50

Resveratrol

Resveratrol (3,4,5-trihydroxystilbene) is a natural product and belongs to

one of the important class of polyphenolic compounds, stilbenoids. Resveratrol

and other stilbenes are found in grapes, red wine, purple grape juice, peanuts and

some berries (Li et al. 2012). Most stilbenes in plants act as antifungal

phytoalexins, compounds that are usually synthesized only in response to

infection or injury. Resveratrol is first identified in red wine and reported in

1992. Scientists became interested in exploring its potential health benefits.

Leading to the hypothesis that resveratrol might help to explain the “French

Paradox”- the observation that mortality from coronary heart disease is relatively

low in France despite o f relatively high levels of dietary saturated fat and

cigarette smoking. This led to the idea that regular consumption of red wine might

provide additional protection from cardiovascular disease than other forms of

alcoholic drink (Li et al. 2012). Resveratrol administration has increased the

lifespan of yeast, worms, fruit flies, fish and mice fed with high-calorie diet,

but it is not known whether resveratrol will have similar effects in humans

(Rascon et al. 2012).

3,4′,5-Trihydroxy-trans-stilbene, 5-[(1E)-2-(4-Hydroxyphenyl)ethenyl]-1,3-benzenediol Fig: Structure of resveratrol

51

6.1 Food Sources Resveratrol is classified by its chemical structure as a polyphenol. These make a

huge group of plant compounds that are further broken down into other

classifications such as flavonoids and proanthocyanidins. Phytoalexins are

antibacterial and anti-fungal chemicals produced by plants as a defense against

infection by pathogens, injuries, stresses, UV irradiation, chemicals and climatic

conditions (Tosun and Inkaya 2010). Resveratrol is found in grapes, grape

products, wine, peanuts, cranberries, strawberry and some other botanical sources.

The quantity of resveratrol in these foods ranges from 0.02 mg/L up to 6 mg/L

(see Table). Resveratrol belongs to a class of polyphenolic compounds called

stilbenes. Resveratrol originates in at least 72 species of plants distributed

amongst 31 genera and 12 families. All of the families found to contain resveratrol

belong to the spermatophytes division: Vitaceae, Myrtaceae,

Dipterocarpaceae,Cyperaceae, Gnetaceae, Leguminosae, Pinaceae, Moraceae,

Fagaceae, and Liliaceae. As a dietary source, it is a naturally occurring

antioxidant found in grapes, grape products such as wine and some other botanical

sources like peanuts, pistachio, strawberries, currants, cranberries and cranberry

juice (Tosun and Inkaya 2010).

52

Table: Resveratrol concentration in foods

Adapted from Tosun and Inkaya 2010

Sources trans-Resveratrol (mg/L) References

Wine (Pinot Noir Red) 3.6 Stervbo et al. 2007

Wine (Merlot, Red) 2.8 Stervbo et al. 2007

Peanut (Spanish Small White) 1.79 Sanders et al. 2000

Wine (Cabernet Sauvignon, Red) 1.70 Stervbo et al. 2007

Dark Chocolate 0.40 Counet et al. 2006

Peanut butter 0.30 Burns et al. 2002

Grape (Emir, White) 0.29 Gurbuz et al. 2007

Cranberry juice 0.24 Wang et al. 2002

Roasted peanut (Yeojoo) 0.13 Lee et al. 2004

Strawberry 0.11 Wang et al. 2007

6.2 Metabolism and Bioavailability

Resveratrol when it is administered orally; better absorption takes place in

humans. It’s bioavailability is low due to rapid metabolism and elimination.

Studies showed the bioavailability of the resveratrol from grape juice contains

mostly glucosides of resveratrol, may be even lower than trans-resveratrol.

Resveratrol metabolites primarily detected upon oral exposure are trans-

resveratrol. Recent studies demonstrate that when six healthy human vo lunteers

took an oral dose of 25 mg of trans-resveratrol, only t races of un-metabolized

resveratrol were detected in plasma (blood). Plasma concentrations of

resveratrol and metabolites peaked around 60 minutes after, at concentrations

around 2 micromoles/ liter (Walle et al. 2004). According to the evidences, the

oral bioavailability of resveratrol is almost zero due to rapid and extensive

metabolism and the consequent formation of various metabolites of resveratrol

which are glucuronides and resveratrol sulfates. The potential biologic activity of

53

resveratrol conjugates should be considered in future investigations (Wenzel and

Somoza 2005).

