Currently evaluated calpain and caspase inhibitors for neuroprotection in experimental brain ischemia.
Currently available therapies for brain ischemia, with a few exceptions, provide only symptomatic relief in patients. Recent investigations in experimental models provided an understanding of the cellular and molecular mechanisms that lead to neurodegeneration in ischemic injury, and also indicate targets for prevention and amelioration of the devastating consequences of stroke. An enormous increase in intracellular free Ca(2+) levels following stroke activates Ca(2+)-dependent enzymes, contributing to neuronal death and dysfunction. Additionally, ischemic injury generates highly reactive free radicals and triggers release of cytotoxic cytokines for activation of cysteine proteases. A number of studies already indicated a prominent role 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. Some current studies have unequivocally confirmed the neuronal apoptosis in ischemia and showed that administration of calpain and caspase inhibitors alone or in combination can provide functional neuroprotection in various animal models of cerebral ischemia. This article will discuss the molecular structures and activities of calpain and caspase inhibitors and their therapeutic efficacy in experimental brain ischemia. However, further investigations are necessary for improvements in the structural design of calpain and caspase inhibitors for their persistent therapeutic efficacy in animal models of stroke and for clinical trials in the future.
Ray
Swapan K
SK
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. raysk@musc.edu
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002154:Calpain / Q000627:therapeutic use*; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D002154:Calpain