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The most extensively studied polyphenol is resveratrol, a widely distributed stilbenoid found naturally in grape skin and grape derivatives, berries and nuts [94].

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Oxidative Stress and Post-Stroke Depression: Possible Therapeutic Role of Polyphenols? Seyed Fazel Nabavi1, Olivia M. Dean2,3,4, Alyna Turner2,3,5, Antoni Sureda6, Maria Daglia7 and Seyed Mohammad Nabavi1,* 1

Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; 2IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, Australia; 3Department of Psychiatry, University of Melbourne, Parkville, Victoria, Australia; 4The Florey Institute of Neuroscience and Mental Health, Victoria, Australia; 5School of Medicine and Public Health, University of Newcastle, NSW, Australia; 6Research Group on Community Nutrition and Oxidative Stress, Laboratory of Physical Activity Sciences, IUNICS, University of Balearic Islands, Palma de Mallorca, IllesBalears, Spain; 7Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section,University of Pavia, Italy Abstract: Post-stroke depression is a common neuropsychiatric affective disorder that may develop after a stroke event. In addition to abnormalities in the biogenic amine neurotransmitters and cytokine expression induced by stroke we will focus on the role of oxidative stress and hypothesize that polyphenols may be useful as therapeutics targets for the treatment of post-stroke depression. In this paper, we discuss the hypothesis that increased oxidative stress in cerebral tissues during ischemia is implicated in the pathogenesis of depressive-like symptoms following stroke. There is substantive evidence regarding the role of oxidative stress in the pathogenesis of both stroke and depression, which provides support to this hypothesis. Reactive oxygen species, generated during stroke, cause oxidative stress, lipid peroxidation, protein oxidation, and DNA damage in neural tissues. The resultant pathophysiological processes in the neural tissues could be considered a leading mechanism in the induction of post-stroke depression. Antioxidants including polyphenols therefore, may play an important role in the outcomes of ischemia and stroke, due to their ability to protect neurons against oxidative stress, to mitigate ischemic damage via inhibition of lipid peroxidation and ability to interact with the generation of nitric oxide from the vascular endothelium, and also to decrease inflammation. These data suggest that polyphenols may therefore be a useful new therapeutic target for the treatment of post-stroke depression.

Keywords: Major depressive disorder, oxidative stress, polyphenols, post-stroke depression. INTRODUCTION Stroke is a cerebrovascular disorder and is estimated to be the second cause of mortality and long-term disability worldwide [1]. According to brain imaging studies, stroke is classified into two types, hemorrhagic stroke and ischemic stroke [2]. Up to 87% of strokes are reportedly ischemic and cause infarction and brain injury via oxygen and glucose deprivation that occur during reduced cerebral blood flow [3, 4]. Although oxygen and glucose are restored in reperfusion, this disruption and the cascade of inflammatory events result in a loss of antioxidant defense and over production reactive oxygen species (ROS) generated through pro-oxidant enzymes and mitochondrial functions [5] This excessive ROS production causes oxidative stress and leads to neuronal dysfunction and death [6]. Oxidative stress plays an important role in the pathophysiology of major depressive disorder (MDD) [7]. MDD is associated with increased oxidative stress and decreases in *Address correspondence to this author at the Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran, Tel/Fax: +98 21 22823734; P.O. Box 19945-546; E-mail: [email protected] 0929-8673/14 $58.00+.00

antioxidant defense systems, leading to neuronal damage [8]. Similar to stroke, there is strong evidence showing inflammation is key to the pathophysiology of MDD and interactions between inflammation and oxidative events are also important. Oxidative stress causes significant abnormal changes in all the biological molecules such as lipids (fatty acids, triglycerides, etc.), proteins, DNA, and mitochondria and thereafter causes neurotoxicity and neurodegeneration, which are reported MDD [9, 10]. This increased oxidative stress is correlated to decreased plasma levels of vitamin E, co-enzyme Q10, alphatocopherol, ascorbic acid, zinc and glutathione [11]. Depression, anxiety, dementia, apathy, psychosis and chronic fatigue syndrome are the most common neuropsychiatric symptoms following acute ischemic stroke [12-14]. Depression is the most common neuropsychiatric disorder developed post-stroke and occurs in one third of stroke patients during the first year following stroke onset [15]. Poststroke depression is associated with increasing mortality and morbidity, disability, cognitive impairment, sleep disorders, social withdrawal and isolation, and poor rehabilitation outcomes [16]. In this paper, we briefly review the role of oxidative stress in both stroke and MDD and thereafter we discuss the © 2014 Bentham Science Publishers

