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Calpain as a novel target for treating acute neurodegenerative disorders
R T Bartus1, P J Elliott, N J Hayward
1Alkermes, Inc., Cambridge, MA 02139, USA.
Abstract:
Calpains are cytosolic, neutral proteases that normally exist in an inactive or quiescent state. They require higher than normal levels of calcium for activation which, once accomplished, lead to irreversible proteolysis of numerous cytoskeletal, membrane-associated and regulatory proteins. Because of these characteristics, calpain is gaining attention as a potentially important pathogenic variable in ischemic neuronal death. This manuscript explores this hypothesis by briefly reviewing current support for the role played by calpain in ischemic neurodegeneration, and then discussing a series of recently published studies which: 1. offer further evidence for the hypothesis, and 2. provide direct support for the idea that selective inhibition of calpain can greatly limit the neuronal damage that would normally occur following both global as well as focal brain ischemia. Thus, the data reviewed in this manuscript support the ideas that unregulated activation and proteolysis of intraneuronal calpain plays a significant role in the brain damage that occurs following an ischemic event and that delivering selective and membrane permeant calpain inhibitors to ischemic tissue may provide a powerfully effective therapeutic means of limiting neuronal damage.
Insights
Unregulated calpain activation contributes to brain damage after ischemic events. Selective calpain inhibitors show promise in limiting neuronal death following global and focal brain ischemia.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Calpains are neutral proteases requiring high calcium levels for activation.
- Activated calpains cause irreversible proteolysis of cellular proteins.
- Calpain's role in ischemic neuronal death is an area of growing research interest.
Purpose of the Study:
- To review evidence supporting calpain's role in ischemic neurodegeneration.
- To discuss studies demonstrating calpain inhibition's neuroprotective effects.
- To evaluate calpain inhibitors as a therapeutic strategy for stroke.
Main Methods:
- Review of current literature on calpain and ischemic brain injury.
- Analysis of studies investigating the effects of calpain inhibition.
- Examination of data on global and focal brain ischemia models.
Main Results:
- Evidence suggests unregulated calpain activation is a significant factor in ischemic brain damage.
- Selective calpain inhibition effectively limits neuronal damage in experimental ischemia.
- Membrane-permeant calpain inhibitors show therapeutic potential.
Conclusions:
- Unregulated intraneuronal calpain proteolysis significantly contributes to ischemic brain damage.
- Selective and membrane-permeant calpain inhibitors represent a promising therapeutic approach.
- Targeting calpain may offer an effective strategy for limiting neuronal damage post-ischemia.