Piroxicam confer neuroprotection in Cerebral Ischemia by inhibiting Cyclooxygenases Acid- Sensing Ion Channel-1a and Aquaporin-4: an in silico comparison with Aspirin and Nimesulide

摘要

Cerebral ischemia (CI), caused by the deprivation of oxygen and glucose to the brain, is the leading cause of permanent disability. Neuronal demise in CI has been linked to several pathways which include cyclooxygenases (COX) − mediated production of prostaglandins (PGs) and subsequently reactive oxygen species (ROS), aquaporin-4 (AQ-4) − mediated brain edema and acidsensing ion channel-1a (ASIC-1a) − mediated acidotoxicity, matrix remodeling, in addition to others. Several non-steroidal antiinflammatory drugs (NSAIDs) are presently in use to prevent these pathways. However, owing to the large number of processes involved, there is high drug load. So, identifying drugs with multimodal role has always been a frequently sought venture. The present in silico study has been performed to find out the relative efficacy of three different NSAIDs (Piroxicam, Aspirin and Nimesulide) in preventing neurodegeneration in CI, with respect to their inhibitory potential on COXs, AQ-4 and ASIC-1a. We find that piroxicam is the most potent inhibitor of these receptors as compared to the NSAIDs under investigation. Since piroxicam has already been reported to inhibit N-methyl-D-aspartate (NMDA) receptor and matrix metalloproteinases (MMPs), which are also linked to CI-induced neurodegeneration, we hereby propose piroxicam to be a gold-standard drug in preventing neurodegeneration in CI.