Attenuation of diabetic retinopathy and neuropathy by resveratrol: Review on its molecular mechanisms of action

Life Sciences 245 (2020) 117350

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Attenuation of diabetic retinopathy and neuropathy by resveratrol: Review on its molecular mechanisms of action Irshad Ahmada, Muddasarul Hodab, a b

T

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National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi 110067, India Department of Biological Sciences, Aliah University, IIA/27-Newtown, Kolkata 700160, India

ARTICLE INFO

ABSTRACT

Keywords: Resveratrol Phytochemicals Flavonoids Diabetic neuropathy Diabetic retinopathy

Resveratrol is an important phenolic phytochemical from the therapeutic perspective. It has therapeutic impacts over wide range of diseases, especially the ones related to oxidative stress. Resveratrol, being primarily a potent anti-oxidant phytochemical, has significant impact against major diseases as inflammatory disorders, diabetes, and cancer. In the current review article, we intend to highlight the molecular aspects of the mechanism of action of resveratrol against major diabetic implications, namely, retinopathy and neuropathy. Both these diabetic implications are among the first fallouts of chronic hyperglycaemia. Resveratrol, via multiple molecular pathways, tend to attenuate and reverse these deformity and other disease-causing implications.

1. Introduction

multiple adverse effects on the patient's body [6,7]. In this regard there is a consistent effort towards designing of anti-diabetic drugs that has ideally no side effect on the patients. Several herbal medicines are in use since ancient times in the prevention and cure of diseases [8]. The identification and isolation of herbal active pharmacological ingredients is based on many factors some of which include safety profile of the herb and its bioavailability. In this context, resveratrol (3,5,4 trihydroxystilbene), a phenolic phytoalexin has emerged as a potential antioxidant that has anti-diabetic activity [9,10]. Resveratrol is mainly obtained from plant sources such as Polygonum cuspidatum [11] and Vitis vinifera [12]. In the French traditions, it has been a custom of consuming red wine along with high fat diet. The scientific aspect of it suggests that red wine significantly reduces cardiovascular diseases (CVD) by overcoming excessive oxidative radicals that is generated from high fat diet [13,14]. In nature, resveratrol exits in two isoforms, namely the cis- and trans- isoforms (Fig. 1), however its biologically active form is trans isoform [15]. Since, resveratrol is principally an effective anti-oxidant, its molecular mechanism of action significantly revolves around oxidative stress related pathways, however, other central signalling pathways are have also been reported to be altered by resveratrol at both translational and transcriptional level (Fig. 2). In vitro and In vivo studies of resveratrol have demonstrated its potential in the prevention and treatment of diabetes [16,17]. In the current review, we intend to focus on the potential use of resveratrol and its mechanism of action in attenuation of diabetes and diabetes related microvascular complications.

Glucose is the ultimate source of energy for our metabolic and physical activity. Its concentration in the blood is typically controlled by the alpha- and beta-cells of the pancreas, which secretes glucoseregulating hormones, insulin and glucagon respectively. Diabetes is a metabolic disorder that results from a chronically abnormal and sustained elevation of glucose concentration in the blood when observed during fasting as well as postprandial conditions. Diabetes may be broadly classified into type-1 and type-2. In type-1 diabetes, complete or relative insufficiency of insulin occurs due to autoimmune mediated destruction of β-cells [1]. It is < 10% of all kinds of diabetes cases, and the patients are dependent on exogenous insulin supply, where as 90% of diabetes cases belong to the type-2 kind [2]. Type-2 diabetes is characterized by the insulin resistance (IR) that results in decreased insulin sensitivity of skeletal muscle, liver and adipose tissue [3]. Physical inactivity and obesity also aggravates the chances of type-2 diabetes [4]. Generally, chronic effect of hyperglycemia may be categorized into two major types of complications, namely, macrovascular and microvascular complications. The macrovascular complications include coronary artery disease (CAD) and peripheral arterial disease (PAD), while the microvascular complications include majorly neuropathy, nephropathy and retinopathy [3]. There are a number of antidiabetic agents including sulphonylureas, thiazolidiones and various types of modulators of glucose-regulating enzymes such as α-glucosidase and dipeptidyl peptidase-4 [5]. Long term use of these agents show