6.3 Biological Activities 6.3.1 Direct Antioxidant Activity

Resveratrol is a natural product; it scavenges the free radicals and oxidants

effectively. Resveratrol inhibits low-density lipoprotein (LDL) oxidation. In vitro

studies, resveratrol had effective antioxidant and radical scavenging activity by

the alteration of DPPH, ABTS, DMPD, O2− and H2O2 scavenging activities, total

antioxidant activity, reducing abilities and Fe2+ chelating activities. It can be used

in pharmacological and food industry due to its anti-oxidant properties (Gulcin

2009).

6.3.2 Anti inflammatory activity

Resveratrol is used to decrease the levels of pro-inflammatory cytokines

in vivo and to reduce inflammatory reactions in certain inflammatory diseases

(Leiro et al. 2010). Resveratrol has anti-inflammatory activities through

modulation of enzymes and pathways that produce mediators of inflammation.

Resveratrol does not produce any adverse effects, even consumed at high

concentrations. However, resveratrol possesses good potential to be used as an

adjunctive or alternative therapy for inflammatory diseases (Udenigwe et al.

2008).

6.3.3 Anti Cancer activity

Resveratrol acts against precancerous or cancer cells by its multiple

biochemical and molecular actions. It affects all three discrete stages of

carcinogenesis (initiation, promotion and progression) by modulating signal

transduction pathways that control cell division and growth, apoptosis,

54

inflammation, angiogenesis and metastasis. The anticancer property of resveratrol

has been supported by its ability to inhibit proliferation of a wide variety of

human tumor cells in vitro (Bishayee et al. 2009). Anti-cancer effect of

resveratrol is associated with induction of apoptosis via mitochondrial pathway

alignment (Sun et al. 2008).

6.3.4 Anti atherosclerosis activity

Atherosclerosis, a progressive disease characterized by the accumulation

of lipids and fibrous elements in the arteries, is a most important contributor to

cardiovascular diseases (Fan et al. 2008). Resveratrol may have protective effects

against atherosclerosis. It could receive consideration as a primary preventive

agent (Agarwal et al. 2012).

6.3.5 Anti Platelet Aggregation activity

Red wine consists of resveratrol. Low or moderate consumption of red

wine has a greater benefit than the consumption of other beverages in the

prevention of coronary heart disease and atherosclerosis. This is attributed

increasingly to the polyphenol compounds present in red wine. Resveratrol

inhibits platelet aggregation both in vitro and in vivo. This may be one of the

mechanisms by which resveratrol prevents atherosclerosis (Wang et al. 2002).

6.3.6 Activation of Autophagy in Parkinsonian Cells

Recently disregulation of the autophagy pathway has been observed in the

brains of PD patients and in animal models of PD, indicating the emerging role of

autophagy in this disease (Agarwal et al. 2012). In PD models, enhanced

clearance of misfolded proteins or injured mitochondria via autophagy has been

reported to have neuroprotective role. Resveratrol showed neuroprotective effects

by autophagy regulation on PD cells (Wu et al. 2011).

55

6.3.7 Inhibition of Vascular Cell Adhesion Molecule Expression

Resveratrol shows potent inhibitory effect on inflammation-induced cell-

cell adhesion, expression of adhesion molecules and activation of the NF-κB

pathway (Deng et al. 2011).

6.3.8 Estrogenic and Anti-estrogenic Activities

Endogenous estrogens are present in humans and other mammals. These

are steroidal hormones. The estrogen receptors bind to steroidal hormones within

cells. The interactions of estrogen-receptor complex modulate expression of

estrogen-responsive genes with unique sequences in DNA. A compound that

binds to estrogen receptors and elicits similar responses to endogenous estrogens

is considered as an estrogen agonist, while a compound that binds estrogen

receptors but prevents or inhibits the response elicited by endogenous estrogens

is considered as an estrogen antagonist. The chemical structure of resveratrol is

very similar to that of the synthetic estrogen agonist, diethylstilbestrol, suggesting

that resveratrol might also function as an estrogen agonist. However,

epidemiological evidence indicates that phytoestrogens inhibit cancer formation

and growth, reduce cholesterol levels and show benefits in treating osteoporosis.

At least some of these activities are mediated through the interaction of

phytoestrogens with estrogen receptors alpha and beta (ER alpha and ER beta)

(Bowers et al. 2000).

6.3.9 Cardio protective activity

Coronary heart disease (CHD) is a major cause of morbidity and death.

