Inhibition of matrix metalloproteinase-2 and 9 by Piroxicam confer neuroprotection in cerebral ischemia: an in silico evaluation of the hypothesis.

Abstract

Matrix metalloproteinases are zinc-containing endopeptidases that are involved in extracellular matrix (ECM) remodeling cascade in many neurological disorders, including cerebral ischemia (CI). Remodeling of the ECM followed by disruption of the blood-brain barrier (BBB) is one of the major factors contributing to the ultimate neurodegeneration in CI. BBB disruption causes a cascade of pathophysiologies that trigger Anoikis-like cell death. While inhibition of MMP-2 and MMP-9 decreases the extent of neuronal damage in CI, MMP-2/9 knock-out mice have reduced infarct volume in experimental animal models of CI. Piroxicam, which is a non-steroidal anti-inflammatory drug (NSAID), has been demonstrated to be protective against aquaporin-4 and acid-sensing ion channel 1a--mediated neurodegeneration in CI. However, no report exists on the inhibitory action of Piroxicam on MMPs. We tested the hypothesis that Piroxicam, with its larger molecular size and more number of interacting pharmacophores, can inhibit MMP-2 and MMP-9. A comparative study on the inhibitory potential of Piroxicam with other reported MMP-inhibitors, viz., Aspirin, Melatonin and Doxycycline, has also been performed. Since the drug has already been reported to be neuroprotective through its inhibitory action in other pathways, it can be the drug of choice in the therapeutic management and prevention of neurodegeneration in CI.

• Authors: Muhammed Khairujjaman Mazumder, Pallab Bhattacharya, Anupom Borah
• Journal: Medical hypotheses (Med Hypotheses) Vol. 83 Issue 6 Pg. 697-701 (Dec 2014) ISSN: 1532-2777 [Electronic] United States
• PMID: 25459137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Ligands
• Matrix Metalloproteinase Inhibitors
• Neuroprotective Agents
• Piroxicam
• MMP2 protein, human
• Matrix Metalloproteinase 2
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Blood-Brain Barrier (drug effects)
• Brain Ischemia (metabolism)
• Edema (pathology)
• Humans
• Ligands
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors (therapeutic use)
• Neurodegenerative Diseases (metabolism)
• Neuroprotective Agents (pharmacology)
• Piroxicam (pharmacology)
• Protein Binding
• Protein Conformation
• Signal Transduction
• Stereoisomerism