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Corresponding author. E-mail addresses: [email protected], [email protected] (M. Hoda).

https://doi.org/10.1016/j.lfs.2020.117350 Received 9 November 2019; Received in revised form 13 January 2020; Accepted 21 January 2020 Available online 23 January 2020 0024-3205/ © 2020 Elsevier Inc. All rights reserved.

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Fig. 1. Chemical structure of resveratrol isoforms, (a) Trans-resveratrol isoform (pubchem ID: 445154); and (b) Cis-resveratrol isoform (pubchem ID: 1548910). Fig. 2. Schematic representation of general mechanisms of action of resveratrol against diabetic microimplications. Hyperglycemia triggers alteration of a number of enzymes, transcription factors, and cell signalling pathways, together all of which contribute to significant oxidative stress that in turn contributes to diabetic neuropathy and retinopathy. Resveratrol, on the other hand, as a potential anti-oxidant, quenches the free radicals directly, as well as through reversal of modulation of pathways that that are otherwise triggered by chronic hyperglycemia.

2.1. Mechanisms of action of resveratrol against diabetic retinopathy

Aldose reductase is an enzyme involved in polyol pathway wherein glucose is converted into sorbitol, an alcohol. Accumulation of sorbitol contributes in the development of diabetic retinopathy. However, targeted inhibition of aldose reductase has proven to be of limited efficacy against diabetic retinopathy [20]. Oxidative stress also plays a major role in cell injury due to hyperglycemia, as generates free radicals such as reactive oxygen species (ROS). Treatment with antioxidants results in significant attenuation of microvascular dysfunction caused by diabetes. Diabetic retinopathy is also characterized by the enhanced production of vascular endothelial growth factor (VEGF) which otherwise contributes to physiological phenomena like angiogenesis, arteriogenesis and lymphangiogenesis [20,21]. Angiogenesis is among the major implications that are common to cancer, diabetes and CVD. The PI3K/ AKT and MEK/ERK pathways are major pathways that are involved in the enhanced angiogenesis [22,23]. Anti-angiogenic targeted inhibition of VEGF and VEGF receptors are effective in suppression of tumors. Resveratrol is also an effective inhibitor of cell migration and cell tube

Diabetic retinopathy is among the most prevalent microvascular implications of the diabetes. It is among the major causes of blindness in United States of America [18]. Diabetic retinopathy is characterized by the thickening of basement membrane of blood vessels, loss of pericytes, and microaneurysm formation due to the accumulation of sugar. It results in the formation of advanced glycosylated end products (AGEs) [19]. The aggravation of diabetic retinopathy depends on both the intensity and sustenance of hyperglycemia. Diabetic retinopathy may be categorized into two types, background retinopathy and proliferative retinopathy. Background retinopathy is characterized by microaneurysm which are tiny vascular dilation in the retina, and typically considered as the first symptom of retinopathy. It is responsible for haemorrhages in middle layers of the retina. In proliferative retinopathy, new blood vessels are formed on the retinal surface, and results in vitreous haemorrhages. 2

