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Abstract

The effect of indomethacin, a non-steroidal anti-inflammatory drug upon purified calpain has been studied. Also, its effects upon Ca2+-mediated degradation of cytoskeletal proteins (neurofilament) in spinal cord homogenate has been investigated. A dose-dependent inhibition of purified calpain activity was observed. A 50% inhibition of 14C-caseinolytic activity was obtained with less than 1.1 mM of indomethacin while the activity was completely inhibited at 3.3 mM concentration. The inhibitory effect of ketorlac, another non-steroidal anti-inflammatory drug, upon calpain was weaker than that of indomethacin. The degradation of myelin basic protein (MBP) by cathepsin B, a lysosomal cysteine protease, was significantly inhibited by indomethacin. It also inhibited the Ca2+-mediated degradation of neurofilament protein (NFP) in spinal cord homogenate. The extent of NFP degradation was analyzed by SDS-PAGE and the inhibition shown by indomethacin was weaker than that observed with leupeptin and the calpain inhibitor E64-d. The inhibitory effect of indomethacin on the activity of multicatalytic proteinase complex was negligible. These results suggest that indomethacin, a non-steroidal anti-inflammatory drug and cyclooxygenase inhibitor also inhibits proteinases, including cathepsin B and calpain.

Non-steroidal anti-inflammatory drugs inhibit calpain activity and membrane localization of calpain 2 protease

“…Previously, we demonstrated that calpain mRNA and total protein expression were decreased by 72 h treatment with indomethacin or NS-398, but not SC-560, and that this was consistent with inhibition of cell migration by these drugs (Raveendran, et al, 2008). Furthermore, other laboratories had also demonstrated that NSAIDs reduce calpain protein levels (Fushimi, et al, 2004; Banik, et al, 2000). But as calpains have pleiotrophic effects on cells and distinct subcellular pools contribute to these, global assessments of calpains can be misleading.…”

Inhibition of Cysteine Proteases in Acute and Chronic Spinal Cord Injury

“…Nevertheless, our investigations suggest that cathepsins also participate in the pathogenesis of SCI and inhibition of cathepsins can be an important strategy to enhance neuroprotection in SCI. 5,54 The cleavage of Bid to tBid and degradation of anti-apoptotic Bcl-2 proteins by the lysosomal cathepsins are supposed to be the links to the release of cytochrome c from mitochondria to cytosol for eventual activation of caspase-3. 55,56 Thus, the cross-talk between the lysosomes and mitochondria is now known to be very crucial process during apoptosis.…”