|Year : 2015 | Volume
| Issue : 4 | Page : 568-575
Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia: a molecular docking study exploring possible neuroprotection
Anand Kumar Pandey Ph.D. 1, Pallab Bhattacharya2, Swet Chand Shukla3, Sudip Paul4, Ranjana Patnaik Ph.D. 1
1 School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
2 School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India; Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
3 School of Biochemical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
4 School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi; Department of Biomedical Engineering, North Eastern Hill University (NEHU), Shillong, India
|Date of Acceptance||14-Feb-2015|
|Date of Web Publication||30-Apr-2015|
Anand Kumar Pandey
School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi
School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi
Source of Support: None, Conflict of Interest: None
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.
Keywords: nerve regeneration; neuroprotection; resveratrol; cerebral ischemia; cerebral infarction; matrix metalloproteinase; molecular docking; extracellular matrix; neural regeneration
|How to cite this article:|
Pandey AK, Bhattacharya P, Shukla SC, Paul S, Patnaik R. Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia: a molecular docking study exploring possible neuroprotection. Neural Regen Res 2015;10:568-75
|How to cite this URL:|
Pandey AK, Bhattacharya P, Shukla SC, Paul S, Patnaik R. Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia: a molecular docking study exploring possible neuroprotection. Neural Regen Res [serial online] 2015 [cited 2018 Apr 26];10:568-75. Available from: http://www.nrronline.org/text.asp?2015/10/4/568/155429
Anand Kumar Pandey, Pallab Bhattacharya, Swet Chand Shukla
These authors contributed equally to this work.
Author contributions: AKP, PB, SCS, SP and RP designed the study. AKP, PB and SCS performed experiments. AKP, SP and RP analyzed the data. AKP and PB wrote the paper. All authors approved the final version of the paper.
Conflicts of interest: None declared.
| Introduction|| |
Extracellular matrix (ECM), which is composed of conglomerate assembly of proteins and proteoglycans, is considered to be one of the key factors to maintain the structural integrity of cells. Triggering of intracellular and extracellular proteolytic processes during cerebral ischemia often leads to ECM degradation (Hamann et al., 2002). These proteolytic cascades result in edema, hemorrhagic transformation, activation of resident microglial cells, infiltration of circulating inflammatory cells into the brain, and neuronal insult (Yurchenko and Schittney, 1990). In cerebral ischemia, the structural integrity of ECM is lost by the action of metalloproteases (Woessner, 1991; Matresian, 1992). As reported in previous studies, cytokines play a critical role in activating matrix metalloproteinases (MMPs) during brain injury or other neurological diseases. Remodeling of ECM during development, tissue injury and inflammation is mainly attributable to the expression of MMPs (Doyle et al., 1997). Gelatinase-A (MMP-2) and gelatinase-B (MMP-9) are the key enzymes for degradation of type IV collagen which is the major component of the basement membrane (Saarialho-Kere et al., 1993; Romanic et al., 1998; Nagaoka and Hirota, 2000). Unregulated activities of MMPs were found to contribute to the development of various diseases, such as arthritis, atherosclerosis, and cancer (Nguyen et al., 2001). Asahi et al. (2000) reported that MMPs inhibition reduces ischemic lesion volume which also confirms the role of MMPs in cerebral ischemia (Asahi et al., 2000).
Resveratrol (3, 5, 4′-trihydroxystilbene) is a naturally occurring polyphenol. Presence of resveratrol has been reported in various plant species including grapes, peanuts as well as in red wine (Soleas et al., 1997; Chen et al., 2002). Resveratrol was found to have antioxidant and anti-inflammatory properties (Franket et al., 1993; Gehm et al., 1997). The neuroprotective role of resveratrol was recently reported against ischemia and other neurodegerative diseases (Huang et al., 2001; Wang et al., 2002).
To the best of our knowledge, molecular docking study between resveratrol with MMP-2 and MMP-9 has not been done. In the present study, we tried to investigate the neuroprotective property of resveratrol using in vivo models and performed molecular docking studies to find out the interaction of resveratrol with MMP-2 and MMP-9.
| Materials and Methods|| |
Animals and drug treatment
Male Charles foster rats, aged 6 weeks, weighing 250 ± 10 g, were included in this study. All rats were kept under standard laboratory conditions. They were allowed free access to food and water and maintained in a 12-hour day/night cycle. 30 rats were randomly divided into four groups: sham (n = 9), vehicle (n = 9), pre-middle cerebral artery occlusion (MCAO) treatment (n = 6) and post-MCAO treatment groups (n = 6). The study was approved by Animal Ethics Committee of Banaras Hindu University, India.
