Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia: a molecular docking study exploring possible neuroprotection

Abstract

The main pathophysiology of cerebral ischemia is the structural alteration in the neurovascular unit, coinciding with neurovascular matrix degradation. Resveratrol has been reported to be one of the most potent chemopreventive agents that can inhibit cellular processes associated with ischemic stroke. Matrix metalloproteinases (MMPs) has been considered as a potential drug target for the treatment of cerebral ischemia. To explore this, we tried to investigate the interaction of resveratrol with MMPs through molecular docking studies. At 30 minutes before and 2 hours after cerebral ischemia/reperfusion induced by occlusion of the middle cerebral artery, 40 mg/kg resveratrol was intraperitoneally administered. After resveratrol administration, neurological function and brain edema were significantly alleviated, cerebral infarct volume was significantly reduced, and nitrite and malondialdehyde levels in the cortical and striatal regions were significantly decreased. The molecular docking study of resveratrol and MMPs revealed that resveratrol occupied the active site of MMP-2 and MMP-9. The binding energy of the complexes was –37.848672 kJ/mol and –36.6345 kJ/mol for MMP-2 and MMP-9, respectively. In case of MMP-2, Leu 164, Ala 165 and Thr 227 were engaged in H-Bonding with resveratrol and in case of MMP-9, H-bonding was found with Glu 402, Ala 417 and Arg 424 residues. These findings collectively reveal that resveratrol exhibits neuroprotective effects on cerebral ischemia through inhibiting MMP-2 and MMP-9 activity.

An In-silico Approach to Explore the Possible Multifunctional Neuroprotective Efficacy of Violacein against Ischemic Stroke

“…Short range Van der walls interactions and electrostatic interactions, entropy losses, hydrogen bonding were included as autodock energy based scoring function [29]. The Lamarckian genetic algorithm parameters for this study were: Number of runs=30, maximum number of evaluations=2500000, population size 150, number of generation=27000, rate of crossover=0.8 and rate of gene mutation=0.02 [9]. Blind docking for MMP2 was performed using grid size 126,126 and 126 along X, Y and Z axis with spacing of 0.375 Å.…”

“…They are activated by cytokines and are reported to hamper the integrity of ECM in ischemic conditions due to there over expression [8]. MMP2 (gelatinase A) and MMP9 (gelatinase B) plays leading role in degrading the collagen type IV protein of ECM or basal lamina thus proving themselves the most potent targets of the disease [9][10][11]. The increased levels of MMPs have also been reported in many diseases, like cardiovascular diseases, cancer, osteoarthritis, lung injury etc.…”

“…Quercetin was also reported by Pandey et al for its structural inhibition of MMPs. Resveratrol was reported by Pandey et al in neuroprotection in cerebral ischemia by directly inhibiting MMPs [9]. Structural inhibition of MMPs by rutin was reported by Selvaraj et al [36].…”

“…causing degradation of extracellular matrix [6]. Many researchers have reported increase in expression of MMPs in cerebral ischemia [5,[9][10][11]. Past researches have proved that MMP 9 knockout mouse models or application of MMP inhibitors and antibodies have shown protective effects and reduction in disease pathogenesis by decreasing the infraction size in ischemic brain [9,11].…”

“…In this study we found that violacein forms Hbonds with Ala217, Ala220, Tyr223, Leu197, Glu202 and Pro 221 residues with a comparatively high binding energy of -11.83 kcal/mol proving high inhibition activity against MMP2 especially because of most effective inhibition residues Ala2, Ala220 and Glu202. Docking of resveratrol with MMP9 in a study gave residues Glu402, Ala417 and Arg424 to form Hbonds with binding energy of -8.75kcal/mol (-36.634 kJ/mol) [9]. Sarkar et al [35] in their docking study of (-)-epicatechin-3-galate and (-)-epigalocatechin-3-galate for proMMP9 inhibition found Try420 as an effective residue for inhibition with high binding energies [36].…”