stilbenes and Brain-Ischemia

Polyphenols are an important family of molecules of vegetal origin present in many medicinal and edible plants, which represent important alimentary sources in the human diet. Polyphenols are known for their beneficial health effects and have been investigated for their potential protective role against various pathologies, including cancer, brain dysfunctions, cardiovascular diseases and stroke. The prevention of stroke promoted by polyphenols relies mainly on their effect on cardio- and cerebrovascular systems. However, a growing body of evidence from preclinical models of stroke points out a neuroprotective role of these molecules. Notably, in many preclinical studies, the polyphenolic compounds were effective also when administered after the stroke onset, suggesting their possible use in promoting recovery of patients suffering from stroke. Here, we review the effects of the major polyphenols in cellular and in vivo models of both ischemic and hemorrhagic stroke in immature and adult brains. The results from human studies are also reported.

Topics: Animals; Brain Ischemia; Cerebral Hemorrhage; Diarylheptanoids; Ellagic Acid; Flavonoids; Gastrointestinal Microbiome; Humans; Hydrolyzable Tannins; Hydroxybenzoates; Lignans; Polyphenols; Stilbenes; Stroke; Subarachnoid Hemorrhage

The prevalence of stroke is high in both developing and developed nations. It causes a heavy social and financial burden to the sufferers and their caregivers. Thrombolytic therapy is the only pharmacological treatment available for stroke. However, thrombolytic agents do not provide substantial improvement on long term motor and cognitive disabilities. Thus, there is a need to explore for new compounds that can halt or reverse the deterioration of neurons in the stroke patients' brain. Polydatin, a precursor of resveratrol, is a natural stilbene commonly found in food. This review article describes how different parameters were altered with ischemic injury and polydatin treatment, why it is important and how it could be beneficial or useful in future studies. Our review of polydatin provides convincing evidence regarding the potential of polydatin to be developed into preventive or therapeutic products for ischemic stroke. Nevertheless, additional studies are necessary in order to properly elucidate the biological mechanisms of polydatin, especially its molecular mechanisms of protection and target proteins, in cerebral ischemia.

Topics: Animals; Brain Ischemia; Glucosides; Humans; Neuroprotective Agents; Stilbenes

Cerebral ischemia is a neurological condition in which energetics and oxidative stress are dysregulated. Resveratrol is a stilbene with potent pharmacological effects associated with its antioxidant properties. In the brain, resveratrol produces protective responses against ischemia, decreases infarct volume and improves neurological function. Adenosine monophosphate-activated protein kinase (AMPK) is a cellular sensor that acts as a switch to initiate adaptive changes in response to fluctuations in energy metabolism.. In ischemia, AMPK is activated, nevertheless conflicting results about its contribution to protection have become apparent, and this matter continues without resolution. Interestingly, AMPK activation by resveratrol has been implicated in regulating cell survival in different experimental models. Although resveratrol's ability to regulate AMPK directly or after signaling is only beginning to be understood, targeting this enzyme by resveratrol in brain suggest that it could contribute to the amelioration of some pathologic features induced after an energetic deficit.. The present review discusses the potential role of resveratrol in regulating AMPK activity on brain before, during, or after ischemia and offer suggestions for feasible future studies.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Antioxidants; Brain; Brain Ischemia; Cell Survival; Energy Metabolism; Mice; Neuroprotection; Neuroprotective Agents; Oxidative Stress; Protein Kinases; Resveratrol; Signal Transduction; Stilbenes

Silent information regulator 1 (SIRT1) is a type of histone deacetylase whose activity is dependent on nicotinamide adenine dinucleotide. SIRT1 plays a key role in the longevity effects elicited by calorie restriction. Recently, a neuroprotective effect of SIRT1 was reported for neurological diseases. The focus of this review is to summarize the protective effects of SIRT1 in cerebral ischemia. First, the posttranslational modifications of SIRT1 are illustrated; then, we discuss the roles of SIRT1 in cerebral immune homeostasis. Next, we introduce the deacetylase activity of SIRT1 in cerebral ischemia and provide some examples of relevant studies. In addition, we discuss several activated mediators of SIRT1, such as resveratrol, caloric restriction, ischemic preconditioning, and other proteins and compounds. Finally, we highlight a few SIRT1-related signaling pathways, such as the peroxisome proliferator-activated receptor γ coactivator 1α, nuclear transcription factor κB, uncoupling protein 2, and forkhead box O pathways. Taken together, the information compiled in this article will serve as a comprehensive reference for the actions of SIRT1 in the nervous system and will help in the design of future experimental research and promote SIRT1 as a new therapeutic target.

Topics: Animals; Brain; Brain Ischemia; Caloric Restriction; Forkhead Box Protein O1; Forkhead Transcription Factors; Histone Deacetylases; Homeostasis; Humans; Ion Channels; Ischemic Preconditioning; Mitochondrial Proteins; Molecular Targeted Therapy; Neuroprotective Agents; NF-kappa B; PPAR gamma; Protein Processing, Post-Translational; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Uncoupling Protein 2

Caloric restriction (CR), resveratrol, and ischemic preconditioning (IPC) have been shown to promote protection against ischemic injury in the heart and brain, as well as in other tissues. The activity of sirtuins, which are enzymes that modulate diverse biologic processes, seems to be vital in the ability of these therapeutic modalities to prevent against cellular dysfunction and death. The protective mechanisms of the yeast Sir2 and the mammalian homolog sirtuin 1 have been extensively studied, but the involvement of other sirtuins in ischemic protection is not yet clear. We examine the roles of mammalian sirtuins in modulating protective pathways against oxidative stress, energy depletion, excitotoxicity, inflammation, DNA damage, and apoptosis. Although many of these sirtuins have not been directly implicated in ischemic protection, they may have unique roles in enhancing function and preventing against stress-mediated cellular damage and death. This review will include in-depth analyses of the roles of CR, resveratrol, and IPC in activating sirtuins and in mediating protection against ischemic damage in the heart and brain.

Topics: Animals; Antioxidants; Biotransformation; Brain Ischemia; Caloric Restriction; Cell Death; DNA Damage; Humans; Ischemic Preconditioning; Mitochondria; Oxidative Stress; Resveratrol; Signal Transduction; Sirtuin 1; Sirtuins; Stilbenes

Cardiovascular pathologies in the French are not prevalent despite high dietary saturated fat consumption. This is commonly referred to as the "French Paradox" attributing its anti-lipidemic effects to moderate consumption of red wine. Resveratrol, a phytoalexin found in red wine, is currently the focus of intense research both in the cardiovascular system and the brain. Current research suggests resveratrol may enhance prognosis of neurological disorders such as, Parkinson's, Huntington's, Alzheimer's diseases and stroke. The beneficial effects of resveratrol include: antioxidation, free radical scavenger, and modulation of neuronal energy homeostasis and glutamatergic receptors/ion channels. Resveratrol directly increases sirtuin 1 (SIRT1) activity, a NAD(+) (oxidized form of nicotinamide adenine dinucleotide)-dependent histone deacetylase related to increased lifespan in various species similar to calorie restriction. We recently demonstrated that brief resveratrol pretreatment conferred neuroprotection against cerebral ischemia via SIRT1 activation. This neuroprotective effect produced by resveratrol was similar to ischemic preconditioning-induced neuroprotection, which protects against lethal ischemic insults in the brain and other organ systems. Inhibition of SIRT1 abolished ischemic preconditioning-induced neuroprotection in CA1 region of the hippocampus. Since resveratrol and ischemic preconditioning-induced neuroprotection require activation of SIRT1, this common signaling pathway may provide targeted therapeutic treatment modalities as it relates to stroke and other brain pathologies. In this review, we will examine common signaling pathways, cellular targets of resveratrol, and ischemic preconditioning-induced neuroprotection as it relates to the brain.

