Caspase inhibition, a potential therapeutic strategy in neurological diseases

Abstract

Caspases are intracellular proteases that participate in apoptotic pathways in mammalian cells, including neurons. Here we review evidence that caspase inhibition, through pharmacological or molecular means, rnay inhibit neuronal cell death in a number of in vitro and in vivo models of neurological disease. It has recently become clear that, at least in most cell culture models, caspase inhibition offers only transient protection, and that a caspase-independent death eventually occurs. This rnay be due to irreversible caspase-independent alterations at the leve1 of the mitochondria. Despite concerns that targeting caspases alone rnay prove insufficient to truly reverse the effects of various death stimuli, in vivo studies indicate that caspase inhibition promotes survival and functional outcome in a variety of neurological disease models. In addition, studies of human post-mortem material suggest that caspases are activated in certain human neurological diseases. Caspase inhibition rnay therefore provide a novel strategy for the treatment of such disorders. Caspas'es, through the generation of toxic fragments of critica1 protein substrates, rnay also be involved in earlier steps of neuronal dysfunction, such as protein aggregation in Huntington's and Alzheimer's disease, and therefore caspase inhibition rnay be of additional value in the treatment of these particular disorders.