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formation. Its activity is also enhanced in the presence of MEK/ERK inhibitor [24]. Anti-proliferative and anti-angiogenic effect of resveratrol is also enhanced by VEGF neutralizing antibody [24]. Suppression of VEGF retards the progression of retinopathy [25,26]. Hyperglycemia induces the inflammation and degradation of gap junction in the retinal epithelial cells [27]. This causes typical upregulation of interleukin 6, interleukin 8 (IL6, IL8) and VEGF markers. However, in the human retinal pigment epithelial cells (ARPE-19), it was observed that treatment with 0-10 μM trans-resveratrol for nine days, inhibited IL6, IL8 and VEGF expressions, thus, suggesting that resveratrol protects the retinal cells from hyperglycemia induced inflammation and gap junction intracellular communication (GJIC) degradation [27]. Resveratrol treatment also increases the activity of AMP-activated protein kinase (AMPK), which in turn increases the activity of Sirt1 that suppresses the retinal NF-κB induced inflammation in diabetic retinopathy [28]. Hyperglycemia is responsible for epigenetic alteration of inflammation-related genes. Acetylation of retinal histone proteins results in the upregulation of expression of inflammatory proteins that contributes to diabetic retinopathy. Two epigenetic enzymes, namely, histone acetylase transferase (HAT) and histone deacetylase (HDAC) are involved in the process of acetylation and deacetylation respectively. When the rMC-1 cells were grown in hyperglycemic condition, it enhanced the activity of HAT, simultaneously inhibiting the activity of HDAC, resulting in generation of inflammatory protein such as inducible nitric oxide synthase (iNOS), VEGF and ICAM-1. However, when treated with resveratrol, the cell line inhibited the expression of these proteins [29]. Angiotensin converting enzyme (ACE), a protein that is involved in the conversion of angiotensin I to angiotensin II, along with VEGF plays an important role in neovascularization, and causes diabetic retinopathy. Upregulation of VEGF expression also results in production of endothelial nitric oxide synthase (eNOS) and Matrix metalloproteinase (MMPs) which are responsible for inflammation and diabetic retinopathy. MMPs are primarily involved in the degradation of basement membrane and retinal revascularization [30]. Streptozotocin induced diabetic rats were observed to have elevated mRNA level of ACE, MMP9 and VEGF, thus inducing the production of eNOS. Resveratrol treated group on the other hand, showed attenuated mRNA levels and eNOS as compared to control group [31]. Hyperglycemia-mediated angiogenesis contributes to development of leaky vessels that results in loss of pericytes in retinal cells, thus, causing blindness due to diabetic retinopathy. Resveratrol treatment effectively blocks the vessel leakage and loss of pericytes, that in turn helps in the prevention of diabetic retinopathy [32]. Resveratrol attenuates the high intraocular pressure (HIOP)-induced retinal ischemia by down-regulating MMP-9 and iNOS expression, and simultaneously up-regulating heme oxygenase-1 (HO1) expression [33]. Hyperglycemia activates NF-κB, an inducible transcription factor which stimulates the production of cytokines and other oxidative stressrelated proteins, which together triggers apoptosis [34]. Retinal cells are highly susceptible to oxidative stress because of the presence of membranes that are rich in polyunsaturated fatty acids, and are characterized by high oxygen consumption [35]. Resveratrol treatment enhances the superoxide dismutase activity (SOD), reduces the NF-κB expression and tumor necrosis factor-α (TNF- α) activity, thus reversing the retinal layer disorganization [36,37]. In an another study, pterostilbene (derivative of resveratrol) was experimented with, wherein it inhibited the hREC proliferation by decreasing the TNF-α and IL-1β mRNA levels, along with inhibition of NF-κB protein expression [38]. Platelet derived growth factor (PDGF) is also involved in retinal epithelial (RPE) cell proliferation and migration in diabetic retinopathy. APRE19 cells, when treated with resveratrol, resulted in the inhibition of cell migration by suppressing the PGDFR, PI3K/Akt and MAPK signalling [39]. In diabetic retinopathy, hypoxia induces the neovascularization by releasing the nuclear high mobility group box 1(HMGB1) peptide from