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hypothesis postulating the role of oxidative stress in establishing better therapeutic options; specifically the potential of polyphenols to treat post-stroke depression. Considering the importance of post-stroke depression, due to its high prevalence rate in stroke patients, the risk of re-stroke, and negative effects on stroke rehabilitation and cognitive functioning, understanding the role of oxidative stress can lead to the discovery of new strategies for the treatment of post-stroke depression. OXIDATIVE STRESS AND ANTIOXIDANT DEFENSE IN STROKE Data suggest that oxidative stress plays a crucial role in stroke-induced injury [17, 18]. The concentration of 4hydroxynonenal, a marker of -6 polyunsaturated fatty acid (PUFA) lipid peroxidation (also formed by other lipid peroxidation-derived aldehydes such as malondialdehyde), is significantly higher in the genetic stroke-prone rats as well as in rats with middle cerebral artery occlusion model of stroke [19]. It has been also reported that plasma homocysteine levels are increased in 15% of stroke patients [20]. Moreover, there is a positive correlation between increased levels of plasma homocysteine concentration and 4hydroxynonenal levels and reduced plasma antioxidant capacity in stroke patients [19, 21]. It is well known that elevated homocysteine induces oxidative damages and inflammation in vascular systems, and also causes thrombogenicity and endothelial cell injuries [22]. A plethora of reports suggest that elevated homocysteine levels are an independent predictor of vascular disorders such as stroke [23, 24]. Decreased levels of antioxidants including glutathione, ascorbic acid, a-tocopherol, uric acid, superoxide dismutase have been reported in stroke survivors [25]. Furthermore, oxidative stress markers are also present in these individuals [26-29]. Specifically, increases in nitric oxide, malondialdehyde, F2-isoprostanes, NADPH oxidase type 2 and 4 and 8hydroxy-2'-deoxyguanosine have been reported in stroke survivors [26, 27, 29, 30]. Oxidative stress leads to the increase of F2-isoprostanes, which has been implicated in the activation of matrix metalloproteinases (MMPs) and brain injury [30]. Kleinschnitz et al. [27] demonstrated that NADPH oxidase type 4-derived oxidative stress plays an important role in pathogenesis of stroke induced neural apoptosis (Figs. 1 & 2). NADPH oxidase (NOX) is a likely source of oxidative stress in the neural tissues [27], therefore NADPH oxidase-produced reactive oxygen species may play a causative role oxidative damage in neuronal tissues during ischemia [31]. Experimental animal stroke studies indicate that the expression of vascular NADPH oxidase type 2 increase the superoxide production [32]. It also well known that there is a correlation between NADPH oxidase, superoxide level, and the activity of superoxide dismutase, that catalyzes the conversion of superoxide which is produced from NADPH oxidases to hydrogen peroxide [33]. In turn Nox2-derived superoxide can react with arachidonic acid to produce isoprostanes [34] and also reacts with nitric oxide to synthetize peroxynitrite [35]. Both peroxynitrite and isoprostanes directly affect cerebrovascular tone and cause vascular cell