Resveratrol (Sigma, St. Louis, MO, USA) was dissolved in normal saline and intraperitoneally (i.p.) administered at 30 minutes prior to (pre-MCAO treatment group) and 2 hours post MCAO (post-MCAO treatment group). Resveratrol pretreatment in vehicle rats showed that 40 mg/kg (i.p.) resveratrol was the optimum dose (data not shown). The rats that either did not show significant reduction in cerebral blood flow by 70% (data not shown) or they died during surgery or after surgery before completion of experiments were excluded from the study. Randomization and exclusion criteria were taken into consideration to assign groups and their findings.
Induction of focal cerebral ischemia in rats
Focal cerebral ischemia was induced by MCAO using a slight modification of the intraluminal technique (Longa et al., 1989). After rats were anesthetized by ketamine (75 mg/kg, i.p.) and xylazine (10 mg/kg, i.p), a midline incision was made to expose the left common carotid artery in the neck region. A 3-0 monofilament nylon suture (4.0 cm in length; Ethicon, USA) was inserted into the external carotid artery lumen through a small nick to block the middle cerebral artery. Monofilament was removed gently after 1 hour of ischemia for reperfusion. All the procedures were performed with the exception of filament insertion in sham-operated rats.
Neurological deficit was assessed on the basis of neurological scores obtained after 24 hours of reperfusion injury in all experimental groups (Longa et al., 1989). Rats with a score of 2-3 were included in the final analysis. The neurobehavioral deficit scores after ischemia were recorded on a 5-point scale: 0, No neurological deficit; 1, failure to extend opposite forepaw fully; 2, contralateral circling; 3, rat lost to grip the wire meshes and fell on the contralateral side of brain damage; 4, unable to walk spontaneously.
Measurement of infarct volume and brain edema
Rat brains were perfused with normal saline after neurological examination. Brains were immediately transferred to -20°C after removal of the cerebellum. Frozen brains were sliced into uniform coronal sections of 2 mm thickness for TTC staining (Bederson et al., 1986). The brain slices were incubated in 2, 3, 5-triphenyl-tetrazolium chloride (TTC; 1%; Sigma) followed by 10% formalin overnight (Bederson et al., 1986). Viable brain tissue was found to be brick red after TTC staining whereas infarcted portion of brain tissue remained unstained (appeared white). The infarcted areas were captured as images using a digital camera (10 mega pixal, Sony). The infarct volumes were calculated as previously reported (Majid et al., 2000). Brain edema was calculated using the formula (Hara et al., 1996): (Infarct volume + ipsilateral undamaged volume - contralateral volume)/contralateral volume × 100%.
To perform biochemical assay, the extent of lipid peroxidation and nitrite production after reperfusion was determined. In brief, cortical and striatal regions from experimental rats were removed quickly after cervical dislocation and homogenized in 0.1 M ice-cold phosphate buffer (pH 7.4). The nitrite level was estimated using Griess reagent and intensity of lipid peroxidation was determined with thio-barbutric acid (Guevara et al., 1998). The nitrite and malondialdehyde (MDA) levels were expressed as pmol/mg and nmol/mg of tissue protein in homogenate. Protein content was estimated with bovine serum albumin as a standard using the Bradford method (Bradford, 1976).
The anti-gelatinolytic activity of MMP-2 and MMP-9 by resveratrol in brain samples was detected using the standard procedure described by MMP gelatinase activity assay kit (Chemicon International, Inc., Temecula, CA, USA). The brain tissue from the striatum and cortex was homogenized in 20 mM Tris HCl buffer (pH 7.5) containing 50 mM CaCl 2 at 4°C with a homogenizer for 60 seconds. Homogenates were centrifuged at 10,000 × g for 60 minutes at 4°C and supernatant was used for assay after addition of kit assay buffer provided by MMP gelatinase activity assay kit. Then the optical density at 450 nm was measured using a microplate reader.
