Molecular targets for pharmacological cytoprotection

Cell death is common to many pathological conditions. In the past two decad es. research into the mechanism of cell death has characterized the cardina l features of apoptosis and necrosis, the two distinct forms of cell death. Studies using in vivo disease models have provided evidence that apoptosis is induced by an array of pathological stimuli. Thus, molecular components of the machinery of apoptosis are potential pharmacological targets. The m echanism of apoptosis can be dissected into: (i) the initiation and signali ng phase, (ii) the signal amplification phase, and (iii) the execution phas e. Reflecting on the diversity of apoptotic stimuli, the initiation and sig naling phase utilizes a variety of molecules: free radicals, ions, plasma m embrane receptors, members of the signaling kinase cascades, transcription factors, and signaling caspases. In most of the apoptotic scenarios, impair ment of mitochondrial function is an early event. Dysfunctioning mitochondr ia release more free radicals and hydrolytic enzymes (proteases and nucleas es), amplifying the primary death signal. In the final phase of apoptosis, executioner caspases are activated. Substrates of the executioner caspases include nucleases, members of the cellular repair apparatus, and cytoskelet al proteins. Partial proteolysis of these substrates leads to distinctive m orphological and biochemical changes, the hallmarks of apoptosis. The first steps toward pharmacological utilization of specific modifiers of apoptosi s have been promising. However, since the potential molecular targets of cy toprotective therapy play important roles in the maintenance of cellular ho meostasis, specificity (diseased versus healthy tissue) of pharmacological modulation is the key to success. (C) 2001 Elsevier Science Inc. All rights reserved.