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damage [36]. The published data show that peroxynitrite decreases the activity of prostacyclin synthase, soluble guanylate cyclase and mitochondrial manganese-superoxide dismutase [37-39] and from this way, contributes to development of ischemic stroke [40]. Moreover, there is evidence suggesting that peroxynitrite activates the nuclear enzyme Poly (ADP-ribose) Polymerase (PARP-1), oxidizes tetrahydrobiopterin (nitric oxide synthase cofactor) and is associated with elevated iNOS expression and uncoupling of NOS [41-43]. Reactive oxygen species generated from mitochondria, are implicated in the pathogenesis of stroke through p53 signaling pathway [6, 44-46]. During oxidative stress, p53 transcriptionally produces pro-apoptotic proteins such as Bax, PUMA, BID and transcription-independent mitochondria and also interacts with anti-apoptotic protein such as Bcl-2 family proteins [47]. Thereafter Bcl2 mediates cytochrome c releasing and caspase activation and then leads to neuronal death [6, 47]. Superoxide dismustase (SOD) is an antioxidant isoenzyme and ROS scavenger that up-regulates phospho-Akt survival pathway and down-regulates cell death pathways such as p53, and has direct role in neuronal survival after ischemic stroke [6, 48]. Previous studies demonstrate that after continual cerebral ischemia and during reoxygenation, infarct size, superoxide level, DNA damage, protein oxidation were higher in SOD2-deficient mice compared with wild-type mouse, leading to activation of mitochondrial death pathways [49]. Similar results were also obtained in a SOD1-deficient model [50, 51]. Conversely, over expression of SOD2 demonstrates protective effects [52]. In another model of compromised antioxidant defense, induced ischemia resulted in greater brain infarction and activation of caspase-3 expression as well as apoptosis, in the glutathione peroxidase-1 (GPx-1)-deficient mice compared with normal animals [48]. Glutathione peroxidase is a key enzyme in ROS scavenging [53]. Infarct size after cerebral ischemia is lower in mutant mice deficient for neural nNOS and iNOS isoforms, while in endothelial NOS knockout mice, elevation of infarcted area size was observed after permanent cerebral ischemia, suggesting a neuroprotective role of endothelial nitric oxide [54, 55]. In the brain of stroke-prone spontaneously hypertensive rats, electron spin resonance (ESR) spectroscopy demonstrated high ROS levels, especially relating to hydroxyl radical, compared with Wistar-Kyoto rats [56]. In another study performed by Alexandrova et al. [57], in patients who suffer from ischemic stroke, circulating phagocytes activity to generate ROS and myeloperoxidase by opsonin-mediated and independent stimulation was higher than healthy patients. Corrêa Mde et al. [58] also reported that ischemic stroke caused abnormalities in thiobarbituric acid reactive substances (TBARSs) level, protein carbonyl, catalase and reduced glutathione levels, and acetylcholinesterase activity in the red blood cells. Taken together, the body of evidence supports the idea that oxidative stress plays a clear and obvious role in pathogenesis of cerebral ischemic stroke.

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Fig. (1). Main source and pathways for ischemic stroke-induced oxidative stress, PKC: Protein kinase C; NADPH-oxidase: nicotinamide adenine dinucleotide phosphate-oxidase.

ROLE OF OXIDATIVE STRESS IN MAJOR DEPRESSIVE DISORDER (MDD) The role of oxidative stress in MDD has received increasing attention as more research is being conducted in this area [10]. A growing body of evidence demonstrates abnormalities in the levels of albumin [59], omega-3 fatty acids [60], total glutathione [61], and lipid peroxidation products [62], serum levels of 8-hydroxy-2'-deoxyguanosine (oxidative DNA damage marker) [63], vitamins C and E [64], plasma (E)-4-hydroxy-2-nonenal [65] and total antioxidant potential [66], and uric acid [67] occur in people with MDD. Also, abnormalities in antioxidant enzyme activity such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase are also reported in individuals with MDD [68]. Associations have been reported between MDD and manganese superoxide dismutase, and myeloperoxidase genes polymorphisms [69, 70]. Other reports showed that major depression is associated with lowering of plasma vitamin E, tryptophan, zinc and coenzyme Q10 [71-74]. It has been reported that depression has been associated with differences in protein carbonylation [75], nitric oxide metabolites [76], lipid hydroperoxides [77], advanced oxidation protein products [78] and total reactive antioxidant potential

[79]. Increased level of urinary F2-isoprostanes, known as an important oxidative stress factor, has been reported in patients with major depression [80]. In addition, oxidative damage to DNA [81], and increasing of the asymmetric dimethylarginine (an endogenous inhibitor of endothelial nitric oxide synthase) and decreased nitric oxide [65] have been reported in depressive patients. Moreover, there is a close correlation between severity of major depression and total plasma peroxide levels [82] and xanthine oxidase [83] in depressive patients. There is close correlation between the increasing of apolipoprotein B-containing lipoproteins oxidation, associated with the decreasing of serum paraoxonase/arylesterase, with the severity of major depression [84]. Also, it has been reported that there is a significant positive correlation between oxidative stress index and Hamilton depression rating scale [64]. POLYPHENOL STROKE




