ToxSci Advance Access originally published online on May 2, 2003
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Toxicological Sciences 74, 4-9 (2003)
Copyright © 2003 by the Society of Toxicology
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Molecular Switches Deciding the Death of Injured Neurons
MRC Toxicology Unit, Hodgkin Building, University of Leicester, LE 1 9HN Leicester, United Kingdom
The endpoints used to evaluate neurotoxicity of drugs and chemicals are multiple and reflect the complexity of the nervous system. In many instances, loss of function can result from a temporary impairment of synaptic activity. However, exposure to some neurotoxic conditions may eventually lead to neuronal loss and be fatal to the organism. Execution of the apoptotic program seems to be the mechanism involved in loss of neurons in human neurodegenerative conditions. Apoptosis is a conserved mode of cell death, prominent in developmental conditions, whose main execution pathway converges on the activation of the caspase family of proteases. However, there is increasing evidence that cell death in postdevelopmental conditions is more complex. Other routines or subroutines of cell death can be activated under toxic or pathological conditions, and several protease families may contribute to produce apoptotic-like features or other phenotypically different forms of cells death. This has posed the question as to whether classical apoptosis is a valid endpoint to test the effect of neurotoxic agents and whether inhibitors of the caspase subroutine to cell death may then be used to treat diseases characterized by an excess of apoptosis. The recognition of the molecular switches that toggle between cell death subroutines becomes, therefore, of central importance in biomedicine and toxicology.
Key Words: apoptosis; caspases; neurodegeneration; ATP.
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