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\def\RunningAuthor{Shilpa A. Deshpande et al.}
\firstPage{1473}
\articleType{Review Article}
\receivedDate{31 Jul 2020}
\acceptedDate{02 Sep 2020}
\revisedDate{23 Aug 2020}
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\title{Resveratrol: A Pleiotropic Phytoconstituent}
\author{Prashant~N.~Amale\textsuperscript{1},  
            Manish~P.~Deshmukh\textsuperscript{2},  
            Ashish~B.~Budhrani\textsuperscript{3}, 
            Shilpa~A.~Deshpande\textsuperscript{*}\textsuperscript{1}~\\[5pt]{\textsuperscript{1}Department of Pharmacology, Priyadarshini J. L College of Pharmacy, MIDC, Electronic Zone Building, Hingna Road, Nagpur, Pin-440016, Maharashtra, India}~\\{\textsuperscript{2}Department of Pharmacology, Jawarharlal Nehru Medical College, Datta Meghe College of Pharmacy, Datta Meghe Institute of Medical Sciences (DU), Wardha, Pin-442001, Maharashtra, India}~\\{\textsuperscript{3}Department of Pharmaceutics, Datta Meghe College of Pharmacy, Datta Meghe Institute of Medical Sciences (DU), Wardha, Pin-442001, Maharashtra, India}}

\begin{abstract}
Resveratrol (RSV) is a plant polyphenol or phytolexin phytoconstituents obtained from the grapes, berries, peanut, and wine. RSV is obtained from natural source and regarded as safe, effective, and hepatoprotective drug with no other serious organ toxicities are reported yet. This property of RSV makes it advantageous over the allopathic medicine having symptomatic cure and plethora of adverse effects. It's a cheap and widely available phytoconstituent approved in the global market in the active form as trans-resveratrol. It has multiple pharmacological actions including, analgesic, anti-inflammatory, anti-anxiety, anti-parkinsonian, anti-alzheimers, antioxidant, antidepressant, anti-cancer, anti-diabetic, anti-atherosclerotic effects. These effects are mediated via modulation of diverse underlying endogenous molecules like reactive oxygen species, nitric oxide, malonaldehyde, neutrophil, sirtulin, cyclo-oxygenase, inducible nitric oxide syntheses, superoxide dismutase, catalase, glutathione s-transferase, alpha-secretase, metalloproteinases, C-reactive protein, dopamine, nor-adrenaline, serotonin, cytokines (interleukins), nuclear factor kappa, signal transducer activator of transcription, brain derived neural nactor, neuropeptide, hypothalamo-pitutary axis, astroglia, mitochondrial dysfunction, glutamate, adrenergic, cholinergic, opioidergic, and purinergic receptors. Researchers are trying to explore its additional health benefits and preparing new analogues for better survival in the field. Present review will help to enlighten the multi-target pleiotropic pharmacological nature of a RSV in relation to the variety of the molecular targets modulation through extensive web science literature survey.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Resveratrol,\newline Pleiotropic,\newline phytoconstituents,\newline pain,\newline inflammation
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Shilpa~A.~Deshpande~\\ Phone:\ +91-9422443171~\\  Email:\ Shilpa@hotmail.co.in
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Resveratrol (RSV) is a polyphenol, abundantly found in grape (skin and seeds), berries, peanuts and wine. This compound has many properties, including activity against glycation, immune response, oxidative stress, inflammation, neurodegeneration, several types of cancer, and aging \unskip~\citep{884141:20311760}. RSV is well tolerated phytoconstituent and believed to be a promising compound in preventing many diseases, like depression, diabetes, asthma and other complications \unskip~\citep{884141:20311756}.RSV is a pleiotropic agent having a variety of pharmacological effects like analgesic, antiviral, antiplatelet, anti-inflammatory, antimutagenic, antioxidant, anti-psoriatic, immunosuppressant, neuroprotective, antidepressant, antianxiety, anti-parkinson's, anti-Alzheimer \unskip~\citep{884141:20311746}.
    
