Resveratrol, a polyphenol extracted from red wine, possesses potential antioxidative and anti-inflammatory effects, including the reduction of free radicals and proinflammatory mediators overproduction, the alteration of the expression of adhesion molecules, and the inhibition of neutrophil function. A growing body of evidence indicates that resveratrol plays an important role in reducing organ damage following ischemia- and hemorrhage-induced reperfusion injury. Such protective phenomenon is reported to be implicated in decreasing the formation and reaction of reactive oxygen species and pro-nflammatory cytokines, as well as the mediation of a variety of intracellular signaling pathways, including the nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, deacetylase sirtuin 1, mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, hemeoxygenase-1, and estrogen receptor-related pathways. Reperfusion injury is a complex pathophysiological process that involves multiple factors and pathways. The resveratrol is an effective reactive oxygen species scavenger that exhibits an antioxidative property. In this review, the organ-protective effects of resveratrol in oxidative stress-related reperfusion injury will be discussed.
Resveratrol, found in various plants, nuts, and fruits and especially abundant in grapes and red wine, is a naturally occurring plant antibiotic known as phytoalexins [
Protective effects and mechanisms of the resveratrol on different organs in oxidative stress-mediated reperfusion injury.
Species/targets | Model of reperfusion injury | Effective dose | Effects and mechanisms | References |
---|---|---|---|---|
Male Wistar rats rat/heart | Langendorff-perfused mode |
25 mg/kg |
MDA↓, CAT↓, peroxidase↑, and SOD↑ | [ |
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Spraque-Dawley rats/heart | Langendorff-perfused mode |
20 mg/kg |
MDA↓, LDH↓, carbonyl↓, and GSH↑ | [ |
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Male Sprague-Dawley rats/heart | Langendorff-perfused mode |
10 |
MDA↓ and infarct volume↓ | [ |
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Male Sprague Dawley rats/heart | Langendorff-perfused mode |
resveratrol |
MDA↓ and no improvement in heart function | [ |
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Sprague-Dawley/Brain | Right middle cerebral artery occlusion |
0.1–1.0 |
Activation of ER- |
[ |
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Male Wistar rats/brain | Bilateral common carotid occlusion (occlusion 4 h) | 5–30 mg/kg |
MDA↓, MPO↓, TNF- |
[ |
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Male Sprague-Dawley rats/brain | Middle cerebral artery occlusion. (occlusion 2 h) | 30 mg/kg |
Adesonine↑, inosine↑, hypoxanthine↓, and xanthine↓ | [ |
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Male Wistar rats/Brain | Bilateral common carotid occlusion (occlusion 10 min) | 30 mg/kg |
ROS↓, MDA↓, NO↓, and Na+K+-aTPase↓ | [ |
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Male Wistar rats/brain | Bilateral common carotid occlusion (occlusion 10 min) | 30 mg/kg |
COX-2↓ and iNOS↓ and NF-kB and JNK activation↓ | [ |
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Male Sprague-Dawley rats/brain | Middle cerebral artery occlusion (occlusion 30 min) | 15 and 30 mg/kg |
MDA↓, SOD↑, Nrf2↑, HO-1↑, and caspase-3↓ |
[ |
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Mongolian gerbils/brain | Bilateral common carotid occlusion (occlusion 5 min) | 30 mg/kg |
Neuronal cell death↓ | [ |
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Male Wistar rats/Brain | Middle cerebral artery occlusion (occlusion 2 h) | 20 mg/kg |
MDA↓, GSH↑, and infarct volume and motor impairment↓ | [ |
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Male New Zealand white rabbits/spinal cord | Occlusion of the infrarenal aorta (ischemia 30 min) | 1–10 mg/kg |
MDA↓ and NO↑ | [ |
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Male New Zealand white rabbits/spinal cord | Abdominal aorta clamp |
100 |
MPO↓, MDA↓, and spinal cord gray matter motor neurons injury↓ | [ |
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Male Wistar albino rats/intestine | Superior mesenteric artery occlusion |
15 mg/kg |
CAT↑, total antioxidant capacity↑, MPO↓, total oxidative status↓, and oxidative stress index (OSI) ↓ | [ |
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Male BALB/c mice/intestine | Superior mesenteric artery occlusion |
50 mg/kg |
NO↓, iNOS↓, MPO↓, MDA↓, SOD↑, GSH-Px↑, SIRT1↑, and NF-kB↓ | [ |
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Wistar albino rats/intestine | Superior mesenteric artery occlusion |
15 mg/kg |
MPO↓, MDA↓, NO↓, and SOD↑ | [ |
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Male Wistar rat/intestine | Superior mesenteric artery occlusion |
0.056 mg/kg |
Intestine damage score↓, MPO↓, and hemoglobin content↓ | [ |
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Male Wistar albino rats/spleen, ileum | Hepatic artery clamping |
15 mg/kg |
MDA↓, NO↓, and GSH↑ | [ |