Molecular docking study
Molecular docking was performed using Autodock 4.0 software (USA). The crystal structure of MMP-2 and MMP-9 (protein data bank ID: 1QIB and 1L6J respectively) was obtained from Research Collaboratory for Structural Bioinformatics (RCSB) protein data bank (www.rcsb.org/). The structure of resveratrol and SMILES notation was generated by ACDLab (www.acdlabs.com). The pdb structure of resveratrol was built using SMILE notation. All heteroatoms, including water molecules, except Zn were removed from pdb file of MMP-2 and MMP-9. Hydrogen atoms were added to the MMP-2 and MMP-9 molecule using autodock program while all non polar hydrogen atoms were merged. Lamarkian genetic algorithm was castoff as a search parameter which is constructed on adaptive local search. Short range Van der Waal and electrostatic interactions, hydrogen bonding, entropy losses were included for energy based autodock scoring function (Morris et al., 1998).
The Lamarckian genetic algorithm parameters used in the study were: numbers of run, 30; population size, 150; maximum number of evaluations, 2500,000; number of generation, 27,000; rate of gene mutation, 0.02; crossover rate, 0.8. Blind docking was carried out using grid size 126, 126, 126 along the X, Y and Z axes with 0.0375 nm spacing. The grid center was set to 7.3011, 2.7073 and 2.0837 nm in case of MMP-2. Grid size was set to 126, 126, 126 along the X, Y and Z axes with 0.0619 nm spacing and grid center was set to 3.6887, 3.8837 and 3.4617 nm in case of MMP-9. According to a previous study of Hu and Shelver (2003), the Docking analysis was carried out using +0.95e charge on both Zn for both MMP-2 and MMP-9.
All data are expressed as the mean ± standard error of mean (SEM). One-way analysis of variance followed by Tukey's post hoc test was performed using Origin 6.0 statistical software (Northampton and Wellesley Hills, MA, USA). P-values of < 0.05 or < 0.01 were considered statistically significant.
| Results|| |
The neurological deficits scores in the vehicle group were significantly higher than in the sham group (P < 0.01). The neurological deficit scores in the pre-MCAO treatment group and post-MCAO treatment group were significantly lower than in the vehicle group (P < 0.01 or P < 0.05; [Figure 1]A).
|Figure 1 Effect of resveratrol on neurological deficit (A), cerebral infarct volume (B) and brain edema (C) following ischemic injury. (A–C) Middle cerebral artery occlusion (MCAO) rats receiving vehicle treatment showed significantly increased neurological deficit scores, cerebral infarct volume, and brain edema compared with rats in the sham group (**P < 0.01, vs. sham group). However, resveratrol (40 mg/kg, intraperitoneally) treatment 30 minutes pre-MCAO or 2 hours post-MCAO significantly reduced neurological deficit scores, cerebral infarct volume, and brain edema of rats (#P < 0.05, ##P < 0.01, vs. vehicle group). Data are expressed as the mean ± SEM. One-way analysis of variance followed by Tukey's post hoc test was used to compare differences between groups. (B, upper panel) Coronal brain sections stained by 2,3,5-triphenyl-tetrazolium chloride. White means damaged and red means normal, i.e., undamaged. I–IV: Sham, vehicle, pre-MCAO treatment and post-MCAO treatment groups, respectively.|
Click here to view
Cerebral infarction and brain edema
Ischemic infarcts were found in the cerebral cortex in MCAO rats. Infarct volume and brain edema were significantly reduced in the cerebral cortex of rats in the pre-MCAO treatment and post-MCAO treatment groups than in the vehicle group (P < 0.01 or P < 0.05; [Figure 1]B, C).
