Resveratrol attenuates early pyramidal neuron excitability impairment and death in acute rat hippocampal slices caused by oxygen-glucose deprivation

Abstract

Accumulating evidence indicates that the polyphenol resveratrol (trans-3, 5, 4′-trihydroxystibene, RVT) potently protects against cerebral ischemia neuronal damage due to its oxygen free radicals scavenging and antioxidant properties. However, it is unknown whether RVT can attenuate ischemiainduced early impairment of neuronal excitability. To address this question, we simulated ischemic conditions by applying oxygen-glucose deprivation (OGD) to acute rat hippocampal slices and examined the effect of RVT on OGD-induced pyramidal neuron excitability impairment using wholecell patch clamp recording. 100 μM RVT largely inhibited the 15 min OGD-induced progressive membrane potential (Vm) depolarization and the reduction in evoked action potential frequency and amplitude in pyramidal neurons. In the parallel neuronal viability study using TO-PRO-3 iodide staining, 20 min OGD induced irreversible CA1 pyramidal neuronal death which was significantly reduced by 100 μM RVT. No similar effects were found with PQQ treatment, an antioxidant also showing potent neuroprotection in the rat rMCAO ischemia model. This suggests that antioxidant action per se, is unlikely accounting for the observed early effects of RVT. RVT also markedly reduced the frequency and amplitude of AMPA mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons, which is also an early consequence of OGD. RVT effects on neuronal excitability were inhibited by the large conductance potassium channel (BK channel) inhibitor paxilline. Together, these studies demonstrate that RVT attenuates OGD induced neuronal impairment occurring early in the simulated ischemia slice model by enhancing the activation of BK channel and reducing the OGD-enhanced AMPA/NMDA receptor mediated neuronal EPSCs. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access INTRODUTIONRecent studies have shown that resveratrol (RVT) can protect ischemia damage in a variety of organs, such as brain, kidney and heart (Ray, et al., 1999; Bastianetto et al., 2000;Chander and Chopra, 2006). RVT is one of the primary active polyphenol compounds identified in red wine (Jang et al., 1997; Bastianetto et al., 2000;Oak et al., 2005), which has attracted increasing research interest on how this compound could offer such a miracle protection. Mechanistically, RVT acts as a potent antioxidant and scavenger of hydroperoxyl free radicals (Pace-Asciak et al., 1996; Mokni et al., 2006;Das et al., 2006). These protective actions of RVT in cerebral ischemia have so far been identified from studies in vivo and in cultured n...

Resveratrol protects PC12 cells against OGD/R-induced apoptosis via the mitochondrial-mediated signaling pathway

“…Resveratrol (trans-3,4′,5-trihydroxystilbene), a unique phytoalexin widely distributed in natural plants, possesses a strong antioxidant activity capable of opposing the potentially cytotoxic stresses of oxidative damage [6]. Several in vitro studies have identified that resveratrol may protect various neuronal cell types from oxidative stress-induced cell death [7][8][9]. A previous in vivo research has suggested that dietary administration of resveratrol to elderly male Wistar rats confers protection against recurrent ischemic insult caused by two mild transient middle cerebral artery occlusions [10].…”

Neuroprotective Effect of Resveratrol Against Glutamate-Induced Excitotoxicity

“…Res also markedly reduced the amplitude and frequency of AMPA-mediated spontaneous excitatory postsynaptic currents in rat hippocampal pyramidal neurons [27]. Furthermore, trans-Res significantly suppressed Glu-induced currents in rat hippocampal postsynaptic CA1 pyramidal neurons, and NMDA and KA receptors were more sensitive than AMPA receptors to trans-Res [17].…”

“…The uncompetitive NMDA receptor antagonist memantine, is able to protect dissociated cortical neurons from Glu-induced excitotoxicity [26]. Res attenuates oxygen-glucose deprivationinduced neuron impairment and death in acute rat hippocampal slices by enhancing the activation of the large-conductance potassium channel and reducing the enhanced AMPA/NMDA receptor-mediated neuronal excitatory postsynaptic currents caused by oxygen-glucose deprivation [27]. Furthermore, some studies support that trans-Res inhibites the postsynaptic Glu receptors in hippocampal neurons, with NMDA receptors being more sensitive than AMPA receptors [17], which probably have an antioxidant effect that ameliorates ischemic brain injury.…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…Other studies have shown that resveratrol decreases the activity of the NMDA receptors and also the related kainate receptors, acting on both the receptor activities themselves [309][310][311] and also acting to increase glutamate transport [312], thus lowering the extracellular glutamate that acts as an NMDA agonist. In each of these actions, resveratrol is thought to act by stimulating the activity of SIRT1, a protein that has a wide ranging activity in regulating gene expression.…”