Polyphenols are non-essential micronutrients, found in plant products, and can affect various human physiological and biochemical functions [85, 86]. Epidemiological studies have demonstrated that a high consumption of plant foods

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Fig. (2). Molecular mechanism of ischemic stroke-induced oxidative damages. AIF: Apoptosis inducing factor; APAF-1: Apoptotic protease activating factor 1; ATP: Adenosine triphosphate; Bax: Bcl-2-associated X protein; Bid: BH3 interacting-domain death agonist; BCl2: B-cell lymphoma 2; MAPK: Mitogen-activated protein kinase; MCP-1: monocyte chemoattractant protein-1; MMP: Matrix metalloproteinase; NO: nitric oxide; NF-kB: Nuclear factor kappa beta; PARP: Poly ADP ribose polymerase; PUMA: p53 upregulated modulator of apoptosis; TNF: Tumor necrosis factor .

rich in polyphenols are associated with a reduced risk of ischemia and stroke [87-90]. In the last decade there has been an increased interest in the potential neuroprotective effects of polyphenols against cerebral ischemia, especially grape and wine polyphenols and green tea extract [91-93]. The most extensively studied polyphenol is resveratrol, a widely distributed stilbenoid found naturally in grape skin and grape derivatives, berries and nuts [94]. Resveratrol has been studied in experimental animal models of stroke [9597]. Animals treated with resveratrol before ischemic damage, during ischemia or immediately after reperfusion. Results showed resveratrol treatment was neuroprotective; with decreased neuronal loss and infarct volume [95-97]. Furthermore, treatment with resveratrol has shown benefit in models of recurrent ischemic stroke [98]. In adult ratsresveratrol treatment, performed after the first ischemic insult, reduced ischemic cell death caused by the second cerebral

ischemia, via the reduction of both inflammatory changes and markers of oxidative stress [98]. It has been suggested that resveratrol could exert its neuroprotective activity through cerebral mitochondria biogenesis, including increased mitochondria number, size and mtDNA [99]. Other polyphenols have been studied for their neuroprotective effects. Ritz et al. [100, 101] have reported that in male Wistar rats subjected to transient ischemia, both chronic pre-treatment and acute treatment with commercial food supplements containing 95% polyphenols (extracted from red wine) was associated with reduced extracellular concentrations of excitatory amino acids, and increased levels of free radical scavengers such as ascorbic and uric acids. Many studies have reported that green tea extract, that includes ()-epigallocatechin-3-gallate (EGCG), ()epigallocatechin, ()-epicatechin-3-gallate, and ()-

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epicatechin, may help reducing neuronal damage, in partdue to its antioxidant effect [102, 103]. Specifically, green tea extract appears to protects the integrity of blood-brain barrier (BBB), reducing the structural and functional alterations in the endothelial cells. This is believed to be due to modulations of factors altering BBB permeability including; plasmin, gelatinases, free radicals, inflammatory factor, vasoactive substances, and neuroglia [104]. Further investigations highlight the capacity of polyphenols to protect neurons against oxidative stress, mitigate ischemic damage via inhibition of lipid peroxidation, interaction with the generation of nitric oxide from the vascular endothelium, and decrease inflammation [97, 105, 106]. Thus, the increasingly welldocumented results have begun to provide a basis for considering the use of polyphenols in the prevention and treatment of stroke. POLPYPHENOL TREATMENT EFFICACY IN MAJOR DEPRESSIVE DISORDER (MDD) Recently, accumulating evidence suggests that dietary polyphenols may be beneficial for MDD [107]. Green tea extract has been associated with decreased depressive symptoms both in experimental animals and in humans, possibly in part via inhibition of monoamine oxidase (MAO) enzyme activity. Anthocyanins and their aglycons, responsible for the typical color of berries, also inhibit MAO isoforms A or B with IC50 corresponding to micromolar values [108-110]. In studies carried out on mice, green tea extract had comparable antidepressant-like effects to desipramine [111]. While epigallocatechin gallate (main catechin of grean tea) was comparable to chlordiazepoxide with regard to both anxiolytic and amnesic effects mediated by GABA (A) receptors as measured by behavioural tests (including elevated plus-maze and passive avoidance) [112]. Other studies suggest that cocoa polyphenolic extract, whose main components are procyanidins, attenuate depressive symptoms both in rats and humans [113, 114]. In a study of rats, cocoa polyphenolic extract administered for 14 days significantly reduced the duration of immobility, as measured by the forced swimming test, with no change of Table 1.

