ReviewResveratrol neuroprotection in stroke and traumatic CNS injury
Introduction
Resveratrol is a naturally occurring stilbene-class of polyphenol produced in the skins of many edible plants as a response to fungal infection (Siemann and Creasy, 1992, Takaoka, 1940). Resveratrol is widely known for its anti-oxidant properties, and has been implicated in the putative anti-atherosclerotic effects of red wine. The neuroprotective benefits of resveratrol were known since it was shown to ameliorate kainate-induced excitotoxicity (Virgili and Contestabile, 2000). Subsequently, resveratrol has been shown to improve histopathological and behavioral outcomes after various types of acute CNS injuries including stroke (Girbovan et al., 2012, Huang et al., 2001, Karalis et al., 2011), traumatic brain injury (TBI) (Singleton et al., 2010, Sonmez et al., 2007), subarachnoid hemorrhage (SAH) (Shao et al., 2014) and spinal cord injury (SCI) (Ates et al., 2006, Kaplan et al., 2005).
The exact mechanism of resveratrol-induced neuroprotection is not clear (Morris-Blanco et al., 2014, Park et al., 2012, Tang, 2010), but many of its beneficial effects were thought to be promoted by activation of silent mating type information regulation 2 homolog 1 (SIRT1) (Borra et al., 2005), AMP-activated kinase (AMPK) (Dasgupta and Milbrandt, 2007) and nuclear factor (erythroid derived 2)-like 2 (Nrf2) (Chen et al., 2005, Ungvari et al., 2010). SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that acts on histone and non-histone targets to improve lifespan and promote a pro-survival environment in the CNS (Wood et al., 2004, Yang et al., 2013). AMPK senses increases in endogenous adenosine levels, specifically AMP or ADP, and compensates by enhancing ATP production. AMPK has been shown to activate acetyl-coA carboxylase and SIRT1, while suppressing the mammalian target of rapamycin complex (mTORC), resulting in an overall improvement in metabolism and increased lifespan (Baur et al., 2006, Spasić et al., 2009). Nrf2 is a transcription factor that is responsible for binding antioxidant response elements (ARE) in the promoters of genes like superoxide dismutase (SOD), heme oxygenase 1 (HO-1), catalase and many other phase II defense enzymes, inducing their expression (Chen et al., 2005, Kansanen et al., 2013, Zhang et al., 2013).
The secondary brain damage and neuronal death after an acute CNS insult like stroke are synergistically mediated by many pathophysiologic mechanisms that include oxidative stress, inflammation, ionic imbalance and apoptosis. Treatment with resveratrol is shown to prevent or slow-down many of these pathological changes and its neuroprotective actions seem to be mediated by many putative effectors and targets (Fig. 1). The goal of this review is to discuss the major mechanisms that are thought to mediate resveratrol-induced neuroprotection.
Section snippets
Pathophysiology of acute ischemic stroke and traumatic CNS injury
In order to appreciate mechanisms of resveratrol-mediated neuroprotection, one must consider the pathophysiology of ischemic stroke and traumatic CNS injury. Ischemic and traumatic injuries to the CNS are very different in nature. Ischemic stroke mostly occurs when the arteries (for example, the middle cerebral artery) that supply blood to the brain are blocked, often by atherosclerotic and thrombotic processes (Dirnagl et al., 1999). TBI/SCI are physical injuries most often caused by sports,
Anti-oxidative effects of resveratrol
Following an ischemic stroke, ROS levels increase quickly during the period of occlusion followed by a second wave upon reperfusion (Domínguez et al., 2010, Zweier and Talukder, 2006). If uncontrolled, oxidative stress kills neurons (Manzanero et al., 2013). Paradoxically pathways that promote as well as fight oxidative stress are induced after stroke, however most often the magnitude of ROS production supersedes ROS disposal. A major target of resveratrol is the anti-oxidant transcription
Anti-apoptotic effects of resveratrol
Resveratrol is well known for its pro-apoptotic role in cancer (Jang et al., 1997, Lin et al., 2011), but interestingly has an anti-apoptotic effect after acute CNS injury. Resveratrol treatment was shown to inhibit cytochrome c immunoreactivity and capase-3 activity after focal ischemia in adult rodents (Andrabi et al., 2004, Ren et al., 2011), after hypoxic-ischemia in neonatal rodents (West et al., 2007) and after oxygen-glucose deprivation (OGD) in primary neuronal cultures (Gong et al.,