\section{Materials and Methods}
Extensive literature survey was done using the PubMed online databases for the selected phrases like Resveratrol and pain, inflammation, anxiety, depression, Alzheimer, Parkinson which were individually feed into the database with time limit of past 10 years (2010-2020). 

Out of the total searched article (1862) the most related and suitable articles (215) were read thoroughly and about 96 were found to have relation with the present study and hence considered further. 

The selected literature out of yielded for the phrases specifically are as ``resveratrol'' and ``pain''(34/145), Resveratrol and inflammation (16/1359), Resveratrol and anxiety (9/43), Resveratrol and ``depression'' (11/87), ``Resveratrol'' and ``parkinsons'' (11/53), ``Resveratrol'' and ``Alzheimers'' (15/175).
    
\section{Results and Discussion}

\bgroup
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\caption{\boldmath {Pleiotropic mechanism of resveratrol in pathological conditions}}
\label{f-14d964188c31}
\end{figure*}
\egroup
\textbf{Pleiotropic Role of Rsv In Management of Pathological Conditions}

\textbf{Pain}

The RSV has revealed its therapeutic efficacy in the relief acute and chronic types of pain including peripheral, inflammatory, cancer, neuropathic, diabetic, post surgery, burn /tissue injury and constriction induced pain. It was found to act by modulation of cytokines, chemokines, neurotransmitters and enzymes involved in the pain pathology Figure~\ref{f-14d964188c31}. Plethora of evidences suggested that inhibition of pro-inflammatory cytokines, Cyclo-oxygenase (COX), and encouragement of the Interleukin (IL)-10 modulation of glutamatergic N-Methyl-D-Aspartate (NMDA), purinergic P\ensuremath{_{2}}X\ensuremath{_{7}}, and serotonergic(5-Hydroxy tryptaminic) 5-HT\ensuremath{_{3}}, and 5-HT\ensuremath{_{7}} receptors are the key targets of RSV\unskip~\citep{884141:20311750}.

RSV also helps in the recovery of spinal cord after injury by inhibition of COX-1, lipoperoxidation and by building theglutathionelevel model of pain. Modulation of spinal 5-HT\ensuremath{_{7\ }} and supra-spinal 5-HT\ensuremath{_{1A}}serotonergic receptor are involved in anti-hyperalgesic action of RSV in thermal stimuli induced algesia \unskip~\citep{884141:20311752}.

RSV has been found to target Adenosine MonophosphateActivated Protein Kinase (AMPK) and inhibits the Extracellular Signal regulated Kinase (ERK) and Mammalian target of Rapamycin (mTOR) signalling in the incision triggered acute and chronic pain \unskip~\citep{884141:20311751}. 

RSV found to alleviate chronic Neuropathic pain (NP) through inhibition of ERK phosphorylation and P\ensuremath{_{2}}X\ensuremath{_{3}} up-regulation, activation of Silent Information Regulator 1 (SIRT1) and up-regulation of miR-182 expression in Dorsal Root ganglia (DRG)to suppress Nav1.7 expression in NP induced rat \unskip~\citep{884141:20311747}. 

RSV reduce IL-1\ensuremath{\beta }, Malonaldehyde (MDA) while increase IL-10 and Superoxide Dismutase (SOD)level resulting inprohibition of paclitaxel-induced mitochondrial damage by blockage of phosphatidylinositol 3-kinase (PI3K)/ Protein Kinase B (Akt)mediated pathway of NP\unskip~\citep{884141:20311767}.

RSV is known to produce analgesia in bone cancer pain by modulation of the AMPK and direct allo-steric activation of SIRT1 \unskip~\citep{884141:20311770}. RSV regulates the nociceptive markers by inhibiting the Tumour Necrosis Factor (TNF) Receptor Associated Factor TRAF6/Nuclear Factor Kappa B (NF-\ensuremath{\kappa }B) communication pathway and reduction of tri-nitrobenzene sulfonic acid (TNBS)-induced spinal GFAP, TRAF6, pNF-\ensuremath{\kappa }B, TNF-\ensuremath{\alpha } and IL-1\ensuremath{\beta } level. In addition, antinociceptive effect of RSV involvesalteration of Ca2+/calmodulin-dependent signalling, TNF-\ensuremath{\alpha }, Transient Receptor Potential channels, and NO levels at spinal level\unskip~\citep{884141:20311764}. 