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Male Wistar albino rats/kidney | Right nephrectomy and left renal pedicle clamping |
30 mg/kg |
ROS↓, MDA↓, MPO↓, LDH↓, TNF- |
[ |
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Male Wistar rats/kidney | Renal pedicles clamping |
5 mg/kg, |
NO↑, BUN↓, creatinine↓, SOD↑, GSH↑, and CAT↑ | [ |
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Male Wistar rats/kidney | Right nephrectomy and left renal pedicle clamping |
5 mg/kg, |
BUN↓, creatinine↓, SOD↑, GSH↑, CAT↑, and NO↑ | [ |
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Male Wistar rats/kidney | Both renal pedicles cross-clamping |
0.23 |
Mortality rate↓, renal damage↓, and NO↑ | [ |
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Male Sprague-Dawley rat/liver | Clamping the portal vein and hepatic artery |
0.02 and 0.2 mg/kg |
IL-1 |
[ |
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Male Sprague-Dawley rats/liver | Clamping the portal vein and hepatic artery |
10 mg/kg |
MDA↓, SOD↑, GSH↑, and CAT↑ | [ |
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Sprague-Dawley rat/lung | Left hilum |
20 mg/kg |
ROS↓, MDA↓, PGC1- |
[ |
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Male Sprague-Dawley rat/testis | Left testis torsion/detorsion |
20 mg/kg |
MDA↓, H2O2↓, and oxidative stress index↓ | [ |
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Male Wistar rats/testis | Right testis torsion/detorsion |
30 mg/kg |
Improved contralateral spermatozoid production and some fertility parameters. | [ |
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Wistar albino rat/ovary | Right unilateral adnexal torsion/detorsion |
10 mg/kg |
MDA↓, XO↓, and GSH↑ | [ |
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Male Sprague Dawley rats/retinal | Anterior chamber saline bag |
30 mg/kg |
Reduce inner retinal layers thinning | [ |
|
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Male Wistar rats rat/Retinal | Anterior chamber saline bag |
0.5 nmole |
MMP-9↓, iNOS↓, and HO-1↑ | [ |
|
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Male Spraque-Dawley rats/skeletal muscle | Abdominal aorta clamp |
20 mg/kg |
MDA↓, CPK↓, LDH↓, GSH↑ carbonyl↓, and myoglobin↓, | [ |
|
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Sprague-Dawley rats/bladder | Abdominal aorta occlusion |
10 mg/kg |
MPO↓, MDA↓, and GSH↑ | [ |
Abbreviations: I/R, ischemia-reperfusion; IP, intraperitonium; IV: intravenous; PO, Orally; MAP mean arterial pressure; ROS, reactive oxygen species; ER, estrogen receptor; HO-1, hemeoxygenase-1; PGC-1
The oxidative stress is still considered to be an important cause of I/R-induced tissue injury. There is a massive increase in oxidants and oxygen radicals during the initiation and progression of I/R injury [
Myocardial ischemia-reperfusion injury is a complex pathophysiological process that involves various factors and pathways [
Resveratrol could reduce oxidative stress by inhibiting ROS production and has been reported to be a scavenger of hydroxyl, superoxide, metal-induced radicals, and H2O2 [
Previous studies have shown that resveratrol-provided cardioprotection is achieved by preserving postischemic ventricular function and reducing myocardial infarct size and cardiomyocytes apoptosis [
NO has been identified as a crucial factor mediating the protective effects of resveratrol [
The cardioprotective mechanisms of resveratrol are complex in I/R injury. A previous report demonstrated that there was less myocardial injury and inflammation in Toll-like receptor 4- (TLR4-) deficient mice in I/R. This protective mechanism was possibly associated to the TLR4/nuclear factor-kappa B (NF-
The mechanisms of brain and spinal cord injuries are complex and multifactorial. Oxidative stress has been regarded as important pathogenesis for neurologic damage after cerebral I/R injury. ROS, like superoxide anions, hydroxyl free radicals, hydrogen peroxide, and nitric oxide, are produced during abnormal metabolic reactions or central nervous system activation in I/R [
Previous studies suggested that the cerebroprotective action of resveratrol could be mediated by both antioxidative and anti-inflammatory effects [
In addition, the resveratrol also has protective effect in spinal cord I/R injury. In a rabbit study, prophylactic use of resveratrol decreased malondialdehyde and myeloperoxidase activity and reduced spinal cord gray matter motor neurons damage following abdominal aorta clamping and reperfusion [
Gastrointestinal tract is highly sensitive to I/R injury. Intestinal I/R could trigger the release of oxidants and tissue injurious factors, leading to interstitial edema, microvascular permeability change, vasoregulation impairment, mucosal barrier dysfunction, and inflammatory cell infiltration [
Resveratrol plays a crucial role in intestinal I/R injuries. Previous study demonstrated that resveratrol exerted its broad spectrum of protective mechanisms through increasing its antioxidative capacity and reducing oxidative status and MPO in intestinal I/R injury [