retinal APRE19 cells. HMGB1 is responsible for the production of angiogenic cytokines. Resveratrol treatment significantly reduces the secretion of HMGBI by activating the Sirt1, thus preventing hypoxia-enhanced diabetic retinopathy [40]. 50 μM concentration of resveratrol significantly inhibits the proliferation of murine endothelial cell [41]. Sirt1 plays an important role in the acetylation and deacetylation reaction of p69. Acetylation of p69 subunit of NF-κB regulates the MMP-9 transcription. Hyperglycemia increases acetylation of p69 that in turn binds to the promoter of MMP-9, thus inducing mitochondrial damage, resulting in triggering of apoptosis. Resveratrol treatment prevents the mitochondrial damage by inhibiting the acetylation of p69 and MMP-9 [42]. Resveratrol activates the Sirt1 and inhibits the secretion of IL17 in PBMCs. Thus, playing a protective role in proliferative diabetic retinopathy [43]. Resveratrol also enhances the glutamine uptake by enhancing glutamine synthetase activity and expression of glutamate transporter (GLAST) and glutamine synthetase (GS), resulting in enhanced prevention of diabetic retinopathy [43]. There are micro RNAs, e.g. microRNA29b, that are involved in neuronal apoptosis [44,45]. Resveratrol suppresses the hyperglycemiainduced apoptosis of retinal cells by up-regulating the microRNA 29b expression and down-regulating the specificity protein 1(SP1) [46]. There are also some caspases like caspase-3, which play significant role during apoptosis [47,48]. Caspase-8 regulates the activation of caspase3 and induces the retinal injury [49]. Resveratrol inhibits the apoptosis by down-regulating the caspase-8 and caspase-3 expression [50], by modulating the AMPK/Sirt1/PGC-1α Pathway [51]. Table 1 summarizes the various mechanisms of action of resveratrol in attenuating progression of diabetic retinopathy. 2.2. Mechanisms of action of resveratrol against diabetic neuropathy Diabetes is a multi-facet disease characterized by hyperglycemia that contributes to multiple medical complications [52]. Among them is diabetic neuropathy that is related to the microvascular complication. Diabetic neuropathy is generally characterized by peripheral nervous system degradation. Similar to diabetic retinopathy, the impact of diabetic neuropathy depends on the intensity and sustenance of hyperglycemia. The exact mechanism of injury to the peripheral nervous system is not known, though it could be due to the accumulation of polyols and oxidative stress [53]. Neurons are very sensitive to oxidative stress as they consume higher quantities of oxygen. Oxidative stress is responsible for free radical generation. Hence, compounds with high antioxidant activity are potential candidates that may prevent the complication associated with diabetes [54,55]. Resveratrol, a plant derived polyphenolic compound has been identified with potential antioxidant and anti-inflammatory properties. It is actively involved in scavenging of the free radicals [56,57], which may result in protection against diabetes-induced neuronal damage [56,58]. Peripheral diabetic neuropathy may be of several forms including autonomic, sensory and focal neuropathies. More than 80% of foot amputation is due to the diabetic neuropathy [59]. Diabetic neuropathy is associated with hyperalgesia, hyperesthesia and cold allodynia. Oxidative stress plays major role in the aetiology of neuropathic pain. Superoxide anions and nitric oxides (NO) are the key mediators for the glucose induced oxidative injury resulting in diabetic neuropathy [60]. Streptozotocin (STZ) induced diabetic rats demonstrate considerable hyperalgesia and cold allodynia, along with the increased blood glucose level and decreased body weight [61]. For the study of thermal hyperalgesia, tails and paws of rats were immersed in warm water bath (47 °C ± 1 °C) till uneasiness was observed (cut off time for tail 15 s and for paw 10 s). Reduced time of tail and paw withdrawal indicates the hyperalgesia [62]. For cold allodynia study, reduced time period (cut off time 15 s) of tail immersion in cold water (10 °C ± 0.5 °C) indicates cold allodynia. After the treatment of resveratrol for two weeks, the withdrawal time of tail and paw was reported to be increased [61]. Resveratrol reduces the cytosolic nitric 3

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Table 1 Mechanism of action of resveratrol in reversal of diabetic retinopathy. Model

Dose and duration of study

Outcome of study

References

Human Umbilical Vein Endothelial Cells (HUVECs)