Topics: Animals; Brain Ischemia; Humans; Ischemic Preconditioning; Neuroprotective Agents; Resveratrol; Signal Transduction; Stilbenes; Synapses

Ischemic stroke, also known as cerebrovascular accident or cerebral stroke, occupies the first place in the world's top 10 causes of death, with high incidence, mortality and disability rates.. To investigate the effect of stilbene glycoside upregulated SIRT3/AMPK expression on neuronal mitochondrial autophagy and neuronal apoptosis in ischemic stroke.. The PC12 cells were cultured without serum to construct an ischemic neuron model. The cells were divided into 6 groups: normal group (untreated cells), model group (ischemic treated cells), TSG group (stilbene glycoside treatment), NC group (SIRT3 and AMPK negative control treatment), si-SIRT3 group (SIRT3 silencing treatment), TSG+si-SIRT3 group (joint treatment), and TSG+si-SIRT3+oe-AMPK group (joint treatment). Cell survival and the expression of related molecules were detected.. Compared with normal group, the model group had significantly decreased cell survival rate, mitochondrial membrane potential, as well as the expression of Bcl-2, LC3II/I, P62, PINK1, Parkin, SIRT3, AMPK, and p-AMPK, while showing significantly increased proportion of apoptosis and the expression of caspase 3 and Bax. Compared with the model group, TSG treatment promoted cell survival rate and mitochondrial autophagy, and inhibited apoptosis, while SIRT3 silencing treatment reduced cell survival rate and mitochondrial autophagy, and increased apoptosis. The SIRT3 silencing could block the inhibitory effect of TSG on the apoptosis of ischemic PC12 cells and promote mitochondrial autophagy, and AMPK overexpression could save the apoptosis of ischemic PC12 cells caused by SIRT3 silencing, and promote mitochondrial autophagy.. By promoting the expression of SIRT3/AMPK, TSG promotes mitochondrial autophagy in ischemic neurons and inhibits their apoptosis.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Autophagy; Brain Ischemia; Glycosides; Ischemic Stroke; Neurons; Rats; Signal Transduction; Sirtuin 3; Stilbenes; Stroke

Isorhapontigenin (ISO) has been shown to have antioxidant activity. This study aimed to investigate the antioxidant effects of ISO on cerebral ischemia/reperfusion (I/R) injury and its possible molecular mechanisms.. Focal cerebral ischemia-reperfusion injury (MCAO/R) model and primary cortical neurons were established an oxygen-glucose deprivation (OGD / R) injury model. After 24 hr of reperfusion, the neurological deficits of the rats were analyzed and HE staining was performed, and the infarct volume was calculated by TTC staining. In addition, the reactive oxygen species (ROS) in rat brain tissue, the content of 4-Hydroxynonenal (4-HNE), and 8-hydroxy2deoxyguanosine (8-OHdG) were detected. Neuronal cell viability was determined by MTT assay. Western blot analysis was determined for protein expression.. ISO treatment significantly improved neurological scores, reduced infarct volume, necrotic neurons, ROS production, 4-HNE, and 8-OHdG levels. At the same time, ISO significantly increased the expression of Nrf2 and HO-1. The neuroprotective effects of ISO can be eliminated by knocking down Nrf2 and HO-1. In addition, knockdown of the PKCε blocked ISO-induced nuclear Nfr2, HO-1 expression.. ISO protected against oxidative damage induced by brain I/R, and its neuroprotective mechanism may be related to the PKCε/Nrf2/HO-1 pathway.

Topics: Animals; Brain Ischemia; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Stilbenes

Ischemic stroke is a severe neurological disease without known effective therapy. Microglia-mediated neuroinflammation plays an important role in ischemic stroke. Therefore, finding a safe and effective microglial activation inhibitor might lead to an effective therapeutic strategy against ischemic stroke. In this project, our goal was to explore both the mechanism and effect of pterostilbene in MCAO/R rats. The potential effect of pterostilbene on ischemic stroke was tested using MCAO/R rats and its effect on microglial activation was tested in LPS-stimulated BV-2 cells. In vivo, pterostilbene decreased the neurological scores, brain water content and infarct volume in MCAO/R rats. Pterostilbene increased the number of mature neurons, decreased the number of activated microglia, and reduced iNOS and IL-1β mRNA expression. Pterostilbene inhibited phosphorylated-IκBα expression, thus promoting IκBα expression and inhibiting ROS overexpression. In vitro, pterostilbene inhibited the expression of inflammatory cytokines and suppressed NAPDH activity as well as activation of both the NF-κB pathway and ROS production. To our knowledge, our study is the first to demonstrate that pterostilbene-mediated alleviation of cerebral ischemia and reperfusion injury in rats may be correlated with the inhibition of the ROS/NF-κB-mediated inflammatory pathway in microglia, indicating the potential for the use of pterostilbene as a candidate therapeutic compound for ischemic stroke.

Topics: Animals; Brain; Brain Ischemia; Cell Line; Disease Models, Animal; Gene Expression Regulation; Inflammation; Interleukin-1beta; Macrophage Activation; Male; Microglia; NF-kappa B; NF-KappaB Inhibitor alpha; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Stilbenes; Stroke

Reperfusion is a critical therapeutic intervention used following acute ischemic stroke; however, it may cause cerebral ischemia/reperfusion injury (CIRI) and aggravate brain damage. Piceatannol (Pic), a hydroxylated analog of resveratrol, has been reported to exhibit anti‑inflammatory effects. However, the detailed molecular mechanisms and its effects on CIRI have not been sufficiently assessed, and, to the best of our knowledge, current methods of prevention of CIRI are limited. The aim of the present study was to investigate the effects of Pic on improving neurological function in a mouse model of CIRI. For the animal experiments, 8‑week‑old C57BL/6 mice were raised and randomly grouped, and an in vivo model of CIRI was established. Mice were administered a low (10 mg/kg/day) or high‑dose (20 mg/kg/d) of Pic 1 h after CIRI orally and once daily for the next 6 days. Neurological dysfunction was assessed using a modified neurological severity score and a rotarod test 1 week after CIRI establishment, and the cognitive status of the mice was assessed using a Morris water maze. Hematoxylin and eosin staining was used to evaluate the histopathological changes. The expression levels of sirtuin 1 (Sirt1), FoxO1, cleaved caspase‑3 (CC‑3), Bax and Bcl‑2 were measured using western blotting. Intracellular reactive oxygen species (ROS) generation, antioxidant enzymes [superoxide dismutase, glutathione (GSH) peroxidase and catalase] and non‑enzymatic antioxidants (GSH) were also detected using spectrophotometry. After inhibition of the Sirt1/FoxO1 pathway, a TUNEL assay was used for the detection of apoptotic cells in vitro and in vivo. The co‑localization of neuron‑specific nuclear protein and CC‑3 was assessing using immunofluorescent staining. Pic improved neurological functions and ameliorated hippocampal neuronal pathology following CIRI. In addition, the expression levels of CC‑3 and Bax and intracellular ROS levels were increased, while levels of antioxidant and non‑enzymatic enzymes were decreased in the mouse model of CIRI. Low and high doses of Pic significantly decreased ROS production and the expression levels of apoptosis‑related proteins, but increased antioxidant enzyme levels. However, a high‑dose of Pic did not result in increased levels of non‑enzymatic enzymes. Furthermore, low and high doses of Pic treatment significantly activated the Sirt1/FoxO1 pathway. Following inhibition of the Sirt1/FoxO1 pathway, the percentage of TUNEL‑positive cells an

