Peptidyl α-keto amide inhibitor of calpain blocks excitotoxic damage without affecting signal transduction events

The cysteine protease calpain is activated by calcium and has a wide range of substrates. Calpain-mediated cellular damage is associated with many neuropathologies, and calpain also plays a role in signal transduction events that are essential for cell maintenance, including the activation of important kinases and transcription factors. In the present study, the hippocampal slice culture was used as a model of excitotoxicity to test whether the neuroprotection elicited by selective calpain inhibition is associated with changes in cell signaling. Pepticlyl alpha-keto amide and alpha-keto acid inhibitors reduced both calpain-mediated cytoskeletal damage and the concomitant synaptic deterioration resulting from an N-methyl-D-aspartate exposure. The alpha-keto amide CX295 was protective when infused into slice cultures before or after the excitotoxic episode. The slices protected with CX295 exhibited normal activation levels of mitogen-activated protein kinase and the transcription factor nuclear factor-kappaB. Thus, selective inhibition of calpain provides neuroprotection without influencing critical signaling pathways. (C) 2002 Wiley-Liss, Inc.