Nitrite and MDA levels in the cortical and striatal regions of the rat brain
Neuronal nitric oxide synthase has been shown to be always associated with the increase in post-ischemic nitrite level in the rat brain (Garry et al., 2015) and MDA is a marker of lipid peroxidation (Gaweł et al., 2004). Both nitrite and MDA levels were measured in the cortical and striatal regions of the rat brain and they were significantly higher in the vehicle group than in the sham group (P < 0.01), while they were significantly reduced in the pre-MCAO treatment and post-MCAO treatment groups (P < 0.05, [Figure 2]A, B).
|Figure 2 Effect of resveratrol on nitrite (A) and malondialdehyde (MDA; B) levels in cortical and striatal regions of rats following ischemic injury. (A, B) Nitrite and MDA levels were significantly increased in the vehicle group than in the sham group (**P < 0.01, vs. sham group). However, nitrite and MDA levels were significantly reduced in the pre-MCAO treatment and post-MCAO treatment groups (#P < 0.05, vs. vehicle group). Data are represented as the mean ± SEM. One-way analysis of variance followed by Tukey's post hoc test was used to compare differences between groups. I–IV: Sham, vehicle, pre-MCAO treatment and post-MCAO treatment groups, respectively.|
Click here to view
Effect of resveratrol on the activity of brain MMPs
MMP-2 and MMP-9 activities in cortical and striatal regions of rats in the vehicle group were significantly higher than in the sham group (P < 0.05), and they were also significantly lower in the pre-MCAO treatment and post-MCAO treatment groups than in the vehicle group (P < 0.05; [Figure 3]A, B).
|Figure 3 Effect of resveratrol on activity of matrix metalloproteinase (MMP)-2 and MMP-9 in cortical and striatal regions of the rat brain following ischemic injury. (A, B) Middle cerebral artery occlusion (MCAO) rats receiving vehicle treatment showed significantly increased activity of MMP-2 and -9 compared|
with rats in the sham group (*P < 0.05, vs. sham group). However, resveratrol (40 mg/kg, intraperitoneally) treatment 30 minutes pre- MCAO or 2 hours post-MCAO significantly reduced activity of MMP-2 and MMP-9 (#P < 0.05, vs. vehicle group). Data are represented as the
mean ± SEM. One-way analysis of variance followed by Tukey's post hoc test was used to compare differences between groups. I–IV: Sham, vehicle, pre-MCAO treatment and post-MCAO treatment groups, respectively.
Click here to view
Molecular docking study
Molecular docking studies revealed that the MMPs interaction with resveratrol was influenced by hydrogen bonding with active site residues. The binding energy of the MMP-2-resveratrol complex was -37.848672 kJ/mol with inhibitory constant (Ki) value of 237.25 nM where as for MMP-9-resveratrol complex -36.6345 kJ/mol with Ki value of 384.27 nM. High ranked conformations were found to have affinity for active site with nearly the same binding energy ([Figure 4], 5). In case of MMP-2, Leu 164, Ala 165 and Thr 227 were engaged in H-bonding with resveratrol whereas two residues Ala 217 and Ala 220 engaged in polar contact with resveratrol as shown in [Figure 4], while Glu 402, Ala 417 and Arg 424 active site residues of MMP-9 were found to be in H-bonding with resveratrol as shown in [Figure 5], There was no interaction between resveratrol and Zn of MMPs. Comparative analysis of binding energies of MMP-2 and MMP-9 with their respective substrate quercetin and resveratrol are shown in [Table 1], which suggests that resveratrol is engaged with same active site residues as previously reported by Pandey et al. (2012).
|Figure 4 Interaction of resveratrol with the active site residue of matrix metalloproteinase-2 (MMP-2) (A) Cartoon structure of resveratrol and MMP-2 complex. (B) Close-up view of the active site of MMP-2 engaged with resveratrol (cyan sphere indicates the presence of Zn ions and green sphere represents the presence of Ca ions). Red color shows the active site residues engaged with resveratrol with H-bonding and green color shows the active site residues engaged with resveratrol in polar contact. (C) Stereo view of resveratrol|
and MMP-2 complex. (D) Stable binding of MMP-2-resveratrol complex.
Click here to view
|Figure 5 Interaction of resveratrol with the active site residue of matrix metalloproteinase-9 (MMP-9). (A) Cartoon structure of resveratrol and MMP 9 complex. (B) Close-up view of the cavity of MMP-9 engaged with resveratrol (cyan sphere indicates the presence of Zn ions and green sphere represents the presence of Ca ions). Green color shows the active site residues engaged with resveratrol with H-bonding. (C) Stereo view of resveratrol and MMP- 9 complex. (D) Stable MMP-9-resveratrol complex.|
Click here to view
|Table 1 Comparative binding energy of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) with their respective natural substrate quercetin and resveratrol|
Click here to view
| Discussion|| |
Persistence of the ischemic condition for a long duration leads to rapid primary neuronal death in the brain core. Following ischemic insult, secondary death is inevitable in the ischemic penumbra that slowly participates in the activation of multiple death pathways. There is no approved therapy currently available which can reduce infarct size or neurological disability caused due to ischemic insult (Parnham and Sies, 2000; Magnoni et ai., 2004). To the best of our knowledge, the mechanism underlying neuronal injury in ischemic stroke has not been fully elucidated. It has been well documented that resveratrol prevents leukocyte migration, inflammatory cytokine production, degranulation and oxidative burst.