Topics: Animals; Antioxidants; Apoptosis; Brain Ischemia; Caspase 3; Forkhead Box Protein O1; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Stroke

Neutrophils are implicated in numerous inflammatory diseases, and especially in acute ischemic stroke (AIS). The unchecked migration of neutrophils into cerebral ischemic regions, and their subsequent release of reactive oxygen species, are considered the primary causes of reperfusion injury following AIS. Reducing the infiltration of inflammatory neutrophils may therefore be a useful therapy for AIS. Here, inspired by the specific cell-cell recognition that occurs between platelets and inflammatory neutrophils, we describe platelet-mimetic nanoparticles (PTNPs) that can be used to directly recognize, intervene, and monitor inflammatory neutrophils in the AIS treatment and therapeutic evaluation. We demonstrate that PTNPs, coloaded with piceatannol, a selective spleen tyrosine kinase inhibitor, and superparamagnetic iron oxide (SPIO), a T2 contrast agent, can successfully recognize adherent neutrophils via platelet membrane coating. The loaded piceatannol could then be delivered to adherent neutrophils and detach them into circulation, thus decreasing neutrophil infiltration and reducing infarct size. Moreover, when coupled with magnetic resonance imaging, internalized SPIO could be used to monitor the inflammatory neutrophils, associated with therapeutic effects, in real time. This approach is an innovative method for both the treatment and therapeutic evaluation of AIS, and provides new insights into how to treat and monitor neutrophil-associated diseases.

Topics: Animals; Biomimetic Materials; Blood Platelets; Brain; Brain Ischemia; Cell Tracking; Contrast Media; Magnetite Nanoparticles; Mice; Neutrophils; RAW 264.7 Cells; Stilbenes; Stroke

The aim of this study was to evaluate the potential molecular mechanism of resveratrol (RSV) that attenuates brain damage from focal cerebral ischemia.. To investigate whether phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway was involved in RSV anti-inflammatory and neuroprotective properties. Middle cerebral artery occlusion (MCAO) animal model was used in this study. Adult male Sprague-Dawley (SD) rats underwent MCAO, and then received treatment with RSV or vehicle after the onset of ischemia. PI3K inhibitor LY294002 was injected intracerebroventricularly to inhibit the PI3K/Akt signaling pathway. Neurological deficit scores and cerebral water content were assessed 24 h after MCAO. The inflammatory factors interleukin (IL)-1β, tumor necrosis factor (TNFα), and cyclooxygenase-2 (COX2) mRNA level were examined by real-time PCR. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after MCAO. The protein expression of phospho-Akt and COX2 in ischemic brain were determined by western blot.. RSV significantly reduced neurological deficit scores, cerebral water content and the enzymatic activity of MPO, all of which were abolished by LY294002 administration. Real-time PCR showed that RSV significantly suppressed the upregulation of the inflammatory factors IL-1β, TNFα, COX2 mRNA levels. RSV significantly inhibited upregulated the protein expression of COX2 24 h after MCAO, which effect was abolished by LY294002 administration.. RSV attenuated ischemic brain damage induced by cerebral artery occlusion mainly through PI3K/Akt signaling pathway. Abbreviation: MCAO: Middle cerebral artery occlusion; RSV: resveratrol; PI3K/Akt: phosphatidylinositol 3-kinase/Akt; TNF: tumor necrosis factor; COX2: cyclooxygenase-2; MPO: myeloperoxidase; IL: interleukin.

Topics: Analysis of Variance; Animals; Antioxidants; Brain Ischemia; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Enzyme Activation; Hypoxia, Brain; Infarction, Middle Cerebral Artery; Male; Neurologic Examination; Oncogene Protein v-akt; Peroxidase; Phosphatidylinositol 3-Kinase; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes

This study was carried out to investigate the expression pattern and role of osteopontin (OPN) in late global ischemia-reperfusion (I/R) injury with or without resveratrol (RES) pre-treatment. Young male rats were divided into 3 groups (n = 12) of I) sham, II) I/R model group and III) I/R + RES. Vehicle and RES (20 mg/kg) were administered to designed groups intraperitoneally 30 days prior global I/R injury (2-VO) induction and continued for 7 days, later. Then, percentages of infarct areas, mRNA levels of OPN, inducible nitric oxide synthase (iNOS) and other biochemical parameter related to endogenous antioxidants activities and inflammation were measured in the cerebral cortices of all groups. Significant elevations in the levels of malondialdehyde (MDA), the inflammatory mediator interleukin 1β (IL-1β), chemokines (KC and MIP-2) and adhesive molecules (ICAM-1) as well as parallel reductions in enzymes activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and chloramphenicol acetyltransferase (CAT) were observed in the cerebral homogenates of rats with late I/R injury. Associated with these changes, mRNA levels of OPN were significantly downregulated and those of iNOS and Bax were upregulated. All these changes were reversed by in 2-VO I/R induced rats pre-administered RES. These findings suggest that inhibition of sustained inflammatory response driven by IL-1β, decreased activities of endogenous antioxidants and downregulation of OPN induced upregulation of iNOS play important roles in the pathogenesis of neurodegeneration during late cerebral I/R injury, effects that can be modulated by RES which might explain its neuroprotection effect during late global ischemia.

Topics: Animals; bcl-2-Associated X Protein; Brain Ischemia; Catalase; Cerebral Cortex; Chemokine CXCL2; Chemokines; Glutathione Peroxidase; Intercellular Adhesion Molecule-1; Interleukin-1beta; Male; Neuroprotective Agents; Nitric Oxide Synthase Type II; Osteopontin; Oxidative Stress; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes; Superoxide Dismutase; Up-Regulation

Resveratrol has been reported to protect against cerebral ischemia/reperfusion (I/R) injury in rats, but the underlying mechanism is unclear. In the current study, we examined whether resveratrol ameliorates cerebral I/R injury by inhibiting NLRP3 inflammasome-derived inflammation and whether autophagy is involved in this process. In addition, we explored the role of Sirt1 in resveratrol-mediated protective effects. To answer these questions, healthy male Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 1h followed by 24h reperfusion. We found that cerebral I/R increased levels of activated NLRP3 inflammasome, caspase-1, IL-1β, and IL-18 and enhanced autophagy activity (ratio of LC3B-II/LC3B-I and p62/SQSTM1). Treatment with resveratrol, a specific Sirt1 agonist, attenuated I/R-induced NLRP3 inflammasome-derived inflammation but upregulated autophagy. Furthermore, resveratrol treatment clearly reduced cerebral infarct volume, decreased brain water content, and improved neurological scores. In addition, inhibition of autophagy using 3-MA intracerebroventricular injection blocked the inhibitory effect of resveratrol on NLRP3 inflammasome activation. Finally, Sirt1 knockdown with siRNA significantly blocked resveratrol-induced enhancement of autophagy activity and suppression of NLRP3 inflammasome activation. In conclusion, our results demonstrate that resveratrol protects against cerebral I/R injury by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy activity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autophagy; Brain Ischemia; Cerebral Arteries; Disease Models, Animal; Humans; Inflammasomes; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Sirtuin 1; Stilbenes

