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 benefit from a combinatorial study of these major pathways in various models of acute injury. This would show which aspect of stroke/TBI/SCI/SAH pathophysiology is the most amenable to modulation. Resveratrol may also affect other aspects of stroke pathophysiology as described in section 2 (Fig. 2). Non-coding RNA and epigenetic modulation of the genome in particular are attractive candidates for future studies of this compound.
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 (). The goal of this review is to discuss the major mechanisms that are thought to mediate resveratrol-induced neuroprotection.
Resveratrol, a stilbene formed in many plants in response to various stressors, elicits multiple beneficial effects in vertebrates. Particularly, resveratrol was shown to have therapeutic properties in cancer, atherosclerosis and neurodegeneration. Resveratrol-induced benefits are modulated by multiple synergistic pathways that control oxidative stress, inflammation and cell death. Despite the lack of a definitive mechanism, both in vivo and in vitro studies suggest that resveratrol can induce a neuroprotective state when administered acutely or prior to experimental injury to the CNS. In this review, we discuss the neuroprotective potential of resveratrol in stroke, traumatic brain injury and spinal cord injury, with a focus on the molecular pathways responsible for this protection.