Trans-RSVproduces analgesia through an opioidergic mechanism similar to the morphine. Moreover, RSV also down-regulates NMDAR; NMDA Receptor (NR)-1 and NR2B subunit expression and alleviates morphine tolerance in experimental animals\unskip~\citep{884141:20311768}. 

\textbf{Inflammation}

Our body responds to various stimuli in various ways of self defence against chemical, mechanical, biological and radiation stimuli. Inflammation is one of protective response. Inflammation is caused by a series of markers contributes which includes cytokines viz. IL-1, IL-2, IL-6, IL-12, TNF-\ensuremath{\alpha }, TNF-\ensuremath{\beta }, chemokines, NF- kB, signal transducer and activator of transcription (STAT)-3, pro-inflammatory enzymes COX-2, 5-lipoxygenase (LOX), 12-LOX, matrix metalloproteinases (MMPs), prostate-specific antigen (PSA), C-reactive protein, intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM)-1, endothelial{\textendash}leukocyte adhesion molecule (ELAM)-1), vascular endothelial growth factor (VEGF) \unskip~\citep{884141:20311745}.

According to a research, inflammation is inhibited by Resveratrol (RSV). This is caused by the inhibition of contributory elements like COX2, ICAM-1, VCAM-1, neutrophil infiltration, oxidative stress, CRP, toll like receptor. It has also been found out that RSV suppresses mRNA, VEGF, and proteins expressions of IL-1\ensuremath{\beta } and MMP-3 by inhibiting the PI3K-AKT pathway in inflammatory conditions. RSV is a pleiotropic agents that suppresses TNF-a, IL-1b, NF-kB, IL-6, iNOS, MDA, ICAM-I, caspase-3 and myeloperoxidase and at the same time it was found that it considerably supported an increased secretion of SOD, catalase, and IL-10 level in inflammation induced rats \unskip~\citep{884141:20311754}.

Moreover, RSV prevents membrane translocation of the p47 subunit and blocks NADPH oxidase which in turn results in reduction of Reactive Oxygen Species (ROS) formation during the inflammation \unskip~\citep{884141:20311743}. Interference of phosphorylation of ERK 1/2, p38 and JNK by RSV suppresses the inflammatory reaction\unskip~\citep{884141:20311747}.

\textbf{Depression}

Antidepressant potential of RSV is well explored in last two decades due to its capacity to cross blood brain barrier. Imbalance of basic brain monoamines level has major contribution in the pathophysiology of depression; however, administration of RSV restores the normal monoamine (5-HT, NA) function, reduced sucrose consumption and exhibited the antidepressant like effect in Forced Swim Test (FST), Tail Suspension Test (TST) model of depression. Gu et al.2019 showed that RSV can significantly increase the levels of Dopamine (DA), 5-HT, Brain Derived Neural Factor (BDNF) and Neuropeptide Y (NPY) in the brain and acts as an antidepressant. 

RSV reversed the coticosterone elevated level of BDNFand serum corticosterone by modulating the Hypothalamo-Pitutary Axis (HPA) axis in mice \unskip~\citep{884141:20311763}. 

RSV is known to protect the mitochondrial function. This is achieved by reduction in mitochondrial oxygen production, glutathione synthase (GSH) deletion, ROS production, Sestrin2, SIRT1, peroxisomeproliferator - activated receptor-\ensuremath{\gamma } co-activator (PGC-)- 1\ensuremath{\alpha } and enhancement in antioxidant enzymes (Chen at al. 2017). 

RSV is not found to increase or decrease locomotor activity and hence the anti-depressant activity of this drug is not related with overall attenuation of psychomotor activity \unskip~\citep{884141:20311742}.

