Repeated resveratrol administration confers lasting protection against neuronal damage but induces dose-related alterations of behavioral impairments after global ischemia

Abstract

Resveratrol, a naturally occurring polyphenol, has been shown to protect the heart and brain against ischemic injury. The current study investigated the effects of administration with either a 1 or 10-mg/kg dose of resveratrol on CA1 neuronal injury and behavioral/cognitive impairments after 10-min global ischemia in rats. The open-field, eight-arm radial maze and object recognition tests served to evaluate effects of resveratrol treatment on ischemia-induced locomotor activity, and spatial and recognition memory impairments, respectively. CA1 and CA3 neuronal injury was assessed upon completion of behavioral testing, 85 days postischemia. A separate series of groups served to assess neuronal injury at 7 days postischemia. Global ischemia (10 min) led to approximately 50% CA1 cell injury, which was prevented at both short (7 days) and long (85 days) postischemic intervals by resveratrol treatment. Importantly, despite comparable neuronal protection, the two resveratrol doses showed distinct behavioral effects. Thus, the 10-mg/kg resveratrol dose led to an enhanced locomotor activity in the open-field 4-days postischemia and an impaired spatial memory in the delayed nonmatching to sample and delayed matching to sample radial-maze tasks initiated on day 13 postischemia. These findings suggest independent actions of resveratrol on distinct physiological systems mediating cellular survival and functional recovery and dose-related actions of the polyphenol on behavioral and memory processes.

Resveratrol downregulates type-1 glutamate transporter expression and microglia activation in the hippocampus following cerebral ischemia reperfusion in rats

“…Evidence supports the use of high doses in animals (up to 750 mg/kg bw/day) and in humans (up to 2000 mg/day) with no reported adverse effects upon short term administration (la Porte et al, 2010;Williams et al, 2009). However, other reports including recent findings from our lab support the need for further investigation into RSV's effects on discrete biological systems and behaviour in healthy controls to ensure no adverse effects occur following chronic treatment (Park et al, 2012;Girbovan et al, 2012).…”

“…Values are expressed as mean optical density7S.E.M. RSV 10 mg/kg daily pretreatment led to significant inhibition of ischemia-induced CD11b/c-ir expression in the CA1 region, an effect not observed with the 1 mg/kg RSV dose, supporting dose-related effects of the polyphenol (Girbovan et al, 2012;Park et al, 2012) and the modulatory actions of RSV on neuroinflammatory processes postischemia (Simao et al, 2012;Zhang et al, 2010a). Consistent with previous studies, we observed a marked increase in the density of CD11b/c-ir in the hippocampal CA1 region in ischemic animals 7 days following reperfusion (Anderova et al, 2011;Bueters et al, 2008;Dos-Anjos et al, 2009;Langdon et al, 2008;Lee et al, 2010;Madinier et al, 2009;Moon et al, 2009;Simao et al, 2012;Sugawara et al, 2002), while only a few scattered ramified microglia, reminiscent of resting glia, were observed in salinetreated sham rats.…”

“…Among nutraceuticals, the naturally occurring polyphenol phytoalexin resveratrol (RSV) demonstrates antioxidant, anti-inflammatory, neuroprotective actions as well as improves learning and memory impairments in a number of disease models (Bhat et al, 2001;Bradamante et al, 2004;Girbovan et al, 2012). In vitro, recent studies have demonstrated its ability to downregulate glial cell activation through inhibition of pro-inflammatory cytokines and key signalling molecules as well as enhance glutamate uptake from astrocytes (Candelario-Jalil, et al, 2007;Lu et al, 2010;Zhang et al, 2010bZhang et al, Q2 2013.…”

Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia

“…The body weight and blood glucose had no significant changes among groups. Girbovan et al (2012) indicated that the level of blood glucose has not been affected by ischemic episode. As, ischemic injury damaged hippocampus and forebrain areas; we could hypothesis that exact region of hypothalamus which are involved in regulating blood glucose and appetite was less destroyed during global cerebral ischemia.…”

Resveratrol protects neurons from cannulae implantation injury: Implications for deep brain stimulation

“…The sirtuin activator resveratrol has consistently been shown to impart protective effects on the brain (Virgil and Contestabile, 2000;Baur and Sinclair, 2006;Singleton et al, 2010;Li et al, 2011;Girbovan et al, 2012). Because of this protective property, resveratrol is currently being evaluated for its potential as a therapeutic drug for several neurodegenerative states.…”