Dose-dependent studies of resveratrol were performed against anti-VEGF Ab1 or anti-VEGF Ab2 with 48 h incubation time in HUVECs Dose-dependent studies of 0–10 μM trans-resveratrol were performed in ARPE-19 cells, with the incubation time of 9 days in presence of 33 mM glucose

Resveratrol enhanced inhibitory effect of MEK inhibitor which in turn inhibited in vitro cell migration and capillary tube formation

[24]

Trans-resveratrol inhibited VEGF, IL6, IL8, COX-2 and TGFβ1accumulation, PKC-β activation, Cx43 degradation and enhanced GJIC and protect cells from hyperglycemia induced inflammation and GJIC degradation. Resveratrol treatment showed the increased level of AMPK, significant increase in the activity of Sirt1 and suppressed the retinal NF-κB induced inflammation in diabetic retinopathy. Significantly inhibited the acetylation of histone protein and also inhibited the expression of iNOS, VEGF and ICAM-1. Suppressed mRNA expressions of VEGF, ACE and MMPs were observed Resveratrol effectively blocked the vessels leakage and loss of pericytes, in addition to reduction of vascular endothelial growth factor IR. Resveratrol enhanced the superoxide dismutase activity (SOD), and simultaneously reduced the NF-κB and TNF- α activity, thus preventing retinal apoptosis. 10 μM concentration of resveratrol showed 100% inhibition of cell migration by suppressing the PDGFR, PI3K/Akt and MAPK pathways. Pre-ischemic and post-ischemic administration of resveratrol ameliorates the ischemia in retinal cells

[27]

IC50 of resveratrol is 50 μM against HECa10 cells. It also significantly inhibits migration of endothelial cells Protects the mitochondrial damage by increasing the deacetylase activity of Sirt1, inhibits the acetylation of p69 and prevents diabetic retinopathy. It attenuated hREC proliferation, lowered the TNF-α level, IL-1β level, and inhibition of NF-κB protein expression It increased the glutamate uptake by cells and upregulated the activity of glutamine synthetase (GS), increases the expression of glutamate transporter (GLAST) and glutamine synthetase (GS). Resveratrol inhibits the secretion of IL17 by activating the Sirt1

[41]

Human Retinal Pigment Epithelial Cells (ARPE-19) C57BL/6 mice Müller (glial) cells (rMC-1 cell line) Wistar albino male rats Male C57BL/6 mice

Resveratrol dose of 50 mg/kg body weight was administered for 7 days in Streptozotocin induced diabetic rats rMC-1 cells were incubated with a dose of 50 μM resveratrol, and incubated for 24 h Resveratrol treatment for four consecutive weeks at fixed dose of 10 mg/kg/day Resveratrol suspended in 0.5% carboxymethyl cellulose, was given orally at a fixed dose of 20 mg/kg for 4 weeks.

Male Wistar rats

Resveratrol was orally administrated at a fixed dose of 5 mg/kg/day for 4 consecutive months.

ARPE19 cells

Cells were treated with resveratrol concentrations ranging between 0 and 10 μM, with 24 h incubation.

Wistar rats

Resveratrol was administered 15 min prior, and 15 min post HIOP induced retinal ischemia at concentrations 0.05 nmol and 0.5 nmol respectively Cells were treated with wide range of resveratrol concentrations i.e. 1–100 μM for 24 h Cells were incubated with for 4 days. The ex vivo cells were incubated for four days with a dose of 25 μM resveratrol Pterostilbene was used as a derivative of resveratrol in concentration of 1 mmol/L for 72 h. Resveratrol was given in different concentration (10, 20 and 30 mmol/L) for 1 to 7 months.

