…”