Anti-inflammatory properties of resveratrol
Uncontrolled inflammation following ischemic and traumatic injuries to CNS is known to promote secondary brain damage. Many studies showed that resveratrol treatment decreases inflammatory burden by reducing microglial activation in in vivo (Girbovan and Plamondon, 2015, Shin et al., 2010, Simao et al., 2012a) and in vitro (Song et al., 2014) models of ischemic stroke. Resveratrol has also been shown to reduce edema (Ren et al., 2011, Yousuf et al., 2009) and prevent the release of
Resveratrol treatment mimics ischemic preconditioning
Ischemic preconditioning (IPC) is a phenomenon wherein a sub-lethal ischemic insult prepares the organ for a more severe ischemic insult, resulting in protection (Mattson, 2008, Stetler et al., 2014). IPC has been established in brain (Dhodda et al., 2004, Liu et al., 1992), heart (Rachmat et al., 2014), kidney (Tsutsui et al., 2013), and liver (Liu et al., 2014), and represents a prophylactic means of preventing ischemic damage. The idea of repeatedly inducing brief ischemia as a preventative
Estrogen receptor activation by resveratrol
Resveratrol is thought to mimic estrogen and is capable of activating α and β estrogen receptors (ERα and ERβ) (Bowers et al., 2000, Gehm et al., 1997). This has relevance to ischemic stroke which affects males more severely than females (Alkayed et al., 1998, Shin et al., 2010). Both estrogen and estradiol are shown to be neuroprotective after experimental ischemic stroke through the activation of ERα (Dubal et al., 2006, Elzer et al., 2010, Westberry et al., 2008). The protection afforded by
Nitric oxide regulation by resveratrol
NO has a complex role in pathology and physiology (Forstermann and Munzel, 2006). Endothelial nitric oxide synthase (eNOS) is responsible for producing vasorelaxing NO in the endothelium, whereas inducible nitric oxide synthase (iNOS) promotes inflammatory NO as a result of immune cell activation (Zamora et al., 2000). As a gaseous free radical, the mere presence of NO can be an indicator of oxidative/nitrosative stress. After ischemic stroke, reperfusion-mediated increase in eNOS activity can
Anti-excitotoxic effects of resveratrol
Glutamate excitotoxicity is a major mechanism that kills neurons after stroke as well as TBI and SCI (Choi, 1992, Hazell, 2007, Obrenovitch and Urenjak, 1997). Resveratrol was first shown to be neuroprotective against kainate-induced excitotoxicity in rats in vivo (Virgili and Contestabile, 2000). Resveratrol has been shown to directly bind and inhibit excitotoxic activation of post-synaptic kainate and NMDA receptors without altering the presynaptic volleys or postsynaptic membrane properties
Matrix metalloproteinase regulation by resveratrol
MMPs are known to be responsible for remodeling the extracellular matrix (ECM) and are particularly important for restoring the neurovascular unit after an injury (Wang et al., 2006). However, overexpression of certain MMPs, particularly MMP-9, can exacerbate BBB disruption and secondary brain damage after ischemia, as shown by a mouse model of transient focal ischemia, in which MMP-9 knockout mice exhibited improved tight junction protein ZO-1 levels, decreased infarct size, and decreased
Conclusion
The sum of the above presented investigations suggests that resveratrol is a potent pharmacological agent that can prevent secondary damage after stroke and acute CNS injury. Furthermore, resveratrol pretreatment is a viable option to induce ischemic tolerance. The beneficial effects of resveratrol are mediated synergistically by multiple major pathways that control inflammation, oxidative stress, mitochondrial function and apoptosis. The field of resveratrol-mediated neuroprotection would
Acknowledgments
Supported partly by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM081061. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
References (146)
- et al.
Ischemic insult induced apoptotic changes in PC12 cells: protection by trans resveratrol
Eur. J. Pharmacol.
(2011) - et al.
Oxyresveratrol (trans-2,3′,4,5′-tetrahydroxystilbene) is neuroprotective and inhibits the apoptotic cell death in transient cerebral ischemia
Brain Res.
(2004) - et al.
Antioxidant therapies in traumatic brain and spinal cord injury
Biochim. Biophys. Acta
(2012) - et al.
Resveratrol inhibits nitric oxide and TNF-α production by lipopolysaccharide-activated microglia
Int. Immunopharmacol.
(2005) - et al.
Mechanism of human SIRT1 activation by resveratrol
J. Biol. Chem.
(2005) - et al.
