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Caspases as treatment targets in stroke and neurodegenerative diseases
J B Schulz1, M Weller, M A Moskowitz
1Department of Neurology, Medical School, University of Tübingen, Germany.
Abstract:
Apoptosis is one of the most exciting and intensely investigated areas of biology and medicine today. Cysteine proteases called caspases serve as the executioners of apoptosis, a form of cell suicide. Hypoxic/ischemic cell death proceeds in part, by apoptosis, particularly within the periinfarct zone or ischemic penumbra. During ischemia, activated caspases dismantle the cell by cleaving multiple substrates including cytoskeletal proteins and enzymes essential for cell repair. Strategies that inhibit caspase activity block cell death in experimental models of mild ischemia, and preserve neurological function. The therapeutic window for caspase inhibition is substantially longer than for glutamate receptor antagonists, and treatment combinations with both classes of drugs decrease ischemic injury and expand the treatment window synergistically. Hence, the caspases are now recognized as novel therapeutic targets for central nervous system diseases in which cell death is prominent. This article will review the evidence and the potential importance of caspase inhibition to cerebral ischemia and briefly summarize an emerging body of data implicating caspases in cell death accompanying neurodegenerative disorders.
Insights
Caspase inhibition blocks cell death and preserves neurological function in experimental ischemia. Targeting caspases offers a promising therapeutic strategy for central nervous system diseases involving cell death.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Apoptosis, or programmed cell death, is executed by caspases.
- Hypoxic/ischemic cell death involves apoptosis, particularly in the brain's periinfarct zone.
- Activated caspases dismantle cells during ischemia, hindering repair.
Purpose of the Study:
- To review the role of caspases in cerebral ischemia.
- To explore the potential of caspase inhibition as a therapeutic strategy.
- To summarize evidence implicating caspases in neurodegenerative disorders.
Main Methods:
- Review of experimental models of mild ischemia.
- Analysis of therapeutic strategies involving caspase inhibition.
- Examination of combination therapies with glutamate receptor antagonists.
Main Results:
- Caspase inhibition blocks cell death and preserves neurological function in experimental ischemia.
- The therapeutic window for caspase inhibitors is longer than for glutamate receptor antagonists.
- Combination therapy synergistically reduces ischemic injury and expands the treatment window.
Conclusions:
- Caspases are critical effectors of ischemic cell death.
- Caspase inhibition is a promising therapeutic target for central nervous system diseases, including cerebral ischemia.
- Caspases also play a role in cell death associated with neurodegenerative disorders.