\textbf{Anxiety}

Anxiety is associated with diabetes and RSV treatment for 2week aggravatedanxiolytic-like effects in streptozotocin-induced diabetic mice. Pre-diabetic condition found to be associated with hyper-anxiety which is significantly ameliorated by RSV with modulation of sirtuins, which may be similar to metformin\unskip~\citep{884141:20311748}.

Trans-RSV HPA (hypothalamic-pituitary-adrenal) axis/pCREB/BDNF pathway and improve the TDS-induced anxiety-like behaviours and fear memory deficits in rodent. 

Tran-RSV increased the percentage of centre zone time and time spent in open arm with entriesin the open field test (OFT) and the elevated plus maze, while reduced freezing time in the contextual test \unskip~\citep{884141:20311753}. 

RSV treatment increased rearing and movement in the OFT, elevated sucrose preference index, and reduced immobility in the FST in subclinical hypothyroidism rats. 

This anxiolyticand antidepressant-like effect was thought to be due to down-regulation of hyperactivity of the HPA axis and regulation of HPT (hypothalamic-pituitary-thyroid) axis and the Wnt/\ensuremath{\beta }-catenin pathway ultimately balancing of the HPA and HPT \unskip~\citep{884141:20311758}.

\textbf{Parkinson's Disease (PD)}

Activation of the AMPK-SIRT1 autophagy pathway involved in the neuroprotective effects of RSV in cellular model of PD. The RSV found to down-regulate the expression of metastasis-associated lung adenocarcinoma transcript (MALAT)-1, which acted as a negative regulator of miR-129. 

Alpha-synuclein (SNCA) gene, a target gene of miR-129 induces neuronal apoptosis and causes PD. MALAT1 is suppressor of the miR-129 and RSV down-regulates the expression of MALAT1 results in indirect inhibition of apoptosis and established anti-parkinsonianphytoconstituents \unskip~\citep{884141:20311761}.

COX-2 and TNF-\ensuremath{\alpha } is a pro-inflammatory enzyme and cytokine involved in aetiology of PD. RSV treatment reduces 6-OHDA-increased expression of TNF-\ensuremath{\alpha } mRNA, COX-2 protein, COX-2 enzyme level and corrected the behavioural impairment, damage of dopaminergic system of substantianigra in rat model of PD.

RSV also attenuates 6-OHDA-induced apoptosis and motor dysfunction by promoting the PI3K/Akt signalling pathway thus delayed the progression and symptoms in 6-OHDA model of PD. 

In addition, RSV may ameliorate the behavioural, biochemical, and histo-pathological abnormalities caused due free radicals formation during PD \unskip~\citep{884141:20311757}.

Mitochondrial fission/fusion and biogenesis majorly regulates mitochondrial homeostasis, while its impairment may underlie the pathogenesis of PD. 

Oxidative stress and mitochondrial dysfunction causes loss of dopaminergic neurons in PD. RSV attenuates MPP+ induced mitochondrial dysfunction and cell apoptosis through AKT/GSK-3\ensuremath{\beta } pathway \unskip~\citep{884141:20311750}.

Liu et al. showed that RSV attenuates MPTP-induced dopaminergicneuronal loss, astroglial activation, expression of \ensuremath{\alpha }-synucle,activation of caspase-3, IL-1\ensuremath{\beta } level, pro-apoptotic Baxmolecule. 

On the contrary RSV increased levels of the anti-apoptotic Bcl-2, pAkt/Akt ratio and enhanced dopaminergic neuronal survival in the striatum. RSV reduced the dose of L-DOPA from alone 8mg/kg to 5mg/kg when given combination in MPTP-induced PD. 

All the biological, molecular, morphological changes behavioural dysfunction in parkinson's enforces RSV as promising therapeutic agent for PD\unskip~\citep{884141:20311755}.

\textbf{Alzheimer's disease (AD)}

RSV have be observed to reduce the neuro inflammation, and it induces adaptive immunity by reducing CSF MMP9 and elevates macrophage-derived chemokine (MDC), IL-4, and fibroblast growth factor (FGF)-2 \unskip~\citep{884141:20311766}.