Recent studies focussed at an epidemiological phenomenon known as the "French

paradox." This observation refers to the coexistence of high risk factors with

unanticipated low incidence of CHD and is postulated to be associated with low-

56

to-moderate consumption of red wine. In vitro and animal studies showed that

resveratrol exerted multifaceted cardioprotective activities (Wu and Hsieh 2011).

6.3.10 Neuroprotection

Resveratrol activates SIRT1, an NAD-dependent deacetylase. SRT501, a

pharmaceutical formulation of resveratrol with enhanced systemic absorption,

prevents neuronal loss without suppressing inflammation in mice with relapsing

experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis

(MS). Resveratrol treatment showed neuroprotective effects without

immunosuppression, suggesting a potential additive benefit of resveratrol in

combination with anti-inflammatory therapies for MS (Fonseca-Kelly et al. 2012).

In cerebral ischemia/reperfusion (I/R), free radicals are known to cause secondary

neuronal damage. Resveratrol treatment improves neurological deficits caused by

reperfusion injury. Histological examination of CA1 hippocampal region revealed

that resveratrol treatment diminished intercellular and pericellular edema and glial

cell infiltration (Yousuf et al. 2009).

6.3.11 Longevity

Recent researchers examine the effect of resveratrol on longevity on six

species like yeast, nematodes, mice, fruit flies, Mexican fruit flies and turquoise

killifish. Longevity is most potent in yeast and nematodes with diminished

reliability in most higher-order species. Turquoise killifish were especially

sensitive to life-extending effects of resveratrol but showed much variation. Much

of the considerable heterogeneity of few species conclusively shows life extension

in response to resveratrol. As such, a question arises to the practice of the

resveratrol being marketed as a life-extending health supplement for humans

(Hector et al. 2012).

57

References

1. Agarwal B, Campen MJ, Channell MM et al. Resveratrol for primary

prevention of atherosclerosis: Clinical trial evidence for improved gene

expression in vascular endothelium. Int J Cardiol 2012; S0167-

5273(12)01133-3.

2. Bishayee A. Cancer prevention and treatment with resveratrol: From rodent

studies to clinical trials. Cancer Prev Res (Phila) 2009; 2(5): 409-18.

3. Bowers JL, Tyulmenkov VV, Jernigan SC et al. Resveratrol acts as a mixed

agonist/antagonist for estrogen receptors alpha and beta. Endocrinology 2000;

141(10): 3657-67.

4. Deng YH, Alex D, Huang HQ et al. Inhibition of TNF-α-mediated endothelial

cell-monocyte cell adhesion and adhesion molecules expression by the

resveratrol derivative, trans-3,5,4'-trimethoxystilbene. Phytother Res 2011;

25(3): 451-7.

5. Fan E, Zhang L, Jiang S et al. Beneficial effects of resveratrol on

atherosclerosis. J Med Food 2008; 11(4): 610-4.

6. Fonseca-Kelly Z, Nassrallah M, Uribe J et al. Resveratrol neuroprotection in a

chronic mouse model of multiple sclerosis. Front Neurol 2012; 3: 84.

7. Gulcin I. Antioxidant activity of L-adrenaline: a structure-activity insight.

Chem Biol Interact 2009; 179(2-3): 71-80.

8. Hector KL, Lagisz M, Nakagawa S. The effect of resveratrol on longevity

across species: a meta-analysis. Biol Lett 2012; 8(5): 790-3.

9. Li F, Gong Q, Dong H, Shi J. Resveratrol, a neuroprotective supplement for

Alzheimer's disease. Curr Pharm Des 2012; 18(1): 27-33.

58

10. Rascon B, Hubbard BP, Sinclair DA et al. The lifespan extension effects of

resveratrol are conserved in the honey bee and may be driven by a mechanism

related to caloric restriction. Aging (Albany NY) 2012; 4(7): 499-508

11. Sun W, Wang W, Kim J et al. Anti-cancer effect of resveratrol is associated

with induction of apoptosis via a mitochondrial pathway alignment. Adv Exp

Med Biol 2008; 614: 179-86.

12. Tosun I, Inkaya AN. Resveratrol as a Health and Disease Benefit Agent. Food

Reviews International 2010; 26: 85–101.

13. Udenigwe CC, Ramprasath VR, Aluko RE et al. Potential of resveratrol in

anticancer and anti-inflammatory therapy. Nutr Rev 2008; 66(8): 445-54.