Resveratrol, at least in part via SIRT1 (silent information regulator 2 homologue 1) activation, protects against cerebral ischemia when administered 2 days before injury. However, it remains unclear if SIRT1 activation must occur, and in which brain cell types, for the induction of neuroprotection. We hypothesized that neuronal SIRT1 is essential for resveratrol-induced ischemic tolerance and sought to characterize the metabolic pathways regulated by neuronal Sirt1 at the cellular level in the brain.. We assessed infarct size and functional outcome after transient 60 minute middle cerebral artery occlusion in control and inducible, neuronal-specific SIRT1 knockout mice. Nontargeted primary metabolomics analysis identified putative SIRT1-regulated pathways in brain. Glycolytic function was evaluated in acute brain slices from adult mice and primary neuronal-enriched cultures under ischemic penumbra-like conditions.. Resveratrol-induced neuroprotection from stroke was lost in neuronal. Our data demonstrate that resveratrol requires neuronal SIRT1 to elicit ischemic tolerance and identify a novel role for SIRT1 in the regulation of glycolytic function in brain. Identification of robust neuroprotective mechanisms that underlie ischemia tolerance and the metabolic adaptations mediated by SIRT1 in brain are crucial for the translation of therapies in cerebral ischemia and other neurological disorders.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Glycolysis; Mice; Mice, Knockout; Neurons; Neuroprotective Agents; Resveratrol; Sirtuin 1; Stilbenes; Stroke

Resveratrol has neuroprotective effects for ischemic cerebral stroke. However, its neuroprotective mechanism for stroke is less well understood. Beneficial actions of the activated Sonic hedgehog (Shh) signaling pathway in stroke, such as improving neurological function, promoting neurogenesis, anti-oxidative, anti-apoptotic, and pro-angiogenic effects, have been noted, but relatively little is known about the role of Shh signaling in resveratrol-reduced cerebral ischemic injury after stroke. The present study tests whether the Shh pathway mediates resveratrol to decrease cerebral ischemic injury and improve neurological function after stroke. We observed that resveratrol pretreatment significantly improved neurological function, decreased infarct volume, enhanced vitality, and reduced apoptosis of neurons in vivo and vitro after stroke. Meanwhile, expression levels of Shh, Ptc-1, Smo, and Gli-1 mRNAs were significantly upregulated and Gli-1 was relocated to the nucleus. Intriguingly, in vivo and in vitro inhibition of the Shh signaling pathway with cyclopamine, a Smo inhibitor, completely reversed the above effects of resveratrol. These results suggest that decreased cerebral ischemic injury and improved neurological function by resveratrol may be mediated by the Shh signaling pathway.

Topics: Animals; Animals, Newborn; Antioxidants; Brain Ischemia; Female; Hedgehog Proteins; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Recovery of Function; Resveratrol; Signal Transduction; Stilbenes; Stroke; Treatment Outcome

Topics: Angiogenesis Inducing Agents; Angiotensin I; Animals; Blotting, Western; Brain Injuries; Brain Ischemia; Fallopia multiflora; Glucosides; Infarction, Middle Cerebral Artery; Male; Neovascularization, Physiologic; Neuroprotective Agents; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Sprague-Dawley; Receptor, TIE-2; Reperfusion Injury; Stilbenes; Stroke; Vascular Endothelial Growth Factor A

The polyphenol resveratrol has shown regulatory effects on hippocampal neurogenesis, which according to the neurovascular niche hypothesis, is likely to involve stimulation of angiogenesis. In rodents, global cerebral ischemia leads to selective CA1 neuronal damage, spatial memory impairments, lasting changes in corticosterone (CORT) secretion, and increased neurogenesis. This study examined dose-related effects of 21-day RSV treatment on markers associated with neurogenesis (DCX, PSA-NCAM) and angiogenesis (CD31) in the hippocampus at short (7-day) and long-term (85-day) intervals following global ischemia. In parallel, post-ischemic and stress-induced CORT levels and spatial memory in the Morris water maze were determined.. Five groups of male Wistar rats were included: sham/saline, ischemia/saline, ischemia/1 mg/kg RSV, ischemia/10 mg/kg RSV, and sham/10 mg/kg RSV. Changes in expression of plasticity markers were paralleled by assessment of basal- and stress-induced CORT secretions, and spatial memory performance.. Our findings revealed a significant attenuation of ischemia-induced DCX/PSA-NCAM expression in RSV-treated rats, whereas RSV treatment increased angiogenesis in the injured CA1 region. RSV attenuated CORT levels 3 days post-ischemia and a trend toward attenuating CORT secretion in response to 15 minutes restraint stress. Increased swimming latencies in the target quadrant during the MWM probe trial in RSV-treated ischemic rats support beneficial effects of RSV on spatial memory retention.. Our findings uncover time- and dose-related effects of RSV and global ischemia on the regulation of hippocampal plasticity. Changes in neuro- and angiogenesis are consistent with RSV neuroprotective effects, but appear independent of RSV regulatory effects on corticosterone secretion.

Topics: Adrenal Cortex; Animals; Behavior, Animal; Biomarkers; Brain Ischemia; CA1 Region, Hippocampal; Corticosterone; Dose-Response Relationship, Drug; Doublecortin Protein; Injections, Intraperitoneal; Male; Neovascularization, Physiologic; Neurogenesis; Neuronal Plasticity; Neurons; Neuroprotective Agents; Random Allocation; Rats, Wistar; Reperfusion Injury; Resveratrol; Spatial Memory; Stilbenes

Ischemia reperfusion (IR) injury (IRI) is harmful to the cerebral system and causes mitochondrial oxidative stress. The antioxidant response element (ARE)-mediated antioxidant pathway plays an important role in maintaining the redox status of the brain. Heme oxygenase-1 (HO-1), combined with potent AREs in the promoter of HO-1, is a highly effective therapeutic target for protection against cerebral IRI. Pterostilbene (PTE), a natural dimethylated analog of resveratrol from blueberries, is a strong natural antioxidant. PTE has been shown to be beneficial for some nervous system diseases and may regulate HO-1 signaling. This study was designed to investigate the protective effects of PTE on cerebral IRI and to elucidate potential mechanisms underlying those effects. Mouse brains and cultured HT22 neuron cells were subjected to IRI. Prior to this procedure, the brains or cells were exposed to PTE in the absence or presence of the HO-1 inhibitor ZnPP or HO-1 small interfering RNA (siRNA). PTE conferred a cerebral protective effect, as shown by increased neurological scores, viable neurons and decreased brain edema as well as a decreased ion content and apoptotic ratio in vivo. PTE also increased the cell viability and decreased the lactate dehydrogenase (LDH) leakage and apoptotic ratio in vitro. ZnPP and HO-1 siRNA both blocked PTE-mediated cerebral protection by inhibiting HO-1 signaling and further inhibited two HO-1 signaling-related antioxidant molecules:. quinone oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTs), which are induced by PTE. PTE also promoted a well-preserved mitochondrial membrane potential (MMP), mitochondria complex I activity, and mitochondria complex IV activity, increased the mitochondrial cytochrome c level, and decreased the cytosolic cytochrome c level. However, this PTE-elevated mitochondrial function was reversed by ZnPP or HO-1 siRNA treatment. In summary, our results demonstrate that PTE treatment attenuates cerebral IRI by reducing IR-induced mitochondrial oxidative damage through the activation of HO-1 signaling.