HECa10 mouse endothelial cell line C57BL/6 mice Human retinal endothelial cells (hRECs) Müller cells from Sprague–Dawley rats Peripheral blood mononuclear cells (PBMCs) Sprague-Dawley rats Human ARPE-19 cell line Male C57BL/6J mice Bovine retinal capillary endothelial cells (BRECs)

PBMCs were incubated with 10 μM resveratrol for 72 h Streptozotocin induced diabetic rats were treated with resveratrol at 5 and 10 mg/kg/day for 1–7 months Cell lines were co-treated with resveratrol and CoCl2 at 20 μM for 24 and 48 h. Resveratrol was given intraperitoneally at a dose of 20 mg/ kg/day for two days before induced of ischemia/ reperfusion (I/R) and then for 3 consecutive days. Resveratrol was used in different concentration (1, 5, 10, 20 μM) for 48 h.

oxide synthase (NOS) and its mRNA expression [63]. Resveratrol improves the neuronal blood flow by scavenging the reactive oxygen species of vascular NO system. Excessive reactive oxygen species (ROS) are responsible for the neuronal damage [64]. These ROS are also responsible for damage of mitochondrial enzymes, destruction of cell membrane lipids, and DNA fragmentation [65,66]. Enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase protect the cells and tissues from oxidative injury [67]. In another study, STZ-induced in vivo diabetes model significantly elevated the expression levels of xanthine oxidase (XO), nitric oxide (NO) and MDA. Resveratrol treatment at regular intervals for six weeks resulted in significant reduction of the ROS and increased glutathione level [58]. Glutathione is a non-enzymatic molecule that scavenges ROS; reduction of glutathione production may trigger cell destruction by oxidative stress and lipid oxidation in induced diabetes conditions. However, resveratrol treated group demonstrates enhanced level of glutathione in neuronal tissues like cortex, cerebellum, spinal cord, brain stem and hippocampus. This is probably due to the free radical scavenging and antioxidant activity of resveratrol [58]. Oxidation of xanthine dehydrogenase converts it into xanthine oxidase which contributes to oxidative injury by generation of superoxide and H2O2

[28] [29] [31] [32] [37] [39] [33]

[42] [38] [43] [101]

Up regulates the microRNA 29b and down regulates specificity protein 1 (SP1) and act as anti-apoptotic agent. Prevents the HMBG1 secretion from the induced ARPE-19 cells and prevents hypoxia related retinopathy. Inhibits the apoptosis by down regulating the caspase-8 and caspase-3 expression.

[46]

Resveratrol suppresses the glucose induced apoptosis by scavenging reactive oxygen species (ROS) and inhibition of caspase-3 activation

[51]

[40] [50]

[68,69]. Xanthine dehydrogenase acts on hypoxanthine and converts it into xanthine and uric acid by using NAD+ as electron acceptor, thus preventing the production of free radical in normal tissues. Reduced xanthine oxidase activity was observed in resveratrol treated mice as compared to the control mice group [58]. Nitric oxide is an important gaseous free radical molecule that is involved in neurotransmission and regulation of blood vessels [70]. However abnormally elevated levels of nitric oxide contributes to oxidative stress as it interacts with oxygen and forms potent oxidizing agent ONOOˉ that is responsible for lipid peroxidation and DNA fragmentation [71]. Control group of STZ-induced has greater level of NO, as compared to the resveratrol treated diabetic mice [58]. Oxidative stress hampers the activity of endogenous antioxidant enzyme defence mechanisms such as SOD, catalase and glutathione peroxidase which plays crucial role in protection of cells and tissues. Oxidative stress is directly involved in the destruction of cellular protein, lipid and DNA and affects cell signalling and gene regulation [72]. Prolonged oxidative stress significantly reduces motor nerve conduction velocity (MNCV) and impairs nerve blood flow [73]. In an in vivo study, STZ-treated diabetic rats were observed to have reciprocal correlation between blood glucose level and MNCV as compared to the 4

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Table 2 Mechanism of action of resveratrol in reversal of diabetic neuropathy. Model

Dose and duration of study

Outcome of study

References

Male Sprague-Dawley rats Adult male Wistar rats

STZ- induced diabetic rats were administered with resveratrol at a dose of 10 mg/kg/day for 4–6 week. STZ- induced rats were treated with resveratrol at the doses of 10 mg/kg/day intraperitoneally for 6 weeks.

