Neuroprotection by μ-calpain and matrix metalloproteinases inhibition by Piroxicam in cerebral ischemia: an in silico study

Abstract

An intervention to reduce brain injury before, during, or after an ischemic injury irrespective of the cause remains an exciting prospect. Increasing evidences suggest that the excessive activation of calcium-dependent neutral proteases, calpains, could play a key role in the pathology of cerebral ischemia. Targeting calcium-activated proteolysis could, therefore, be an alternative strategy for protecting neurons against post-ischemic injury. In addition, blood brain barrier (BBB) breakdown after stroke is linked to the up-regulation of metalloproteinases (MMPs) and inflammation. MMPs are zinc-dependent endopeptidases which are capable of degrading many types of extracellular matrix proteins and are also involved in the process of tissue remodeling in various pathologic conditions. Previous studies suggest that MMPs, in particular MMP-2 and MMP-9, are deleterious in the brain after stroke. In acute stage after ischemic stroke, the effects of MMP activity is correlated to the degradation of neurovascular matrix and opening of the BBB which promotes vasogenic edema and results in neurological deficits. Hence, calpain and MMPs are considered to be a potential drug target to develop novel therapeutics against cerebral ischemia. To explore such, we have tried to study the interaction of Piroxicam with calpain and MMPs by exploring molecular docking studies. The in silico studies revealed that Piroxicam occupied the active site of μ-calpain, MMP-2, and MMP-9. The binding energy of the complexes was −5.27, −9.75, and −6.47 kcal/mol for μ-calpain, MMP-2, and MMP-9, respectively. On the basis of these in silico studies collectively, we hypothesize for the first time that Piroxicam might have a strong potential to inhibit μ-calpain, MMP-2, and MMP-9 concomitantly which can be explored as a potent therapeutic target for treating cerebral ischemia in future.