14. Walle T, Hsieh F, DeLegge MH et al. High absorption but very low

bioavailability of oral resveratrol in humans. Drug Metab Dispos 2004;

32(12): 1377-82.

15. Wang Z, Zou J, Huang Y et al. Effect of resveratrol on platelet aggregation in

vivo and in vitro. Chin Med J (Engl) 2002; 115(3):378-80.

16. Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol.

Mol Nutr Food Res 2005; 49(5): 472-81.

17. Wu JM, Hsieh TC. Resveratrol: a cardioprotective substance. Ann N Y Acad

Sci 2011; 1215:16-21.

18. Wu Y, Li X, Zhu JX et al. Resveratrol-activated AMPK/SIRT1/autophagy in

cellular models of Parkinson's disease. Neurosignals 2011; 19(3):163-74.

19. Yousuf S, Atif F, Ahmad M et al. Resveratrol exerts its neuroprotective effect

by modulating mitochondrial dysfunctions and associated cell death during

cerebral ischemia. Brain Res 2009; 1250: 242-53.

59

Review of Literature

Resveratrol is a bioflavone, obtained from grape skin. It exerts variety of

biochemical and pharmacological effects. Recently considerable interest has been

focused on resveratrol because of its anti-oxidant, anti-inflammatory and anti-

proliferative activities. Oxidative stress and inflammation are thought to be key

pathological events in ischemic reperfusion injury. ROS overproduction leads to

inflammatory cascades which further worsen the ischemic condition by damaging

lipids, proteins and nucleic acids. There is an increasing evidence supporting the

hypothesis that resveratrol can provide protection against neurodegenerative

changes associated with cerebral ischemia and reperfusion injury. This chapter

reviews the neuroprotective effect of resveratrol that have been studied by several

authors in experimental models of cerebral ischemia and reperfusion. Resveratrol

has been suggested as a therapeutic agent in cerebral ischemia and reperfusion

injury.

Simao et al. 2012 investigated that resveratrol has neuroprotection by its anti-

inflammatory effects. In this experiment, adult male rats were subjected to 10 min

of four-vessel occlusion and sacrificed at selected post-ischemic time points. They

examined inflammatory markers like NF-κB inflammatory cascade, COX-2, iNOS

and JNK levels in experimental I/R rats. Finally they found that resveratrol 30

mg/kg pretrement for 7days prior to I/R induction, reduces astroglial and

microglial activation after I/R. It also decreases I/R-induced NF-κB and JNK

activation with decreased COX-2 and iNOS production.

Li et al. 2012 tested whether resveratrol play a neuroprotective effect in ischemic

rat brain model induced by middle cerebral artery occlusion (MCAO). They have

observed that resveratrol treatment alters infarction size, Long-term potentiation

60

induced by high-frequency stimulation and expression of apoptosis-related

proteins, i.e., Bcl-2 and Bax. Finally these results concluded that resveratrol can

decrease the harmful effects of cerebral ischemia-reperfusion induced brain injury

and has potential neuroprotective effect.

Simao et al. 2011 suggested that resveratrol has neuroprotective effect by

inhibiting underlying oxidative mechanisms. In this study they have estimated

infarction (stained with Nissl and fluoro jade C), ROS, nitric oxide (NO), lipid

peroxidation and Na+/ K+-ATPase levels after 7 days of I/R injury and concluded

that resveratrol may be used as a preventive or therapeutic agent in global cerebral

ischemia and reperfusion injury.

Gresele et al. 2011 suggested that resveratrol contributed to protection from

oxidative stress and radical oxygen species production, a facilitating activity on

nitric oxide production and activity. The ability to modulate the expression of

adhesive molecules by blood cells and the vascular wall seem to be the most

important mechanism. This review gave evidence on the activity of resveratrol on

vascular function and circulating blood cells in in vitro and in vivo.

Li et al. 2011 investigated that resveratrol has protective effect against ischemic

injury by alleviating oxidative stress and improving brain energy metabolism. In

this study they have examined histological changes and levels of ATP, ADP,

AMP, adenosine, inosine, hypoxanthine and xanthine. The levels of

malondialdehyde and the activities of xanthine oxidase in brain tissues were

analyzed. Their findings showed that resveratrol could exert neuroprotective effect

against ischemia injury by improving brain energy metabolism and alleviating

oxidative stress via inhibiting xanthine oxidase activity and preventing the

61

production of hypoxanthine, xanthine and oxygen radicals during

ischemia/reperfusion.