Significantly attenuated the thermal hyperalgesia and cold allodynia.

[61] [58]

Male Sprague-Dawley rats

Treatment with resveratrol at the doses of 10 and 20 mg/kg body weight for two weeks.

Male Sprague-Dawley rats

Combination of resveratrol and 4-ANI at a concentration of 10 mg/kg and 3 mg/kg body weight, respectively, for 2 weeks Dorsal root ganglion (DRG) was treated with resveratrol in concentration of 1-25 μM for 1 h. Diabetic rats were treated with resveratrol at doses 10 and 20 mg/kg body weight for 2 weeks. Resveratrol was orally administered at 5 mg/kg body weight for nine weeks.

Resveratrol treatment reduces MDA, XO and NO significantly. There was significant increase in the level of glutathione as compared to the control group Attenuated the alterations in hyperalgesia, motor nerve conduction velocity (MNCV) and nerve blood flow (NBF), also attenuated the enhanced level of malondialdehyde and peroxynitrite level. Increases the catalase level and there was significant reduction in DNA fragmentation. attenuated conduction and NBF deficit, reversal of peroxynitrite, MDA and NAD levels were observed, 1 μM concentration of resveratrol reduces the DRG neuron death from 70% to 50% whereas 25 μM concentration decreases the DRG neuron death to 42%. Showed the improved nerve conduction velocity, inhibited the TNF-α and IL-6 levels, reduction in elevated MDA level. Sensory neurons when treated with resveratrol, significantly increases the level of adenosine monophosphate activated protein kinase (AMPK), enhanced neurite outgrowth and normalized mitochondrial membrane potential. Resveratrol also contributed to reversal of thermal hypoalgesia and attenuation of foot skin intraepidermal nerve fibre loss Resveratrol partially normalized the oxidative biomarkers like MDA and by oxidizing the glutathione level, and thus increases the antioxidant property in brain tissue. Resveratrol treated animals were observed to lose weight in addition to decreased water consumption. It also contributed in significant attenuation of neuronal loss.

[81]

Sprague-Dawley rats Male Sprague-Dawley rats Male Sprague-Dawley rats

Male Wistar rats

Resveratrol was administered at the doses of 20 mg/kg/day intraperitonially for four weeks.

Male Wistar rats

Resveratrol was given at doses of 10 mg/kg/d for 120 days.

[56]

[76]

[102] [84]

[99] [100]

for inflammation of nerve cell by triggering release of IL-6 [88]. PC12 cell line incubated with high FFA concentrations results in increased IL6 release that is mediated by P2X7 receptor and activated by extracellular ATP. Its activation causes the entry of Na+ and release of K+ resulting in membrane depolarization and subsequent increase of Ca2+ that is responsible for release of pro-inflammatory cytokines and TNF-α [89–91]. Exposure of neurons to IL-6 is among the major factors that contribute to neurodegenerative changes [92]. Resveratrol treated PC12 cells experiences reduced mRNA expression level of P2X7 receptor. It also inhibits an ATP-induced Ca2+ signal that inhibits the phosphorylation of p38 mitogen-activated protein kinase (MAPK) by deactivating P2X7 receptor. Ultimately, it prevents the neuronal damage by down-regulating IL6 expression [93]. Chronic hyperglycemia accelerates the generation of AGEs, and alters the protein kinase C activity, resulting in enhanced oxidative stress that causes the dysfunction of peripheral nervous system [94]. Schwann cells play an important role in the saltatory movement by forming myelin sheath, and are highly susceptible for hyperglycemia. Schwann cell line (IFRS1), treated with high glucose condition does not induce polyol accumulation but enhances the expression of galectin-3 (GAL-3) [95] which is involved in the regulation of cell-to-cell and cell-to-matrix interaction [96,97]. IFRS1 cell lines when treated with trans-resveratrol suppresses the expression of GAL-3 [98]. STZ-induced diabetic rats demonstrate increased levels of MDA and total oxidants, in addition to reciprocal decrease in total antioxidants and glutathione level. When these rats were treated with resveratrol, it is reported to have increased activity of SOD and GST, and reduced level of MDA [99], thus preventing neuronal damage from oxidative stress. Diabetes mellitus also causes damage to the enteric nervous system by oxidative stress. Higher level of lipid hydroxide and nitric oxide are observed in ileum and jejunum of diabetic rat, however, resveratrol attenuates this oxidative stress by lowering its level to normal physiological levels [100]. Hence, resveratrol plays significant role in the treatment of type-2 diabetes-induced neuropathy by quenching the excessive ROS, thereby improvising the endogenous antioxidant enzyme defence mechanism. Table 2 summarizes the various mechanisms of action of resveratrol in attenuating progression of diabetic neuropathy.