Topics: Animals; Apoptosis; Brain; Brain Edema; Brain Ischemia; Cell Line; Cell Survival; Glutathione Transferase; Heme Oxygenase-1; Ions; L-Lactate Dehydrogenase; Male; Mice, Inbred C57BL; Mitochondria; NAD(P)H Dehydrogenase (Quinone); Neurons; Oxidative Stress; Protoporphyrins; Reperfusion Injury; RNA, Small Interfering; Signal Transduction; Stilbenes

Resveratrol (3,5,4'-trihydroxystilbene) is a natural polyphenol which is rich in grape seeds and skin. Several studies have revealed that resveratrol possesses neuroprotective effects. In the case of global brain ischemia, there are few reports regarding the protective effect of resveratrol. Therefore, the influence of resveratrol on neuronal damage after transient global brain ischemia remains to be clarified. In the current study, C57BL/6 black mice were subjected to 20 min of transient global brain ischemia and followed by 72 h of reperfusion. Resveratrol (20 or 40 mg/kg, once daily, dissolved in 0.5% carboxymethylcellulose) was administered orally for 7 days before ischemia and daily until the mice were euthanized. The effect of lower or higher dose of resveratrol on neuronal damage, matrix metalloproteinase (MMP) activity and in situ DNA fragmentation (TUNEL) assay in the hippocampus after global ischemia was examined. Neuronal damages were remarkable in CA1 and CA2 pyramidal cell layers after global ischemia. In resveratrol-treated mice (40 mg/kg), neuronal damage was significantly reduced compared with vehicle-treated mice. Mice treated with resveratrol showed reduced MMP-9 activity. Resveratrol also inhibited TUNEL staining. These data suggest that resveratrol, a natural polyphenol, reduces hippocampal neuronal cell damage following transient global ischemia by reducing MMP-9 activity.

Topics: Animals; Brain Ischemia; Male; Mice; Mice, Inbred C57BL; Neurons; Resveratrol; Stilbenes

In the current study, we aimed to investigate the mechanistic role of DJ-1/PI3K/Akt survival pathway in ischemia/reperfusion (I/R) induced cerebral damage and to investigate if the resveratrol (RES) mediates its ischemic neuroptotection through this pathway. RES administration to Sham rats boosted glutathione level and superoxide dismutase activity and downregulated inducible nitric oxide synthase expression without affecting redox levels of DJ-1 forms or components of PI3K/Akt pathway including PTEN, p-Akt or p/p-GSK3b. However, RES pre-administration to I/R rats reduced infarction area, oxidative stress, inflammation and apoptosis. Concomitantly, RES ameliorated the decreased levels of oxidized forms of DJ-1 and enhancing its reduction, increased the nuclear protein expression of Nfr-2 and led to activation of PI3K/Akt survival pathway. In conclusion, overoxidation of DJ-1 is a major factor that contributes to post-I/R cerebral damage and its reduction by RES could explain the neuroprotection offered by RES.

Topics: Animals; Antioxidants; Apoptosis; Blotting, Western; Brain Ischemia; Glycogen Synthase Kinase 3 beta; Immunoenzyme Techniques; Male; Neuroprotective Agents; Oxidative Stress; Phosphatidylinositol 3-Kinases; Protein Deglycase DJ-1; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Stilbenes

Resveratrol is known to improve metabolic dysfunction associated with obesity. Visceral obesity is a sign of aging and is considered a risk factor for ischemic stroke. In this study, we investigated the effects of resveratrol on inflammation in visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol (0.1 mg/kg, p.o.) for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. These results showed that resveratrol counteracted inflammation in visceral adipose tissue and in the brain and reduced stroke-induced brain injury and peripheral inflammation in aged female mice. Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women.

Topics: Adipocytes; Animals; Brain; Brain Ischemia; Encephalitis; Female; Humans; Immunoglobulin G; Inflammation; Interleukin-1beta; Intra-Abdominal Fat; Mice, Inbred C57BL; Postmenopause; Resveratrol; Stilbenes; Stroke; Tumor Necrosis Factor-alpha

The health benefits of the plant-derived polyphenol resveratrol were established in multiple disease systems. Notably, pre-treatment with resveratrol was shown to be neuroprotective in several models of cerebral ischemia. Mechanisms of resveratrol-mediated neuroprotection have been explored in the context of canonical resveratrol targets, but epigenetic and non-coding RNA processes have not yet been evaluated. Resveratrol was shown to alter microRNAs in cancer and cardiac ischemia. Previous studies also showed that ischemic preconditioning that induces ischemic tolerance significantly alters cerebral microRNA levels, particularly those that target neuroprotective pathways. Therefore, we tested if resveratrol-mediated ischemic tolerance also alters microRNA expression with a goal to identify microRNAs that are amenable to manipulation to induce neuroprotection after cerebral ischemia. Hence, we tested the microRNA profiles in mouse brain following intraperitoneal administration of resveratrol that induced significant tolerance against transient focal ischemia. We analyzed microRNA profiles using microarrays from both Affymetrix and LC Sciences that contain probes for all known mouse microRNAs. The results show that there is no consistent change in any of the microRNAs tested between resveratrol and vehicle groups indicating that microRNAs play a minimal role in resveratrol-mediated cerebral ischemic tolerance.

Topics: Animals; Brain Ischemia; Gene Expression Profiling; Ischemic Preconditioning; Mice; MicroRNAs; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Resveratrol; Stilbenes

The neuroprotective effect of polydatin (PD) against hemorrhagic shock-induced mitochondrial injury has been described previously, and mitochondrial dysfunction and apoptosis were reportedly involved in ischemic stroke. In the present study the neuroprotective effect of PD in preventing apoptosis was evaluated following induction of focal cerebral ischemia by middle cerebral artery occlusion (MCAO) in rats. PD (30 mg/kg) was administered by caudal vein injection 10 min prior to ischemia/reperfusion (I/R) injury. 24 h following I/R injury, ameliorated modified neurological severity scores (mNSS) and reduced infarct volume were observed in the PD treated group. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and Annexin V/propidium iodide assays demonstrated the anti-apoptotic effect of PD in the ischemic cortex. In addition, PD improved I/R injury‑induced mitochondrial dysfunction, reflected by morphological observations and measurements of mitochondrial membrane potential and intracellular ATP measurement. Western blot analysis revealed an increase in B‑cell lymphoma 2 apoptosis regulator (Bcl-2) expression, and a decrease in Bcl‑2‑associated protein X apoptosis regulator expression in the PD group in comparison with the vehicle treated group. PD treatment also prevented the release of cytochrome c from mitochondria into the cytoplasm, and blunted the activities of caspase‑9 and caspase‑3. Furthermore, PD treatment decreased the levels of reactive oxygen species in neurons isolated from the ischemic cortex. The findings of this study, therefore, suggest that PD has a dual effect, ameliorating both oxidative stress and mitochondria‑dependent apoptosis, making it a promising new therapy for the treatment of ischemic stroke.

Topics: Adenosine Triphosphate; Animals; Apoptosis; bcl-2-Associated X Protein; Biomarkers; Brain Ischemia; Cerebral Cortex; Cytochromes c; Disease Models, Animal; Glucosides; Male; Membrane Potential, Mitochondrial; Mitochondria; Neurons; Neuroprotective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species; Reperfusion Injury; Signal Transduction; Stilbenes