Liu et al. 2011 suggested that resveratrol significantly promotes the recovery of

rat dorsal neuronal function after spinal cord injury (SCI) and this effect is related

to its characteristics of anti-oxidation, anti-inflammation and anti-apoptosis.

Sakata et al. 2010 revealed that resveratrol, an enriched bioactive polyphenol in

red wine has neuroprotection against heme oxygenase 1 (HO1) induced free-

radical or excitotoxicity damage in cultured mouse cortical neuronal cells (a dose-

and time-dependent manner).

Siddiqui et al. 2010 investigated that the neuroprotective potentials of trans-

resveratrol against 4-hydroxynonenal (4-HNE) induced damage in PC12 cells.

Cells were pretreated with trans-resveratrol (5, 10 and 25 microM) for 24 hr,

further exposed to 4-HNE (25 microM) for 2 hr. Reactive oxygen species

generation, restoration of intracellular glutathione, and lipid peroxidation levels

were significantly reduced in pretreated trans resveratrol cells, as well as in

mitochondria-mediated apoptosis markers (Bax, Bcl-2 and Caspase-3) were

significantly restored. These findings concluded that trans resveratrol has

neuroprotection in vitro.

Zhang et al. 2010 suggested that after brain injury microglia activation occurs.

During activation of microglia, various pro-inflammatory factors were released,

causing reactive oxygen species production and the activation of signal pathways,

which lead to neuroinflammation. In the review they suggested that the microglia

is an important target for anti-inflammatory activities of resveratrol in the brain.

Cheng et al. 2009 suggested that resveratrol inhibited MMP-9 expression by up-

regulating PPAR alpha. In this experiment, an oxygen glucose deprivation-

62

exposed neuron model was used for estimation of MMP-9 and PPAR alpha or

gamma expression.

Wang et al. 2009 suggested that grape polyphenol extract oral administration may

have protection against I/R induced rats and emphasized that early intervention

may be an effective therapeutic measure for ameliorating brain injury in stroke.

Kang et al. 2009 reported that resveratrol has exerted a regulatory effect on

inflammatory reactions mediated by mast cells. Human mast cell lines (HMC-1)

were stimulated with phorbol 12-myristate 13-acetate (PMA) plus A23187 in the

presence or absence of resveratrol. ELISA, RT-PCR, real-time RT-PCR, Western

blot analysis, fluorescence, and luciferase activity assays were used in this study.

Resveratrol significantly inhibited the PMA plus A23187-induction of

inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin

(IL)-6 and IL-8.

Yousuf et al. 2009 investigated that the resveratrol has neuroprotective effect

against cerebral I/R-induced mitochondrial dysfunctions in hippocampus. In this

study they used MCAO model of brain ischemia to induce brain infarction. They

have examined ATP content and the activity of mitochondrial respiratory

complexes, cytochrome c release, DNA fragmentation, mitochondrial glutathione

(GSH), glucose 6-phosphate dehydrogenase, serum lactate dehydrogenase, protein

carbonyl and intracellular H2O2, brain infarct and histological analysis in I/R and

resveratrol treated rats. These findings highlighted the ability of resveratrol in

anatomical and functional preservation of ischemic neurovascular units and its

relevance in the treatment of ischemic stroke.

Karaoglan et al. 2008 investigated the efficacy of resveratrol, a stilbene

polyphenol and tyrosine kinase inhibitor that occurs naturally in grapes and red

63

wine, in a murine basilar artery vasospasm model. This study showed that

resveratrol induced the relaxation of smooth muscle in the wall of the basilar

artery and provided neuroprotection against cerebral ischemia in rat model. These

effects may be associated with the anti-oxidant and vasodilatory effects of

resveratrol.

Dong et al. 2008 reported that resveratrol has provided an important

neuroprotective effect on focal cerebral ischemic injury in the delayed phase. The

elevated MMP-2 and VEGF levels might be important in the neuroprotective

effect of resveratrol administration by inducing angiogenesis.

Sonmez et al. 2007 aimed to estimate resveratrol effect on behavioral deficits and

hippocampal damage in 7-day-old rat pups subjected to continuing injury. In this

study they have examined hippocampal damage and behavioral alterations 2

weeks after trauma. Resverarol 100 mg/kg dose treatment after the trauma

significantly ameliorated the trauma induced hippocampal neuron loss at

ipsilateral and contralateral hippocampal brain regions of rats. Additionally,

treatment with resveratrol decreased anxiety and increased cortex/hippocampus

dependent memory of animals subjected to blunt head trauma. These findings

concluded that resveratrol has a neuroprotective role against trauma induced

hippocampal neuron loss associated with cognitive impairment in rats.

