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Caspase inhibition: a potential therapeutic strategy in neurological diseases
1Department of Neurology, Columbia University, New York, NY 10032, USA.
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, may 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 may be due to irreversible caspase-independent alterations at the level of the mitochondria. Despite concerns that targeting caspases alone may 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 may therefore provide a novel strategy for the treatment of such disorders. Caspases, through the generation of toxic fragments of critical protein substrates, may also be involved in earlier steps of neuronal dysfunction, such as protein aggregation in Huntington's and Alzheimer's disease, and therefore caspase inhibition may be of additional value in the treatment of these particular disorders.
Insights
Caspase inhibition shows promise for treating neurological diseases by reducing neuronal cell death. While offering transient protection, targeting caspases may improve survival and function in various conditions.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Caspases are intracellular proteases crucial for apoptosis in mammalian neurons.
- Neuronal cell death is a hallmark of many neurological diseases.
- Current therapeutic strategies for neurological disorders have limitations.
Purpose of the Study:
- To review evidence on the role of caspase inhibition in preventing neuronal cell death.
- To explore the potential of caspase inhibitors as a therapeutic strategy for neurological diseases.
- To discuss the implications of caspase activation in human neurological disorders.
Main Methods:
- Review of in vitro and in vivo studies on caspase inhibition in neurological disease models.
- Analysis of molecular and pharmacological approaches to caspase inhibition.
- Examination of human post-mortem data for caspase activation in neurological diseases.
Main Results:
- Caspase inhibition demonstrates neuroprotective effects in various neurological disease models.
- While offering transient protection in cell cultures, in vivo studies show improved survival and function.
- Caspase activation is observed in human neurological diseases, suggesting therapeutic relevance.
Conclusions:
- Caspase inhibition is a potential therapeutic strategy for neurological disorders.
- Further research is warranted to overcome limitations like transient protection and explore broader applications.
- Targeting caspases may also address early neuronal dysfunction, including protein aggregation in diseases like Alzheimer's and Huntington's.