Resveratrol: A Pleiotropic Phytoconstituent

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 addi-tional health bene(cid:976)its and preparing new analogues for better survival in the (cid:976)ield. 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.

A 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 transresveratrol. It has multiple pharmacological actions including, analgesic, anti-in lammatory, 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 bene its and preparing new analogues for better survival in the ield. 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.

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, in lammation, neurodegeneration, several types of cancer, and aging (Kataria and Khatkar, 2019).

Pain
The RSV has revealed its therapeutic ef icacy in the relief acute and chronic types of pain including peripheral, in lammatory, 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 1. Plethora of evidences suggested that inhibition of pro-in lammatory cytokines, Cyclo-oxygenase (COX), and encouragement of the Interleukin (IL)-10 modulation ofglutamatergicN-Methyl-D-Aspartate (NMDA), purinergic P 2 X 7 , and serotonergic(5-Hydroxy tryptaminic) 5-HT 3 , and 5-HT 7 receptors are the key targets of RSV (Zeng et al., 2017).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 7 and supraspinal 5-HT 1A serotonergic receptor are involved in anti-hyperalgesic action of RSV in thermal stimuli induced algesia (Zhao et al., 2014).
RSV has been found to target Adenosine Monophos-phateActivated 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 (Tillu et al., 2012). RSV found to alleviate chronic Neuropathic pain (NP) through inhibitionof ERK phosphorylation and P 2 X 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 (Jia et al., 2020). RSV reduce IL-1β, 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 (Li et al., 2019).
RSV is known to produce analgesia in bone cancer pain by modulation of the AMPK and direct allo-steric activation of SIRT1 (Kulkarni and Canto, 2015).RSV regulates the nociceptive markers by inhibiting the Tumour Necrosis Factor (TNF) Receptor Associated Factor TRAF6/Nuclear Factor Kappa B (NF-κB) communication pathway and reduction oftri-nitrobenzene sulfonic acid (TNBS)-induced spinal GFAP, TRAF6, pNF-κB, TNF-α and IL-1β level. In addition, antinociceptive effect of RSV involvesalteration of Ca2+/calmodulin-dependent signalling, TNF-α, Transient Receptor Potential channels, and NO levels at spinal level . 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 (Tsai et al., 2012).
According to a research, in lammation is inhibited by Resveratrol (RSV). This is caused by the inhibition of contributory elements like COX2, ICAM- 1,VCAM-1, neutrophil in iltration, oxidative stress, CRP, toll like receptor. It has also been found out that RSV suppresses mRNA, VEGF, and proteins expressions of IL-1β and MMP-3 by inhibiting the PI3K-AKT pathway in in lammatory 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 in lammation induced rats (Tain et al., 2013).
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 in lammation .Interference of phosphorylation of ERK 1/2, p38 and JNK by RSV suppresses the in lammatory reaction (Jia et al., 2020).

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 pathophysiol-ogy 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 signi icantly 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 (Xu et al., 2010).
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-γ coactivator (PGC-)-1α 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 (Liu et al., 2016).

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 signi icantly ameliorated by RSV with modulation of sirtuins, which may be similar to metformin (Reddy et al., 2016).
Trans-RSV HPA (hypothalamic-pituitary-adrenal) axis/pCREB/BDNF pathway and improve the TDSinduced anxiety-like behaviours and fear memory de icits in rodent.Tran-RSV increased the percentage of centre zone time and time spent in open arm with entriesin the open ield test (OFT) and the elevated plus maze, while reduced freezing time in the contextual test .
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-pituitarythyroid) axis and the Wnt/β-catenin pathway ultimately balancing of the HPA and HPT (Ge et al., 2016).

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 downregulate the expression of metastasis-associated lung adenocarcinoma transcript (MALAT)-1, which acted as a negative regulator of miR-129. Alphasynuclein (SNCA) gene, a target gene of miR-129 induces neuronal apoptosis and causes PD. MALAT1 is suppressor of the miR-129 and RSV downregulates the expression of MALAT1 results in indirect inhibition of apoptosis and established antiparkinsonianphytoconstituents (Xia et al., 2019).
COX-2 and TNF-α is a pro-in lammatory enzyme and cytokine involved in aetiology of PD. RSV treatment reduces 6-OHDA-increased expression of TNF-α 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 (Huang et al., 2019).

Mitochondrial
ission/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-3β pathway (Zeng et al., 2017). Liu et al. showed that RSV attenuates MPTP-induced dopaminergicneuronal loss, astroglial activation, expression of α-synucle,activation of caspase-3, IL-1β 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 .
RSV facilitates clearance of neurotoxicamyloid beta (Aβ) peptides and breakdown of the amyloid precursor protein (APP). RSV also promotes SIRT1 expression, regulates cholesterol homeostasis and reduced the amyloidogenicplaque formation in AD (Braidy et al., 2016).RSV and oxy-RSV cause activation of α-secretase and MMP-9 to lower Aβ levels without causing cell death. RSV, metalloporphyrins, and nicotinamideriboside synergistically reduced amyloid β protein leading to improvement of mitochondrial and cognitive function in AD (Dragicevic et al., 2017).Elevated concentration of RSV increased thigmotaxis response and slow β-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 (Zhu et al., 2019).
RSV was also found to af irmatively 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, Aβ1-42-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-IIinduced Aβ precursors, active caspase 3, and glycogen synthasekinase 3β (GSK-3β)Y216 expressions are signi icantly 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 (Lin et al., 2018).
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 α7-nAChR with increased m1AChR. Apart from this, RSV administration signi icantly yielded better results when it was administered to the IBO lesioned rat model of AD (Karthick et al., 2016).

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, in lammation, 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.