Ataie et al. (2010) reported the neuroprotective effects of the various polyphenolic antioxidant molecules against homocysteine-induced cognitive impairment and oxidative stress in the rat (Ataie et al., 2010). Kaplan et al. (2005) reported that pre-ischemic infusion of resveratrol protects the spinal cord from ischemia/reperfusion injury in rabbits. Inhibition of only oxidative stress and inflammation pathways is not the enough targets for neuroprotection, so it is necessary to target and focus other pathways of cell death for regeneration and repair. Li et al. (2012) reported that resveratrol promotes the non-amyloidogenic cleavage of the amyloid precursor protein and enhances clearance of amyloid beta-peptides to protect against Alzheimer's disease. Resveratrol shows neuroprotective effects in in vitro and in vivo animal models of Alzheimer's disease (AD) and it is also beneficial in use for the treatment of Parkinson's disease, Huntington's disease, epilepsy, and chronic-progressive multiple sclerosis.
Recently, Wang et al. (2013) reported that dietary resveratrol provides neuroprotection in recurrent stroke models by regulating AMPK and SIRT1 signaling (Fonseca et al., 2012; Li et al., 2012; Wang et al., 2013). The neuroprotective role of resveratrol has been already established against various oxidative stroke models besides antioxidant and anti-inflammatory property (Huang et al., 2001; Wang et al., 2002). In the present study, the attenuation of elevated nitrite level and lipid peroxidation ([Figure 2]) supports the neuroprotective role of resveratrol against ischemia/reperfusion mediated oxidative injury. Diagrammatic representation of the possible mechanism underlying the MMP-targeted neuroprotective effect of resveratrol in cerebral ischemia is shown in [Figure 6].
|Figure 6 A flow chart describing the possible pathway of matrix metalloproteinase-targeted neuroprotection of resveratrol in cerebral ischemia.|
Click here to view
Results from this study showed that resveratrol administration in the vehicle group improved neurological deficits ([Figure 1]A). The brain edema in the pre-MCAO treatment group was significantly reduced than in the vehicle group, which suggests the anti-inflammatory property of resveratrol and supports the findings of Issuree et al. (2009) that the anti-inflammatory property of resveratrol is possible due to the inhibition of phospholipase D and sphingosine kinase activity ([Figure 1]C). A study done by Magnoni et al. (2004) showed the significant role of MMPs during cerebral ischemia/reperfusion injury (Magnoni et al., 2004; Saragusti et al., 2010). Several studies have reported that the expression of MMPs is directly proportional to the increase in cerebral infarction during focal cerebral ischemia in rats and inhibition of MMPs reduces the infarct size (Rosenberg et al., 1998; Fujimura et al., 1999). In the present study, reduction in cerebral infarct might be due to inhibition of MMPs by resveratrol.
There are three proposed mechanisms underlying the inhibition of MMPs: (i) transcriptional inhibition (Jonat et al., 1996; Hanemaaijer et al., 1998), (ii) direct effects on the catalytic site after posttranslational modification (Golub et al., 1998) and (iii) indirect effects by regulating the endogenous inhibitors or activators (Courtman et al., 2004). As MMP-2 and MMP-9 play a significant role in the processes following ischemic insult, there is an increasing interest in designing MMP inhibitors to treat cerebral ischemia (Romanic et al., 1998). Our molecular docking study revealed that resveratrol directly interacts with active site residues to inhibit MMP-2 and MMP-9 activities.
There is evidence that MMP-9 has a pocket-like S1' cavity with a floorboard and MMP-2 has a channel-like S1' cavity (Babine and Bender, 1997; Kiyama et al., 1999; Tochowicz et al., 2007). The interaction with Leu 164 and Ala 165 is a very significant characteristic of broad range of MMP-2 inhibitors which exhibit the potent inhibitory role of resveratrol.