Zamin et al. 2006 investigated the neuroprotective effect of resveratrol in an in

vitro model of ischemia. They used organotypic hippocampal cultures exposed to

oxygen-glucose deprivation (OGD). In OGD-vehicle exposed cultures, about 46%

of the hippocampus was labeled with propidium iodide (PI), indicating a robust

percentage of cell death. When cultures were treated with resveratrol 10, 25 and

50 microM, the cell death was reduced to 22, 20 and 13% respectively. To

64

elucidate a possible mechanism by which resveratrol exerts its neuroprotective

effect, they have investigated the phosphoinositide3-kinase (PI3-k) pathway using

LY294002 (5 microM) and mitogen-activated protein kinase (MAPK) using

PD98059 (20 microM). The resveratrol (50 microM) neuroprotection was

prevented by LY294002 but was not by PD98059. Immunoblotting revealed that

resveratrol 50 microM induced the phosphorylation/activation of Akt and

extracellular signal-regulated kinase-1 and -2 (ERK1/2) and the phosphorylation/

inactivation of glycogen synthase kinase-3beta (GSK-3beta). These results

suggested that PI3-k/Akt pathway is involved in the neuroprotective effect of

resveratrol.

Gao et al. 2006 evaluated the effect of resveratrol on MMP-9 induced by cerebral

ischemia-reperfusion in vivo. Male Balb/C mice were treated with resveratrol for 7

days (50 mg/kg, gavage). Thereafter, middle cerebral artery occlusion (MCAO)

was performed for 2 h with the help of intraluminal thread. Drug-treated mice

showed improvement in necrotic changes in cortex and basal ganglia. Detection of

MMP-9 activity and gene expression was performed at various time points after

MCAO. The elevated levels of MMP-9 were significantly attenuated in the

resveratrol-treated mice as compared to the vehicle treated mice. The study

suggests that resveratrol has protective effects against acute ischemic stroke,

which could be attributed to its property against MMP-9. Thus, resveratrol may be

a potential agent for the treatment of neuronal injury associated with stroke.

Breuer et al. 2006 investigated that the hydroxystilbene oxyresveratrol (trans-

2,3,4,5-tetrahydroxystilbene) was an excellent complementary drug for the

treatment of neurodegenerative disorders that causally involved

oxidative/nitrosative stress, especially in stroke.

65

Zhuang et al. 2003 investigated that the resveratrol exerted its neuroprotective

abilities by increased heme oxygenase activity, a unique pathway by which this

compound can exerted its neuroprotective actions.

Inoue et al. 2003 examined whether PPAR alpha agonists and resveratrol would

protect the brain against ischemia. Resveratrol (20 mg/kg, 3 days) reduced infarct

volume by 36% at 24 h after middle cerebral artery occlusion in wild-type mice.

The PPARalpha agonist’s fenofibrate (30 mg/kg, 3 days) and Wy-14643 (30

mg/kg, days) exerted similar brain protection. However, resveratrol and

fenofibrate failed to protect the brain in PPAR alpha knockout mice.

Ikeda et al. 2003 suggested that anti-oxidant nutrients such as vitamin E, green

tea extract, ginkgo biloba extract, resveratrol and niacin have beneficial effects in

cerebral ischemia and recirculation brain injury.

Wang et al. 2002 demonstrated that the resveratrol, a polyphenolic antioxidant,

can cross the blood-brain barrier and exert protective effects against cerebral

ischemic injury. Transient global cerebral ischemia was induced by occlusion of

both common carotid arteries (CCA) for 5 min in mongolian gerbils. Resveratrol

was injected i.p. (30 mg/kg body weight), either during or shortly after CCA

occlusion, and again at 24 hr after ischemia. They examined blood flow rate

before and after CCA occlusion using laser Doppler flowmeter. A time course

study was also carried out to assess the bioavailability of resveratrol in serum,

liver and brain using high performance liquid chromatography (HPLC).