RSV facilitates clearance of neurotoxicamyloid beta (A\ensuremath{\beta }) peptides and breakdown of the amyloid precursor protein (APP). RSV also promotes SIRT1 expression, regulates cholesterol homeostasis and reduced the amyloidogenicplaque formation in AD\unskip~\citep{884141:20311749}.

RSV and oxy-RSV cause activation of \ensuremath{\alpha }-secretase and MMP-9 to lower A\ensuremath{\beta } levels without causing cell death. RSV, metalloporphyrins, and nicotinamideriboside synergistically reduced amyloid \ensuremath{\beta } protein leading to improvement of mitochondrial and cognitive function in AD \unskip~\citep{884141:20311762}.

Elevated concentration of RSV increased thigmotaxis response and slow \ensuremath{\beta }-amyloid toxicity progression for C. elegans strain cl4176 in normal and diabetic conditions (glucose toxicity). In addition 5 mg RSV, 5g dextrose/glucose and malate in grape juice for 1 year reduced the progression of AD \unskip~\citep{884141:20311769}. 

RSV was also found to affirmatively modulate antioxidant and anti-aging factors by increasing the expression of genes of catalase, copper chaperone for SOD 1, glutathione S-transferase zeta 1, sirtuin 1 and 3 in AD, healthy, controlled and lymphoblastoid cell lines. 

According to a study, RSV is found to reduce oxidative stress, A\ensuremath{\beta }1{\textendash}42-induced cell death with enhanced mitophagy and is also known to produce neuroprotective effects. RSV or Losartan at 10 mg/kg dose increases hippocampal BDNF level along with causing a decrease in blood pressure and nucleus tractussolitarius (NTS) ROS production in the Ang-II. group. 

Hippocampal TauT231 phosphorylation activated AktS473 phosphorylation is inhibited by Losartan, and Ang-II-induced A\ensuremath{\beta } precursors, active caspase 3, and glycogen synthasekinase 3\ensuremath{\beta } (GSK-3\ensuremath{\beta })Y216 expressions are significantly abolished. 

Losartan and RSV, both decrease the secretion level of NADPH oxidase 2 (NOX2) and elevate the level of SOD2, which in turn causes restoration of hippocampal-dependent contextual memory \unskip~\citep{884141:20311759}.

Memory impairments, \ensuremath{\beta }-amyloid plaques, tau protein hyperphosphorylation, and neuronal loss are caused by the elevated. RSV is found to reduce the formaldehyde-induced damages by promoting phosphoseryl/phosphothreonyl protein phosphatase-2A (PP2A) activity and suppressing glycogen synthasekinase (GSK-3\ensuremath{\beta }), calmodulin-dependent protein kinase II (CaMKII), hyperphosphorylation of tau protein and cytotoxicity in N2a Cells \unskip~\citep{884141:20311765}.

Intra-hippocamply administration of Ibotenic Acid (IBO) produces excitotoxicity, alteration of mRNA expression of NR2A and NR2B subunits of glutamate (NMDA) receptors. It is also reported to result in decreased in expression particularly \ensuremath{\alpha }7-nAChR with increased m1AChR. 

Apart from this, RSV administration significantly yielded better results when it was administered to the IBO lesioned rat model of AD \unskip~\citep{884141:20311744}.
    
\section{Conclusions}
RSV is plant constituent and a recommended phytoconstituent as supplemental for the well being. RSV being a single molecule possesses multi target modulation ability involved in the number of pathological conditions. Present study has shown the evidence based pleiotropic potential of the RSV in the management of the pain, inflammation, anxiety, depression, parkinson's and Alzheimer disease . It also provides future scope for the development of the most suitable congener of RSV with appropriate dose in treatment of number of clinical conditions. It also draws the attention of researches to minimize number of molecule for single or multiple pathologies and reduces the patient suffering with greater therapeutic outcome.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.
    

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