Leu 164 was previously known to form strong hydrogen bond with oxygen atom of either amidic carbonyl group or sulfonamide (Babine and Bender, 1997). Both Leu 164 and Ala 165 play a very important role in the selectivity and binding affinity of inhibitors. Additionally, H-bonding with Thr 227 provides high binding affinity with MMP-2. Ala 220 and Ala 217 are also engaged in polar contact with resveratrol and enhance the stability of MMP-2-resveratrol complex.
Active site of MMP-9 comprises catalytic Zn ion and is separated into large "upper" and small "lower" subdomains. These subdomains produce two substrate binding pockets like structure Sn (n = 1, 2, 3) and Sn' (n' = 1, 2, 3). The S1' is a substrate binding pocket, formed by these two subdomains. S1' pocket is found in the center of active site cleft neighboring to active site zinc ion. S1' pocket consists of Asp 185-Leu 188 and Pro 421-Tyr 423 which are accountable for hydrogen bonding to substrates/inhibitors. The hedge of S1' cavity is formed by side chains of Leu 188, Leu 397, Val 398, His 401, Leu 418, and Met 422-Tyr 423 main chain. Leu 397 and Val 398 are specific to MMP-9 (Tochowicz et al., 2007). Resveratrol occupies S1' cavity through establishing H-bonding with Glu 402, Ala 417, and Arg 424. Previous studies on polyphenol showed the similar type of MMP-9 inhibition (Tochowicz et al., 2007; Saragusti et al., 2010). The inhibitory effect of quercetin versus resveratrol on MMP-2 and MMP-9 activities reported in our previous study is shown in [Table 1] and suggests that resveratrol occupies the same binding site as quercetin (Babine and Bender, 1997; Pandey et al., 2012). Therefore, it is hypothesized that the neuroprotective property of resveratrol is not only due to their antioxidant and anti-inflammatory properties but might also be due to its action in inhibiting MMPs, thus reducing infarct area which has already been supported by Romanic et al. (1998).
| Conclusion|| |
Results from the present study suggest that resveratrol can enhance the neuroprotective effects against cerebral ischemia/reperfusion injury in rat models of MCAO. The interaction of resveratrol with MMP active site suggests that resveratrol mediated neuroprotection is due to the inhibition of MMPs, which may have therapeutic potential against stroke. Therefore, neuroprotection by resveratrol enhances the application of resveratrol in dietary supplements and in the clinical treatment of ischemia and other MMP-mediated damage.
| References|| |
Albani D, Polito L, Signorini A, Forloni G (2010) Neuroprotective properties of resveratrol in different neurodegenerative disorders. Biofactors 36:370-376.
Asahi M, Asahi K, Wang X, Lo EH (2000) Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab 20:452-457.
Ataie A, Sabetkasaei M, Haghparast A, Moghaddam AH, Kazeminejad B (2010) Neuroprotective effects of the polyphenolic antioxidant agent, Curcumin, against homocysteine-induced cognitive impairment and oxidative stress in the rat. Pharmacol Biochem Behav 96:378-385.
Babine RE, Bender SL, Kazeminejad B (1997) Molecular recognition of protein-ligand complexes: Application to drug design. Chem Rev 97:1359-1472.
Bederson JB, Pitts LH, Germano SM, Nishimura MC, Davis RL, Bartkowski HM (1986) Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17:1304-1308.
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248-254.
Chen RS, Wu PL, Chiou RY (2002) Peanut roots as a source of resveratrol. J Agric Food Chem 50:1665-1667.
Courtman DW, Franco CD, Meng Q, Bendeck MP (2004) Inward remodeling of the rabbit aorta is blocked by the matrix metalloproteinase inhibitor doxycycline. J Vasc Res 41:157-165.
Doyle GA, Pierce RA, Parks WC (1997) Transcriptional induction of collagenase-1 in differentiated monocyte-like (U937) cells is regulated by AP-1 and an upstream C/EBP-h site. J Biol Chem 272:11840-11849.
Fonseca-Kelly Z, Nassrallah M, Uribe J, Khan RS, Dine K, Dutt M, Shindler KS (2012) Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front Neurol 3:84.