Morphometric measurements indicated extensive delayed neuronal death in the

hippocampal CA1 region 4 days after ischemia and that neuron cell death was

marked by the increase in reactive astrocytes and microglial cells. Administration

of resveratrol, either during or after CCA occlusion, significantly (P<0.05)

66

decreased DND as well as glial cell activation. Analysis of resveratrol after i.p.

injection indicated its presence in serum, liver and brain with peak activity at 1, 4

and 4 hr, respectively.

Sharma et al. 2002 suggested that trans resveratrol involved in preventing the

cognitive deficits and reduction of oxidative stress caused by

intracerebroventricular (ICV) administration of streptozotocin in rats.

Sinha et al. 2002 suggested that chronic treatment of trans resveratrol was

effective in focal ischemia induced by middle cerebral artery (MCA) occlusion in

rats. Male Wistar rats were pretreated with trans resveratrol 20 mg/kg i.p. for 21

days and were subjected to focal ischemia by occlusion of MCA using

intraluminal thread. After two hours of MCA occlusion reperfusion was allowed

by retracting the thread. In this study they were assessed motor performance in

animals after 24 hrs and subsequently rats were sacrificed for estimation of

markers oxidative stress markers (malondialdehyde and reduced glutathione) and

for infarction volume. Significant motor impairment, with elevated levels of MDA

and reduced glutathione was observed in the vehicle treated MCA occluded rats.

Treatment with trans resveratrol prevented motor impairment, decresed levels of

MDA and reduced glutathione and also significantly decreased the volume of

infarct as compared to control. These results provided evidence of effectiveness of

trans resveratrol in focal ischemia most probably by virtue of its antioxidant

property.

Huang et al. 2001 suggested that the resveratrol was a potent neuroprotective

agent in focal cerebral ischemia. Its beneficial effects may be related to its anti-

platelet aggregation activity, vasodilating effect, antioxidant property or by all

67

mechanisms together. In this study they performed middle cerebral artery

occlusion for 1 hr followed by 24 hr reperfusion in anesthetized Long-Evans rats.

Wang et al. 2001 investigated that resveratrol might be useful in treating

ischemic-induced inflammatory processes in stroke. In this study they have

examined cytokine induction and inhibition in rat cortical mixed glial cells

exposed to in vitro ischemia-like insults (hypoxia plus glucose deprivation) by

anti oxidants. The results showed that interleukin-6 (IL-6) mRNA and protein, but

not tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta), were

induced during hypoxia/hypoglycemia followed by reoxygenation in the mixed

glial cells. The accumulation of IL-6 mRNA was induced as early as 15 min after

hypoxia/hypoglycemia and its level was further increased after subsequent

reoxygenation. Among the antioxidants studied, only resveratrol suppressed IL-6

gene expression and protein secretion in mixed glial cultures under

hypoxia/hypoglycemia followed by reoxygenation.

68

References

1. Breuer C, Wolf G, Andrabi SA et al. Blood-brain barrier permeability to the

neuroprotectant oxyresveratrol. Neurosci Lett 2006; 393(2-3): 113-8.

2. Cheng G, Zhang X, Gao D et al. Resveratrol inhibits MMP-9 expression by

up-regulating PPAR alpha expression in an oxygen glucose deprivation-

exposed neuron model. Neurosci Lett 2009; 451(2): 105-8.

3. Dong W, Li N, Gao D, Zhen H et al. Resveratrol attenuates ischemic brain

damage in the delayed phase after stroke and induces messenger RNA and

protein express for angiogenic factors. J Vasc Surg 2008: 48(3): 709-14.

4. Gao D, Zhang X, Jiang X et al. Resveratrol reduces the elevated level of

MMP-9 induced by cerebral ischemia-reperfusion in mice. Life Sci 2006;

78(22): 2564-70.

5. Gresele P, Cerletti C, Guglielmini G et al. Effects of resveratrol and other

wine polyphenols on vascular function: An update. J Nutr Biochem 2011:

22(3): 201-11.

6. Huang SS, Tsai MC, Chih CL et al. Resveratrol reduction of infarct size in

Long-Evans rats subjected to focal cerebral ischemia. Life Sci 2001; 69(9):

1057-65.

7. Ikeda K, Negishi H, Yamori Y. Antioxidant nutrients and hypoxia/ischemia

brain injury in rodents. Toxicology 2003; 189(1-2): 55-61.

8. Inoue H, Jiang XF, Katayama T et al. Brain protection by resveratrol and

fenofibrate against stroke requires peroxisome proliferator-activated receptor

alpha in mice. Neurosci Lett 2003; 352(3): 203-6.