This study was conducted to investigate the recovery of motor function in rats through the silent information regulator factor 2-related enzyme 1 (Sirt1) signal pathway-mediated rehabilitation training. Middle cerebral artery occlusion (MACO) was used to induce ischemia/reperfusion injury. The rats were subjected to no treatment (model), rehabilitation training (for 21 days), resveratrol (5 mg/kg for 21 days), and rehabilitation training plus resveratrol treatment. 24 h later, They were assessed for neurobehavioral score and motor behavior score and expression of brain derived-nerve neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB). Compared with sham group, models had significantly higher neurobehavioral scores, balance beam, and rotary stick scores. Compared with the model group, rats in rehabilitation training and resveratrol groups had significantly reduced scores. Compared with rehabilitation training or resveratrol treatment alone, rehabilitation plus resveratrol further reduced the scores significantly. The percentage of cells expressing BDNF and TrkB and expression levels of BDNF and TrkB were similar between the model and sham groups, significantly increased in rehabilitation training and resveratrol groups, and further increased in rehabilitation training plus resveratrol group. These results indicate that rehabilitation raining plus resveratrol can significantly improve the recovery of motor function in rats after cerebral ischemic injury, which is likely related to the upregulation of the BDNF/TrkB signaling pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain Ischemia; Combined Modality Therapy; Exercise Therapy; Male; Movement Disorders; Neurological Rehabilitation; Rats; Rats, Sprague-Dawley; Recovery of Function; Resveratrol; Sirtuin 1; Stilbenes; Treatment Outcome

Polyphenols possess antioxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular unit. Endothelial cell swelling may contribute to a leaky blood-brain barrier which may result in vasogenic edema in the continued presence of the existing cytotoxic edema. We investigated the protective effects of polyphenols on cytotoxic cell swelling in bEND3 endothelial cultures subjected to 5 hours oxygen-glucose deprivation (OGD). A polyphenol trimer from cinnamon (cinnamtannin D1), a polyphenol-rich extract from green tea, and resveratrol prevented the OGD-induced rise in mitochondrial free radicals, cell swelling, and the dissipation of the inner mitochondrial membrane potential. Monocyte chemoattractant protein (also called CCL2), a chemokine, but not tumor necrosis factor-α or interleukin-6, augmented the cell swelling. This effect of monochemoattractant protein 1-1 was attenuated by the polyphenols. Cyclosporin A, a blocker of the mitochondrial permeability transition pore, did not attenuate cell swelling but BAPTA-AM, an intracellular calcium chelator did, indicating a role of [Ca(2+)]i but not the mPT in cell swelling. These results indicate that the polyphenols reduce mitochondrial reactive oxygen species and subsequent cell swelling in endothelial cells following ischemic injury and thus may reduce brain edema and associated neural damage in ischemia. One possible mechanism by which the polyphenols may attenuate endothelial cell swelling is through the reduction in [Ca(2+)]i.

Topics: Animals; Antioxidants; Brain Ischemia; Calcium; Cell Line; Chemokine CCL2; Cyclosporine; Egtazic Acid; Endothelial Cells; Glucose; Hypoxia; Interleukin-6; Membrane Potential, Mitochondrial; Mice; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Oxidative Stress; Plant Extracts; Polyphenols; Proanthocyanidins; Reactive Oxygen Species; Resveratrol; Stilbenes; Tea; Tumor Necrosis Factor-alpha

The naturally occurring polyphenol phytoalexin resveratrol (RSV) regulates neuronal inflammation in various disease models and protects the brain against ischemic injury. Cell surface glutamate transporters on perisynaptic astrocytes are important regulators of extracellular glutamate levels and synaptic activation. Following cerebral ischemia, reduced astroglial type-1 glutamate transporter (GLT-1) expression in the CA1 pyramidal layers of the hippocampus contribute to neurotoxic glutamate levels. The current study examined the effects of 21-day RSV pretreatment (1 or 10mg/kg dose; i.p.) on microglia and astrocyte activation and characterized GLT-1 expression in the dentate gyrus (DG), CA1 and CA3 layers of the hippocampus 7 days following 10min global ischemia. Male Wistar rats were divided into five groups; sham/saline, ischemia/saline, ischemia/1mg/kg RSV, ischemia/10mg/kg RSV and sham/10mg/kg RSV. Immunohistochemical detection of GLT-1, CD11b/c, glial fibrillary acidic protein (GFAP) assessed type 1 glutamate transporter expression and microglial/glial cell activation following sham surgery or global ischemia. Our findings demonstrate prevention by RSV of ischemia-induced reduction of GLT-1 expression in the vulnerable CA1 layer 7 days following global ischemia, which was accompanied by the polyphenol's inhibition of post ischemic increase in CD11b/c and GFAP expression. RSV also conferred significant CA1 neuronal protection positively correlated with attenuation of glutamate transporter activation. These findings support beneficial effects of RSV in modulation of the excitotoxic cascade postischemia, which are congruent with anti-inflammatory effects observed in various pathological models.

Topics: Analysis of Variance; Animals; Antigens, CD1; Antioxidants; Brain Ischemia; Cell Count; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Excitatory Amino Acid Transporter 2; Glial Fibrillary Acidic Protein; Hippocampus; Male; Neurons; Rats; Rats, Wistar; Reperfusion; Resveratrol; Stilbenes

Nuclear erythroid 2 related factor 2 (Nrf2) is an astrocyte-enriched transcription factor that has previously been shown to upregulate cellular antioxidant systems in response to ischemia. Although resveratrol preconditioning (RPC) has emerged as a potential neuroprotective therapy, the involvement of Nrf2 in RPC-induced neuroprotection and mitochondrial reactive oxygen species production after cerebral ischemia remains unclear. The goal of our study was to study the contribution of Nrf2 to RPC and its effects on mitochondrial function.. We used rodent astrocyte cultures and an in vivo stroke model with RPC. An Nrf2 DNA binding ELISA and protein analysis via Western blotting of downstream Nrf2 targets were performed to determine RPC-induced activation of Nrf2 in rat and mouse astrocytes. After RPC, mitochondrial function was determined by measuring reactive oxygen species production and mitochondrial respiration in both wild-type and Nrf2-/- mice. Infarct volume was measured to determine neuroprotection, whereas protein levels were measured by immunoblotting.. We report that Nrf2 is activated by RPC in rodent astrocyte cultures, and that loss of Nrf2 reduced RPC-mediated neuroprotection in a mouse model of focal cerebral ischemia. In addition, we observed that wild-type and Nrf2-/- cortical mitochondria exhibited increased uncoupling and reactive oxygen species production after RPC treatments. Finally, Nrf2-/- astrocytes exhibited decreased mitochondrial antioxidant expression and were unable to upregulate cellular antioxidants after RPC treatment.. Nrf2 contributes to RPC-induced neuroprotection through maintaining mitochondrial coupling and antioxidant protein expression.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Astrocytes; Brain Ischemia; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation; Male; Mice; Mice, Knockout; Mitochondria; Neuroprotective Agents; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Stilbenes

Post-stroke depression (PSD) occurs about 40% among all stroke survivors, but the effective pharmacotherapy is inadequately understood. The present study investigated the effects of a natural polyphenol trans-resveratrol (RES) on behavioral changes after middle cerebral artery occlusion (MCAO) and examined what its molecular targets may be. RES was shown to decrease the infarct size and neurological scores after MCAO, suggesting the amelioration of brain damage and motor activity. RES also reversed the depressive-like behaviors 13 days after MCAO, both in the forced swimming and sucrose consumption tests. Moreover, MCAO-induced series abnormalities related to depressive-like behaviors, such as an abnormal adrenal gland weight to body weight ratio, an increased expression of the corticotropin-releasing factor (CRF) in the frontal cortex, hippocampus and hypothalamus, the differential expression of glucocorticoid receptor (GR) in these three brain regions, and a decreased brain-derived neurotrophic factor (BDNF) level, were ameliorated after treatment with increasing doses of RES at 10, 20 and 40 mg/kg via gavage. These findings provide compelling evidence that RES protects the brain against focal cerebral ischemia-induced injury, but most of all is its antidepressant-like effect on PSD, which might at least in part be mediated by regulation of hypothalamus-pituitary-adrenal axis function.