Franket EN, Kanner J, German JB (1993) Inhibition of oxidation of human low density lipoprotein by phenolic substrates in red wine. Lancet 341:454-457.
Fujimura M, Gasche Y, Morita-Fujimura Y (1999) Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res 842:92-100.
Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KT (2015) The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside. Exp Neurol 263:235-243.
Gaweł S, Wardas M, Niedworok E, Wardas P (2004) Malondialdehyde (MDA) as a lipid peroxidation marker. Wiad Lek 57:453-455.
Gehm BD, Meandrews JM, Chien PY (1997) Resveratrol, a polyphenolic compound found in graps and wine is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A 94:14138-14143.
Golub LM, Lee HM, Ryan ME (1998) Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 12:12-26.
Guevara I, Iwanejko J, Dembinska-Kiec A (1998) Determination of nitrite / nitrate in human biological material by the simple Griess reaction. Clin Chim Acta 274:177-188.
Hamann GF, Liebetrau HK, Martens H, Burggraf D, Kloss CU, Bültemeier G, Wunderlich N, Jäger G, Pfefferkorn T (2002) Microvascular basal lamina injury following experimental focal cerebral ischemia and reperfusion. J Cereb Blood Flow Metab 22:526-533.
Hanemaaijer R, Visser H, Koolwijk P, Sorsa T, Salo T, Golub LM, van Hinsbergh VW (1998) Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. Adv Dent Res 12:114-118.
Hara H, Huang PL, Panahian N, Fishman MC, Moskowitz MA (1996) Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion. J Cereb Blood Flow Metab 16:605-611.
Hu X, Shelver WH (2003) Docking studies of matrix metalloproteinase inhibitors: zinc parameter optimization to improve the binding free energy prediction. J Mol Graph Model 22:115-126.
Huang SS, Tsai MC, Chih CL, Hung LM, Tsai SK (2001) Resveratrol reduction of infarct size in Long-Evans rats subjected to focal cerebral ischemia. Life Sci 69:1057-1065.
Issuree PD, Pushparaj PN, Pervaiz S, Melendez AJ (2009) Resveratrol attenuates C5a-induced inflammatory responses in vitro and in vivo by inhibiting phospholipase D and sphingosine kinase activities. FASEB J 23:2412-2424.
Jonat C, Chung FZ, Baragi VM (1996) Transcriptional downregulation of stromelysin by tetracycline. J Cell Biochem 60:341-347.
Kaplan S, Bisleri, Morgan JA, Cheema FH, Oz MC (2005) Resveratrol, a natural red wine polyphenol, reduces ischemia-reperfusion-induced spinal cord injury. Ann Thorac Surg 80:2242-2249.
Kilic U, Kilic E, Dietz GP, Bähr M (2003) Intravenous TAT-GDNF is protective after focal cerebral ischemia in mice. Stroke 34:1304-1310.
Kiyama R, Tamura Y, Watanabe F, Tsuzuki H, Ohtani M, Yodo M (1999) Homology modeling of gelatinase catalytic domains and docking simulations of novel sulfonamide inhibitors. J Med Chem 42:1723-1738.
Li F, Gong Q, Dong H, Shi J (2012) Resveratrol, a neuroprotective supplement for Alzheimer's disease. Curr Pharm Des 18:27-33.
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84-91.
Magnoni S, Baker A, George SJ, Duncan WC, Kerr LE, McCulloch J, Horsburgh K (2004) Differential alterations in the expression and activity of matrix metalloproteinases 2 and 9 after transient cerebral ischemia in mice. Neurobiol Dis 17:188-197.
Majid A, He YY, Gidday JM, Kaplan SS, Gonzales ER, Park TS, Fenstermacher JD, Wei L, Choi DW, Hsu CY (2000) Differences in vulnerability to permanent focal cerebral ischemia among 3 common mouse strains. Stroke 31:2707-2714.
Matresian LM (1992) The matrix-degrading metalloproteinases. Bioessays 14:455-463.
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639-1662.
Nagaoka I, Hirota S (2000) Increased expression of matrix metalloproteinase-9 in neutrophils in glycogen-induced peritoneal inflammation of guinea pigs. Inflamm Res 49:55-62.