69

9. Kang OH, Jang HJ, Chae HS et al. Anti-inflammatory mechanisms of

resveratrol in activated HMC-1 cells: Pivotal roles of NF-kB and MAPK.

Pharmacol Res 2009; 59(5): 330-7.

10. Karaoglan A, Akdemir O, Barut S et al. The effects of resveratrol on

vasospasm after experimental subarachnoidal hemorrhage in rats. Surg Neurol

2008; 70(4): 337-43.

11. Li H, Yan Z, Zhu J et al. Neuroprotective effects of resveratrol on ischemic

injury mediated by improving brain energy metabolism and alleviating

oxidative stress in rats. Neuropharmacology 2011; 60(2-3): 252-8.

12. Li Z, Pang L, Fang F, Zhang G et al. Resveratrol attenuates brain damage in a

rat model of focal cerebral ischemia via up-regulation of hippocampal Bcl-2.

Brain Res 2012; 1450: 116-24.

13. Liu C, Shi Z, Fan L et al. Resveratrol improves neuron protection and

functional recovery in rat model of spinal cord injury. Brain Res 2011; 1374:

100-9.

14. Sakata Y, Zhuang H, Kwansa H et al. Resveratrol protects against

experimental stroke: Putative neuroprotective role of heme oxygenase 1. Exp

Neurol 2010; 224(1): 3259.

15. Sharma M, Gupta YK. Chronic treatment with trans resveratrol prevents

intracerebroventricular streptozotocin induced cognitive impairment and

oxidative stress in rats. Life Sci 2002; 71(21): 2489-98.

16. Siddiqui MA, Kashyap MP, Kumar V et al. Protective potential of trans-

resveratrol against 4-hydroxynonenal induced damage in PC12 cells. Toxicol

In Vitro 2010; 24(6): 1592-8.

70

17. Simao F, Matte A, Matte C et al. Resveratrol prevents oxidative stress and

inhibition of Na+/K+-ATPase activity induced by transient global cerebral

ischemia in rats. J Nutr Biochem 2011; 22(10):921-8.

18. Simao F, Matte A, Pagnussat AS et al. Resveratrol preconditioning modulates

inflammatory response in the rat hippocampus following global cerebral

ischemia. Neurochem Int 2012; 61(5): 659-65.

19. Sinha K, Chaudhary G, Gupta YK. Protective effect of resveratrol against

oxidative stress in middle cerebral artery occlusion model of stroke in rats.

Life Sci 2002; 71(6): 655-65.

20. Sonmez U, Sonmez A, Erbil G et al. Neuroprotective effects of resveratrol

against traumatic brain injury in immature rats. Neurosci Lett 2007; 420(2):

133-7.

21. Wang MJ, Huang HM, Hsieh SJ et al. Resveratrol inhibits interleukin-6

production in cortical mixed glial cells under hypoxia/hypoglycemia followed

by reoxygenation. J Neuroimmunol 2001; 112 (1-2): 28-34.

22. Wang Q, Sun AY, Simonyi A et al. Oral administration of grape polyphenol

extract ameliorates cerebral ischemia/reperfusion-induced neuronal damage

and behavioral deficits in gerbils: Comparison of pre and post-ischemic

administration. J Nutr Biochem 2009; 20(5): 369-77.

23. Wang Q, Xu J, Rottinghaus GE, Simonyi A et al. Resveratrol protects against

global cerebral ischemic injury in gerbils. Brain Res 2002; 958 (2): 439-47.

24. Yousuf S, Atif F, Ahmad M et al. Resveratrol exerts its neuroprotective effect

by modulating mitochondrial dysfunctions and associated cell death during

cerebral ischemia. Brain Res 2009; 1250: 242-53.

71

25. Zamin LL, Dillenburg-Pilla P, Argenta-Comiran R et al. Protective effect of

resveratrol against oxygen-glucose deprivation in organotypic hippocampal

slicencultures: Involvement of PI3-K pathway. Neurobiol Dis 2006; 24(1):

170-82.

26. Zhang F, Liu J, Shi JS. Anti-inflammatory activities of resveratrol in the

brain: Role of resveratrol in microglial activation. Eur J Pharmacol 2010;

636(1-3): 1-7.

27. Zhuang H, Kim YS, Koehler RC et al. Potential mechanism by which

resveratrol, a red wine constituent, protects neurons. Ann N Y Acad Sci 2003;

993: 276-86.