The loss of estrogen efficacy against cerebral ischemia in aged postmenopausal female mice
Neurosci. Lett.
(2014) - et al.
Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells
Biochem. Biophys. Res. Commun.
(2005) - et al.
Resveratrol inhibits MMP-9 expression by up-regulating PPAR alpha expression in an oxygen glucose deprivation-exposed neuron model
Neurosci. Lett.
(2009) - et al.
Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway
Neuroscience
(2009) - et al.
Involvement of estrogen receptors in the resveratrol-mediated increase in dopamine transporter in human dopaminergic neurons and in striatum of female mice
Neuropharmacology
(2012)
Pathobiology of ischaemic stroke: an integrated view
Trends Neurosci.
Ischemic tolerance and endogenous neuroprotection
Trends Neurosci.
Resveratrol reduces the elevated level of MMP-9 induced by cerebral ischemia-reperfusion in mice
Life Sci.
Inhibition of excitatory synaptic transmission by trans-resveratrol in rat hippocampus
Brain Res.
Resveratrol downregulates type-1 glutamate transporter expression and microglia activation in the hippocampus following cerebral ischemia reperfusion in rats
Brain Res.
Antioxidant therapies for traumatic brain injury
Neurother.: J. Am. Soc. Exp. Neurother.
Excitotoxic mechanisms in stroke: an update of concepts and treatment strategies
Neurochem. Int.
Resveratrol reduction of infarct size in Long-Evans rats subjected to focal cerebral ischemia
Life Sci.
Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor α in mice
Neurosci. Lett.
The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer
Redox Biol.
Resveratrol, a natural red wine polyphenol, reduces ischemia-reperfusion-induced spinal cord injury
Ann. Thorac. Surg.
Resveratrol ameliorates hypoxia/ischemia-induced behavioral deficits and brain injury in the neonatal rat brain
Brain Res.
The effects of resveratrol on vasospasm after experimental subarachnoidal hemorrhage in rats
Surg. Neurol.
Resveratrol protects spinal cord dorsal column from hypoxic injury by activating Nrf-2
Neuroscience
Modulation of inflammation by reactive oxygen species: implications for aging and tissue repair
Free Radic. Biol. Med.
Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α
Cell
Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window
Neurobiol. Dis.
Neuroprotective effects of resveratrol on ischemic injury mediated by modulating the release of neurotransmitter and neuromodulator in rats
Neurochem. Int.
Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease
Curr. Opin. Pharmacol.
Resveratrol attenuates brain damage in a rat model of focal cerebral ischemia via up-regulation of hippocampal Bcl-2
Brain Res.
Resveratrol improves neuron protection and functional recovery in rat model of spinal cord injury
Brain Res.
Protection of rat hippocampus against ischemic neuronal damage by pretreatment with sublethal ischemia
Brain Res.
Oxyresveratrol and resveratrol are potent antioxidants and free radical scavengers: effect on nitrosative and oxidative stress derived from microglial cells
Nitric Oxide Biol. Chem./Off. J. Nitric Oxide Soc.
Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury
Neurochem. Int.
Hormesis defined
Ageing Res. Rev.
Altered glutamatergic transmission in neurological disorders: from high extracellular glutamate to excessive synaptic efficacy
Prog. Neurobiol.
Resveratrol augments nitric oxide generation and causes store calcium release in chromaffin cells
Eur. J. Pharmacol.
Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases
Cell
Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review
J. Stroke Cerebrovasc. Dis.
Resveratrol protects against experimental stroke: putative neuroprotective role of heme oxygenase 1
Exp. Neurol.
Resveratrol preconditioning induces cellular stress proteins and is mediated via NMDA and estrogen receptors
Neuroscience
Resveratrol induced neuroprotection is mediated via both estrogen receptor subtypes, ER(alpha) and ER(beta)
Neurosci. Lett.
Gender-linked brain injury in experimental stroke
Stroke J. Cereb. Circ.
Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia
J. Neurosci.
Effects of resveratrol and methylprednisolone on biochemical, neurobehavioral and histopathological recovery after experimental spinal cord injury
Acta Pharmacol. Sin.
Neuroprotection by resveratrol against traumatic brain injury in rats
Mol. Cell. Biochem.
Resveratrol improves health and survival of mice on a high-calorie diet
Nature
Resveratrol acts as a mixed agonist/antagonist for estrogen receptors α and β 1
Endocrinology
Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation
J. Neurosci. Res.
Resveratrol and its metabolites bind to PPARs
ChemBioChem.
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