Topics: Animals; Antidepressive Agents; Brain Ischemia; Depressive Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Frontal Lobe; Hypothalamo-Hypophyseal System; Imipramine; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Pituitary-Adrenal System; Random Allocation; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Stroke

Pterostilbene (3,5-dimethoxy-4-hydroxystilbene) is a component of blueberry. It has been reported that long-term treatment with blueberry has a neuroprotective effect. However, it has not been reported whether pterostilbene is effective in attenuating cerebral ischemia/reperfusion (I/R) injury. In the present study, focal cerebral ischemia was induced by middle cerebral artery occlusion for 90min followed by reperfusion. To observe the dose-dependent effect, pterostilbene (2.5-80mg/kg, ig) was administered for 3days before ischemia. To determine the time-dependent effect, pterostilbene (10mg/kg, ig) was administered as a single dose at 0, 1, or 3h after reperfusion. Twenty-four hours after I/R, pterostilbene dose-dependently improved neurological function, reduced brain infarct volume, and alleviated brain edema. The most effective dose was 10mg/kg; the therapeutic time window was within 1h after I/R and treatment immediately after reperfusion showed the best protective effect. The protective effect is further confirmed by the results that post-ischemic treatment with pterostilbene (10mg/kg) significantly improved motor function, alleviated blood brain barrier disruption, increased neurons survival and reduced cell apoptosis in cortical penumbra after cerebral I/R. We also found that pterostilbene (10mg/kg) significantly reversed the increased content of malondialdehyde and the decreased activity of superoxide dismutase in the ipsilateral hemisphere. Furthermore, pterostilbene decreased the oxidative stress markers 4-hydroxynonenal and 8-hydroxyguanosine positive cells in the cortical penumbra. All these findings indicate that pterostilbene dose- and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury. This neuroprotective effect of pterostilbene may be associated with its inhibition of oxidative stress and subsequent neuronal apoptosis in the cortical penumbra.

Topics: Administration, Oral; Animals; Apoptosis; Blood-Brain Barrier; Brain Ischemia; Cell Survival; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Male; Malondialdehyde; Mice; Neuroprotective Agents; Oxidative Stress; Postural Balance; Psychomotor Performance; Reperfusion Injury; Stilbenes; Superoxide Dismutase

Prophylactic treatments that afford neuroprotection against stroke may emerge from the field of preconditioning. Resveratrol mimics ischemic preconditioning, reducing ischemic brain injury when administered 2 days before global ischemia in rats. This protection is linked to silent information regulator 2 homologue 1 (Sirt1) and enhanced mitochondrial function possibly through its repression of uncoupling protein 2. Brain-derived neurotrophic factor (BDNF) is another neuroprotective protein associated with Sirt1. In this study, we sought to identify the conditions of resveratrol preconditioning (RPC) that most robustly induce neuroprotection against focal ischemia in mice.. We tested 4 different RPC paradigms against a middle cerebral artery occlusion model of stroke. Infarct volume and neurological score were calculated 24 hours after middle cerebral artery occlusion. Sirt1-chromatin binding was evaluated by ChIP-qPCR. Percoll gradients were used to isolate synaptic fractions, and changes in protein expression were determined via Western blot analysis. BDNF concentration was measured using a BDNF-specific ELISA assay.. Although repetitive RPC induced neuroprotection from middle cerebral artery occlusion, strikingly one application of RPC 14 days before middle cerebral artery occlusion showed the most robust protection, reducing infarct volume by 33% and improving neurological score by 28%. Fourteen days after RPC, Sirt1 protein was increased 1.5-fold and differentially bound to the uncoupling protein 2 and BDNF promoter regions. Accordingly, synaptic uncoupling protein 2 level decreased by 23% and cortical BDNF concentration increased 26%.. RPC induces a novel extended window of ischemic tolerance in the brain that lasts for at least 14 days. Our data suggest that this tolerance may be mediated by Sirt1 through upregulation of BDNF and downregulation of uncoupling protein 2.

Topics: Animals; Brain; Brain Ischemia; Drug Administration Schedule; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Resveratrol; Stilbenes; Time Factors

According to the French paradox, red wine consumption reduces the incidence of vascular diseases even in the presence of highly saturated fatty acid intake. This phenomenon is widely attributed to the phytoalexin resveratrol, a red wine ingredient. Experimental studies suggesting that resveratrol has neuroprotective properties mostly used prophylactic delivery strategies associated with short observation periods. These studies did not allow conclusions to be made about resveratrol's therapeutic efficacy post-stroke. Herein, we systematically analyzed effects of prophylactic, acute and post-acute delivery of resveratrol (50mg/kg) on neurological recovery, tissue survival, and angioneurogenesis after focal cerebral ischemia induced by intraluminal middle cerebral artery occlusion in mice. Over an observation period of four weeks, only prolonged post-acute resveratrol delivery induced sustained neurological recovery as assessed by rota rod, tight rope and corner turn tests. Although prophylactic and acute resveratrol delivery reduced infarct volume and enhanced blood-brain-barrier integrity at 2 days post-ischemia by elevating resveratrol's downstream signal sirtuin-1, increasing cell survival signals (phosphorylated Akt, heme oxygenase-1, Bcl-2) and decreasing cell death signals (Bax, activated caspase-3), a sustained reduction of infarct size on day 28 was not observed in any of the three experimental conditions. Instead, enhanced angiogenesis and neurogenesis were noted in animals receiving post-acute resveratrol delivery, which were associated with elevated concentrations of GDNF and VEGF in the brain. Thus, sustained neurological recovery induced by resveratrol depends on successful brain remodeling rather than structural neuroprotection. The recovery promoting effect of delayed resveratrol delivery opens promising perspectives for stroke therapy.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Cell Death; Cell Survival; Cells, Cultured; Cerebral Cortex; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Neurogenesis; Neurons; Oxidative Stress; Recovery of Function; Resveratrol; Rotarod Performance Test; Signal Transduction; Sirtuin 1; Stilbenes; Stroke

Cerebral ischemia-reperfusion (I/R) is associated with increased levels of reactive oxygen species (ROS) and brain edema, which lead to the deterioration of patient prognosis. Resveratrol serves a neuroprotective role in I/R injury, and this role may be associated with its anti‑oxidative effects. However, resveratrol's mechanism of action in cerebral I/R injury remains to be fully understood. In order to investigate the effect of resveratrol in cerebral I/R‑induced injury, male Sprague‑Dawley rats were randomly assigned to four groups: The sham‑operation group, the I/R group and the edaravone and resveratrol groups (I/R + E and I/R + R groups). Infarct volume was evaluated by 2,3,5‑tripenyltetrazolium chloride staining, brain edema was evaluated by the water content in the reperfused brain and malondialdehyde (MDA) was measured by the thiobarbituric acid method. Superoxide dismutase (SOD) levels were measured using the Total Superoxide Dismutase Assay kit. Inducible nitric oxide synthase (iNOS) levels in the hippocampus and cortex were measured by ELISA, and aquaporin 4 (AQP4) expression was measured by immunohistochemical staining and western blot analysis. The results demonstrated that resveratrol reduced the infarct volume and the incidence of brain edema and reduced neurological deficits. These outcomes were accompanied by reduced levels of MDA, iNOS and AQP4, and increased SOD levels in cerebral I/R injury. In conclusion, resveratrol protected against cerebral I/R injury by ameliorating oxidative stress and reducing AQP4 expression.