motor function [114]. More recent clinical studies demonstrate the positive effects of dark chocolate polyphenols on mood both in healthy participants [113] and in patients with chronic fatigue syndrome [115]. Resveretrol has also been shown to affect mood. Resveratrol has been shown to inhibit noradrenaline and serotonin reuptake in rats [116] and significantly decreases anxiety/depressive behaviors while increasing hippocampal serotonin and noradrenaline levels in mice [117]. Moreover, in all the four brain regions, particularly in the frontal cortex and hippocampus, trans-resveratrol dose dependently inhibited monoamine oxidase-A activity [118]. Further mechanisms of action are being proposed as emerging evidence suggests that some dietary polyphenols could exert their effect via regulation of adult hippocampal neurogenesis (AHN), which is shown to play a role in different psychiatric disorders, including depression [119, 120]. In a small reduction of hippocampal volume has been found in people with depression, suggesting a reduced AHN and the involvement of hippocampus may be relevant to the pathophysiology of depression. In summary, while there is some discrepancy in the literature, there is growing evidence for a beneficial effect of polyphenols in depression [119]. POSTULATING THE ROLE OF POLYPHENOLS IN POST-STROKE DEPRESSION Based on the role of oxidative stress in the pathophysiology of ischemic stroke as well as MDD, it is hypothesized that oxidative stress plays an important role in post-stroke depression. . During acute ischemic stroke, derangement of the oxidant-antioxidant balance systems further leads to alterations of monoaminergic response (decreasing the concentrations of dopamine and serotonin). We propose that this cyclic oxidant insult may result in post-stroke depression and that antioxidants, in particular polyphenol treatment, have great potential to be therapeutic. Indeed, there is evidence obtained from animal studies suggesting that post-ischemia natural polyphenolic antioxidant treatment reduces depressive-like symptoms (Table 1). Taken together with the clini-

Summary of the numbers of studies on promising effects of some antioxidants or herbal extracts with antioxidant activity on post stroke depression.



Drug Dose

Liu et al. [121]

Abelmoschus manihot L.

Lan et al. [122] Yan et al. [123]

Aggarwal et al. [124]

Treatment Period


40, 80 and 160 mg/kg

24 days

Reduces immobility time in the forced, decreases lipid peroxidation, and increases the activity of superoxide dismutase and glutathione peroxidase, and up-regulates BDNF expression and cAMP response element-binding protein mRNA levels

Radix puerariae

75, 150, and 300 mg/kg

2 and 3 days

Increases sucrose preference, improving the mRNA expression of hippocampus

Radix puerariae

75, 150, and 300 mg/kg

Single dose

Reduces depressive-like behaviors, increases the levels of norepinephrine and dopamine in the hippocampus and striatum

10 days

Reduced neurobehavioral alterations, lipid peroxidation and nitrite concentration and improves glutathione, glutathione-S-transferase, superoxide dismutase and catalaseoxidative damage and restored mitochondrial enzyme complex activities


50 and 100 mg/kg

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cal evidence of polyphenol efficacy in both stroke and depression, we postulate that polyphenol therapy may be used as a promising strategy for treatment of post-stroke depression.

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[10] [11]

CONCLUSION AND RECOMMENDATIONS While inferences can be made from the evidence in depression and stroke independently, there are few scientific data regarding the specific role of polyphenols in post-stroke depression. We proposed that polyphenol treatment may be a viable avenue for future investigation for post-stroke depression. To explore this, studies determining differences in serum levels of antioxidants and oxidative stress markers between those with depression, stroke and post-stroke depression should be investigated. Based on these investigations and the understanding of antioxidant treatments in depression and stoke, novel polyphenol treatment targets may be identified. Comparisons with existing depression and stroke studies would also be valuable. Due to safety, tolerability and availability of dietary polyphenols, future studies should also focus on the possible promising effects of these compounds on patients suffering from post stroke depression.


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CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS



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Received: April 07, 2014

Revised: September 22, 2014

Accepted: October 07, 2014




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