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Currently Evaluated Calpain and Caspase Inhibitors for Neuroprotection in Experimental Brain Ischemia

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Abstract:

Currently available therapies for brain ischemia, with a few exceptions, provide only symptomaticrelief in patients. Recent investigations in experimental models provided an understanding of the cellular andmolecular mechanisms that lead to neurodegeneration in ischemic injury, and also indicate targets forprevention and amelioration of the devastating consequences of stroke. An enormous increase in intracellularfree Ca2+ levels following stroke activates Ca2+-dependent enzymes, contributing to neuronal death anddysfunction. Additionally, ischemic injury generates highly reactive free radicals and triggers release ofcytotoxic cytokines for activation of cysteine proteases. A number of studies already indicated a prominentrole for the cysteine proteases of the calpain and caspase families in the pathogenesis of brain ischemia.Proteolytic activities of these proteases degrade various cytoskeletal proteins and membrane proteins,destabilizing the structural integrity and forcing the neurons to delayed death in ischemic penumbra. Somecurrent studies have unequivocally confirmed the neuronal apoptosis in ischemia and showed thatadministration of calpain and caspase inhibitors alone or in combination can provide functionalneuroprotection in various animal models of cerebral ischemia. This article will discuss the molecularstructures and activities of calpain and caspase inhibitors and their therapeutic efficacy in experimental brainischemia. However, further investigations are necessary for improvements in the structural design of calpainand caspase inhibitors for their persistent therapeutic efficacy in animal models of stroke and for clinical trialsin the future.

Keywords: Brain ischemia; Ca2+ influx; Calpain; Caspases; Inhibitors; Neurodegeneration; Neuroprotection; Proteolytic activities

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986706779010342

Affiliations: Department of Neurosciences, Medical University of South Carolina (MUSC), 96 Jonathan Lucas Street, Suite 323K, Charleston, SC 29425, USA.

Publication date: December 1, 2006

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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