Resveratrol at a dose of 0.056 mg/kg significantly decreased the hemoglobin content, the histopathologic score, and tissue myeloperoxidase activity in intestinal I/R injury, without improving the systemic and metabolic parameters [
Renal I/R causes an increase in ROS and isoprostane levels and a decrease of the antioxidant enzyme glutathione in the urological system [
NO expression is generated in renal tissue and plays an important role in the regulation of renal blood flow and glomerular filtration function. In kidney, resveratrol was found to exert its protective action through the upregulation of NO. Previous studies demonstrated that resveratrol could stimulate NO production during renal I/R [
I/R stimulates the hepatic Kupffer cells and the residing macrophage activation, to generate ROS and proinflammatory cytokines and to upregulate iNOS [
Previous studies showed that resveratrol reduced liver damage after ischemia-reperfusion. This beneficial effect was due to the replacement of the depleted antioxidant defense system in hepatic I/R injury [
Lung I/R injury occurs in lung transplantation and cardiopulmonary surgery, resulting in an excessive production of reactive ROS [
Testicular torsion is urological emergency in which damaged germinal cells may lead to infertility [
Ovarian torsion is also a gynecological emergency due to the twisting of the adnexa on its ligamentous support. Insufficiency in tissue blood flow due to various reasons such as torsion or embolism leads to ischemia [
The retina is a very sensitive neural structure that is easily damaged by free radicals and inflammation following ischemia-reperfusion injury [
Previous studies showed that matrix metallopeptidase 9 (MMP-9) expression was upregulated during brain ischemia [
I/R injuries of skeletal muscles are serious clinical problems and are commonly seen in a variety of injuries including traumatic damage, peripheral vascular surgery, plastic surgery, or limb surgery with long time tourniquet application [
Urinary bladder I/R injury is associated with vascular atherosclerotic disease or pelvic embolization operations [
Reperfusion injury after hemorrhage results in an excessive production of oxidants and proinflammatory mediators. The enhanced ROS and proinflammatory cytokines play important factors in the initiation and perpetuation of organ injury [
The SIRT1 transcription-modulating proteins showed a fine balance in response to intracellular cues such as hypoxia or stress signals. The beneficial effects of resveratrol mediated by SIRT1 activation can be contributed to by different organs [
HO-1 appears to act as a protective agent in many organs against insults, such as ischemia and oxidative stress [
Resveratrol has been indicated to have many beneficial effects in various studies and experimental conditions. There is increasing evidence suggesting that resveratrol protects organ function after ischemia or shock-like reperfusion injury. Resveratrol can attenuate organs reperfusion injury through multiple pathways. However, the protective benefits of resveratrol may not simply be attributed by its scavenging, antioxidative, or anti-inflammatory effect. It is implicated that resveratrol is also mediated in part via a variety of intracellular signaling pathways including the regulation of the NOS, HO-1, SIRT1, ER, MAPK, PGC-1
The mechanisms and pathways of resveratrol in oxidative stress-mediated ischemia-reperfusion injury. The protective benefits of resveratrol involved are its scavenging, antioxidant, and anti-inflammatory effect and the signaling mechanisms mediated may be via a variety of intracellular signaling pathways, including upregulation of ER-related MAPK/HO-1 and Sirt1/PGC-1
Ischemia-reperfusion
Intraperitonium
Intravenous
Orally
Mean arterial pressure
Reactive oxygen species
Estrogen receptor
Hemeoxygenase-1
Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha
Nuclear factor-kappa B
c-Jun N-terminal kinase
Metallopeptidase 9
Superoxide dismutase
Catalase; GSH: glutathione
Nicotinamide adenine dinucleotide phosphate-oxidase
Xanthine oxidase
Hydrogen peroxide
Tumor necrosis factor-alpha
Interleukin 6
Interleukin 10
Intercellular adhesion molecule 1
Myeloperoxidase
Nitric oxide
Inducible nitric oxide synthase.
The authors declare that they have no competing interests.
Huang-Ping Yu, MD, PhD, is the principle investigator for the studies providing oversight and contributed fundamental conceptualization for the research, writing a grant proposal and paper. Fu-Chao Liu, MD, PhD contributed to paper preparation and data collection and assisted in writing the paper. Hsin-I Tsai, MD, assisted in writing the paper.
This work was partially supported by grants from the National Science Council (NSC102-2314-B-182A-051-MY3) and Chang Gung Memorial Hospital (CMRPG3B1052 and CMRPG3B1053) to Huang-Ping Yu. Support was also provided by the National Science Council (NSC103-2314-B-182-046-MY2) and Chang Gung Memorial Hospital (CMRPG3B1622) to Fu-Chao Liu.