Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models

Abstract

Resveratrol, a natural stilbene present at relatively high concentrations in grape skin and seeds and red wine, is known for its purported antioxidant activity in the vascular and nervous systems. In contrast to its direct antioxidant role within the central nervous system, recent research supports a protective mechanism through increasing endogenous cellular antioxidant defenses, which triggers a cascade of parallel neuroprotective pathways. A growing body of in vitro and in vivo evidence indicates that resveratrol acts through multiple pathways and reduces ischemic damage in vital organs, such as the heart and the brain, in various rodent models. Most of the protective biological actions of resveratrol have been associated with its antioxidative, anti-inflammatory, and antiapoptotic properties and other indirect pathways. Continued public interest and increasing resveratrol supplements on the market warrant a review of the available in vitro and in vivo science reported in the stroke-related literature. Rigorous clinical trials evaluating the effects of resveratrol in stroke are absent, though the general population consumption appears to be relatively safe. Resveratrol has shown potential for treating stroke in laboratory animals and in vitro human cell studies, yet there is still a need for human research in preclinical settings. This review summarizes many of the findings on the neuroprotective potential of resveratrol in cerebral stroke, focusing on both the in vitro and in vivo experimental models and some proposed mechanisms of action.

Figure 1

Potential targets associated with anti-stroke activity of resveratrol. Resveratrol exhibits therapeutic response against stroke by preventing brain infarct, edema, mitochondrial dysfunction and cognitive and motor impairment. Furthermore, it diminishes nitrosative, oxidative, and DNA damage, which leads to preclusion of apoptosis and neuroinflammation.

Figure 2

Schematic image showing pathophysiology of stroke-induced damage, endogenous repair, and regeneration. Adapted and modified from refs ( and 21). Reduced blood to the brain during stroke initially affects neuronal activity and subsequently influences the metabolic and structural activity of the affected area. Several signaling cascades are activated that may be neuroprotective or detrimental to the ischemic brain. This progresses in an overlapping manner and is governed by the duration and intensity of the insult. Ischemic cascade is initiated within minutes of declined blood flow resulting in energy failure, glutamate-induced excitotoxicity, calcium overload, depolarization of the cells, and generation of free radicals. Inflammatory signaling is initiated within an hour of brain injury, and blood–brain barrier is disrupted during transition from ischemia to inflammation leading to edema and cell death. At the same time, cells initiate endogenous neuroprotective pathways to combat ischemic injury. The fate of brain cells are determined by the extent and duration of the event and the area affected by reduced blood supply. If ischemia is for longer duration, this will lead to cell death and irreversible brain damage. This review suggests that resveratrol can serve as a potential therapeutic target because it regulates and, to some extent, inhibits the detrimental pathways that are activated following injury and also up-regulates endogenous repair and regeneration processes.