control. However, when these STZ-treated diabetic rats were treated with resveratrol in concentrations of 10 mg/kg and 20 mg/kg individually, there was improvement in the nerve conduction deficit by 82% and 90% respectively, in addition to the nerve blood deficit of 71% and 92% respectively [56]. This improvement in nerve blood flow may be due to the vasodilation potential of resveratrol [74]. Peroxynitrite is a potent oxidant and causes significant damage to the cells in diabetic condition [72]. It mainly targets the lipids of mitochondria, plasma membrane and endoplasmic reticulum, thereby degrading the lipid-rich membranes. Resveratrol treatment significantly reduces the peroxynitrite and MDA levels, and enhances the catalase activity [56], resulting in attenuation of lipid peroxidation due the quenching of free radical [75]. Resveratrol treatment also significantly controls the DNA fragmentation by directly scavenging the peroxynitrite in sciatic nerve [56]. Additionally, combined effect of resveratrol and 4-amino-1,8-naphthalimide significantly improves the sciatic nerve conduction and nerve blood flow [76]. This improvement may be due to the inhibition of PARP and peroxynitrite mediated neuronal damage [77]. Hyperglycemic condition induces the production of ROS in dorsal root ganglia (DRG) neurons that triggers apoptosis [78–80]. Treatment with 1 μM concentration of resveratrol decreases DRG neuronal death from 70% to 50% and increased concentration (25 μM) decreases DRG neuronal death to 42% [81]. Resveratrol increases the expression of antioxidant enzymes, namely, GST and quinine oxidoredutase-1(NQO1). NQO1 detoxifies the excessive ROS that is generated in nervous system [82]. Resveratrol also inhibits NF-kB signal pathway by reducing the expression of various genes involved in inflammation and oxidative stress [83]. In diabetic neuropathy, sensory neurons are characterized by mitochondrial dysfunction, and involves distal axonopathy due to the reduced level of adenosine monophosphate activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) [84]. When the neurons of the DRG of STZ-induced diabetic rats were treated with resveratrol, it elevated the level of phosphorylation and expression of AMPK, and normalized the mitochondrial membrane potential [84], thus preventing the intraepidermal nerve fibre loss. In type 2 diabetes, increased level of free fatty acids (FFA) contributes to diabetic neuropathy due to lack of suitable suppression of adipocyte lipolysis [85–87]. The increased level of FFA is responsible 5

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3. Conclusion Resveratrol is a potential drug candidate for reversing type-2 diabetic progression, while it also attenuates diabetic complications that could otherwise have significant clinical implications such as diabetic foot, vision deformities, renal failure and cardiac complications. The molecular mechanisms of action of resveratrol suggest that it may alter specific signalling molecules and pathways that are at the core of a number of diseases. Hence, altering these pathways also significantly contribute to prevention and reversal of several other major diseases such as cancer, CVD, hepatic disorders, etc.

[23] [24] [25]

[26]

Declaration of competing interest

[27]

There is no conflict of interest, whatsoever, among the authors, for the current manuscript entitled “Attenuation of diabetic retinopathy and neuropathy by resveratrol: Review on its molecular mechanisms of actions”.

[28]

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