Nguyen M, Arkell J, Jackson CJ (2001) Human endothelial gelatinases and angiogenesis. Int J Biochem Cell Biol 33:960-970.
Pandey AK, Verma S, Bhattacharya P, Paul S, Mishra A, Patnaik R (2012) An in-silico strategy to explore neuroprotection by quercetin in cerebral ischemia: A novel hypothesis based on inhibition of matrix metalloproteinase (MMPs) and acid sensing ion channel 1a (ASIC1a). Med Hypotheses 79:76-81.
Parnham DM, Sies H (2000) Ebselen: prospective therapy for cerebral ischemia. Expert Opin Investig Drugs 9:607-619.
Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29:1020-1030.
Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29:2189-2195.
Saarialho-Kere UK, Welgus HG, Parks WC (1993) Distinct mechanisms regulate interstitial collagenase and 92-kDa gelatinase expression in human monocytic-like cells exposed to bacterial endotoxin. J Biol Chem 268:17354-17361.
Saragusti AC, Ortega MG, Cabrera JL, Estrin DA, Marti MA, Chiabrando GA (2010) Inhibitory effect of quercetin on matrix metalloproteinase 9 activity molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction. Eur J Pharmacol 644:138-145.
Soleas GJ, Diamandis EP, Goldberg DM (1997) Wine as a biological fluid; history, production and role in disease prevention. J Clin Lab Anal 11:287-313.
Tochowicz A, Maskos K, Huber R, Oltenfreiter R, Dive V, Yiotakis A, Zanda M, Pourmotabbed T, Bode W, Goettig P (2007) Crystal structures of MMP-9 complexes with five inhibitors: contribution of the flexible Arg424 side-chain to selectivity. J Mol Biol 371:989-1006.
Wang LM, Wang YJ, Cui M, Luo WJ, Wang XJ, Barber PA, Chen ZY (2013) A dietary polyphenol resveratrol acts to provide neuroprotection in recurrent stroke models by regulating AMPK and SIRT1 signaling, thereby reducing energy requirements during ischemia. Eur J Neurosci 37:1669-1681.
Wang Q, Xu J, Rottinghaus GE, Simonyi A, Lubahn D, Sun GY, Sun AY (2002) Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res 958:439-447.
Woessner JF (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5:2145-2154.
Yurchenko PD, Schittney JC (1990) Molecular architecture of the basement membrane. FASEB J 4:1577-1590.
|48.|Copyedited by Li A, Leak RK, Li CH, Song LP, Zhao M
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
|This article has been cited by|
||Current evidence for AMPK activation involvement on resveratrol-induced neuroprotection in cerebral ischemia
| ||Narayana Pineda-Ramírez,Germán Fernando Gutiérrez Aguilar,Mónica Espinoza-Rojo,Penélope Aguilera |
| ||Nutritional Neuroscience. 2017; : 1 |
|[Pubmed] | [DOI]|
||Inhibition of Gelatinases (MMP-2 and MMP-9) by Withania somnifera Phytochemicals Confers Neuroprotection in Stroke: An In Silico Analysis
| ||Gaurav Kumar,Ranjana Patnaik |
| ||Interdisciplinary Sciences: Computational Life Sciences. 2017; |
|[Pubmed] | [DOI]|
||New insights into the antiangiogenic and proangiogenic properties of dietary polyphenols
| ||Carmen Diniz,Joanna Suliburska,Isabel M.P.L.V.O. Ferreira |
| ||Molecular Nutrition & Food Research. 2017; 61(6): 1600912 |
|[Pubmed] | [DOI]|
||The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia
| ||Kyung-Eon Lee,Kyung-Ok Cho,Yun-Sik Choi,Seong Yun Kim |
| ||The Korean Journal of Physiology & Pharmacology. 2016; 20(2): 185 |
|[Pubmed] | [DOI]|
||Resveratrol and Alzheimer’s Disease: Mechanistic Insights
| ||Touqeer Ahmed,Sehrish Javed,Sana Javed,Ameema Tariq,Dunja Šamec,Silvia Tejada,Seyed Fazel Nabavi,Nady Braidy,Seyed Mohammad Nabavi |
| ||Molecular Neurobiology. 2016; |
|[Pubmed] | [DOI]|