Topics: Animals; Antioxidants; Aquaporin 4; Brain; Brain Ischemia; Male; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

The present study demonstrates the benefits of combinatorial antioxidant therapy in the treatment of ischemic stroke. Male Sprague-Dawley rats were anaesthetised and the middle cerebral artery (MCA) was occluded for 30 minutes followed by 5.5 hours of reperfusion. Pretreatment with resveratrol 30 minutes prior to MCA occlusion resulted in a significant, dose-dependent decrease in infarct volume (p<0.05) compared to vehicle-treated animals. Neuroprotection was also observed when resveratrol (2 × 10(-3) mg/kg; iv) was administered within 60 minutes following the return of blood flow (reperfusion). Pretreatment with non-neuroprotective doses of resveratrol (2 × 10(-6) mg/kg) and lipoic acid (LA; 0.005 mg/kg) in combination produced significant neuroprotection as well. This neuroprotection was also observed when resveratrol and LA were administered 15 minutes following the onset of MCA occlusion. Subsequently, we synthetically combined resveratrol and LA in both a 1 ∶ 3 (UPEI-200) and 1 ∶ 1 (UPEI-201) ratio, and screened these new chemical entities in both permanent and transient ischemia models. UPEI-200 was ineffective, while UPEI-201 demonstrated significant, dose-dependent neuroprotection. These results demonstrate that combining subthreshold doses of resveratrol and LA prior to ischemia-reperfusion can provide significant neuroprotection likely resulting from concurrent effects on multiple pathways. The additional protection observed in the novel compound UPEI 201 may present opportunities for addressing ischemia-induced damage in patients presenting with transient ischemic episodes.

Topics: Animals; Antioxidants; Brain Ischemia; Disease Models, Animal; Humans; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Stroke; Thioctic Acid

The present study investigated the neuroprotective effects of Resveratrol (RSV) in rats submitted to chronic cerebral hypoperfusion (CCH) in a model of permanent two-vessel occlusion (2VO).. For this purpose, adult Wistar rats received daily i.p. injections of RSV (20 mg/kg) for 7 days, starting 1 hour after the 2VO procedure. Behavioral testing was run between the 30th and 45th days after the 2VO surgery. Accordingly, spatial working memory function in the Morris water maze was evaluated. At the end of the behavioral assessment (45th day post-surgery) part of experimental animals underwent transcardiac perfusion for histological analysis. Another group was euthanized on the 3rd, 14th, and 45th days post-surgery for nerve growth factor (NGF) evaluation.. Resveratrol treatment along 7 days after CCH significantly attenuated pyramidal cell death in the CA1 hippocampal subfield and prevented both spatial working and reference memory impairments. Our results revealed an enhancement of NGF expression 3 days after CCH in all ischemic animals. A late increase in hippocampal NGF levels was detected after 45 days only in CCH-RSV treated animals.. Results presented here show morphological and functional neuroprotective actions of RSV treatment for CCH, as well as support the inducing effects of RSV on the expression of NGF and its possible association to the neuroprotective action in this rodent model of vascular dementia.

Topics: Animals; Brain Ischemia; Cell Count; Cognition Disorders; Hippocampus; Male; Maze Learning; Memory, Short-Term; Nerve Growth Factor; Neurons; Neuroprotective Agents; Neuropsychological Tests; Random Allocation; Rats, Wistar; Resveratrol; Spatial Memory; Stilbenes

Topics: Animals; Brain Ischemia; Disease Models, Animal; Humans; Resveratrol; Stilbenes; Stroke; Treatment Outcome

Resveratrol has shown potent antioxidant activity in ischemia models. The present study was performed to determine whether resveratrol protects against cerebral ischemia-induced neuronal and myocardial injury by interfering with mitochondrial homeostasis.. Wistar rats were pretreated with resveratrol or vehicle intraperitoneally for one week and then subjected to cerebral ischemia via middle cerebral artery occlusion (MCAO) for 24 h. Oxidation was evaluated by quantitating SOD activity and MDA levels. Apoptosis and autophagy were measured based on TUNEL staining and the expression levels of Bcl-2, Bax and LC3II. Mitochondrial changes were evaluated by transmission electron microscopy and by analyzing the mitochondrial membrane potential.. Resveratrol significantly decreased mortality, neurological deficits, infarction volume and MDA levels and increased SOD activity. Furthermore, neurocyte apoptosis was alleviated by resveratrol as indicated by the increased Bcl-2/Bax ratio, increased LC3II expression and a decreased number of TUNEL-positive neurocytes. Resveratrol preserved the mitochondria in neurons and cardiomyocytes and significantly improved cardiac function.. Resveratrol protected brain tissues against ischemic damage by interfering with mitochondrial homeostasis and inhibiting apoptosis. Furthermore, resveratrol attenuated myocardial damage, suggesting that it may be a novel therapy for cerebral ischemia diseases.

Topics: Animals; Apoptosis; Brain Ischemia; Cardiotonic Agents; Disease Models, Animal; Heart; Male; Membrane Potential, Mitochondrial; Mitochondria; Myocardium; Neurons; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes

CDP-choline has shown neuroprotective effects in cerebral ischemia. In humans, although a recent trial International Citicoline Trial on Acute Stroke (ICTUS) has shown that global recovery is similar in CDP-choline and placebo groups, CDP-choline was shown to be more beneficial in some patients, such as those with moderate stroke severity and not treated with t-PA. Several mechanisms have been proposed to explain the beneficial actions of CDP-choline. We have now studied the participation of Sirtuin1 (SIRT1) in the neuroprotective actions of CDP-choline. Fischer rats and Sirt1⁻/⁻ mice were subjected to permanent focal ischemia. CDP-choline (0.2 or 2 g/kg), sirtinol (a SIRT1 inhibitor; 10 mg/kg), and resveratrol (a SIRT1 activator; 2.5 mg/kg) were administered intraperitoneally. Brains were removed 24 and 48 h after ischemia for western blot analysis and infarct volume determination. Treatment with CDP-choline increased SIRT1 protein levels in brain concomitantly to neuroprotection. Treatment with sirtinol blocked the reduction in infarct volume caused by CDP-choline, whereas resveratrol elicited a strong synergistic neuroprotective effect with CDP-choline. CDP-choline failed to reduce infarct volume in Sirt1⁻/⁻ mice. Our present results demonstrate a robust effect of CDP-choline like SIRT1 activator by up-regulating its expression. Our findings suggest that therapeutic strategies to activate SIRT1 may be useful in the treatment of stroke. Sirtuin 1 (SIRT1) is implicated in a wide range of cellular functions. Regarding stroke, there is no direct evidence. We have demonstrated that citicoline increases SIRT1 protein levels in brain concomitantly to neuroprotection. Citicoline fails to reduce infarct volume in Sirt1⁻/⁻ mice. Our findings suggest that therapeutic strategies acting on SIRT1 may be useful in the treatment of stroke.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzamides; Blotting, Western; Brain Ischemia; Cells, Cultured; Cytidine Diphosphate Choline; Drug Synergism; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Knockout; Monocytes; Naphthols; Neurons; Neuroprotective Agents; Nootropic Agents; Rats; Rats, Inbred F344; Resveratrol; Sirtuin 1; Stilbenes; Stroke

Resveratrol, a dietary polyphenol with antioxidant and anti-inflammatory activity, has been shown to provide neuroprotection in models of ischemia. However, the mechanism of action of resveratrol-induced neuroprotection remains unclear. Previous work in our laboratory has provided evidence that acute, systemic administration of resveratrol is neuroprotective in a permanent model of cerebral ischemia, an effect that was blocked when animals received the non-selective estrogen receptor antagonist, ICI, 182,780. The present study was designed to investigate whether the source of neuroprotection afforded by resveratrol action within the cerebral cortex itself is mediated preferentially via selective activation of either α or β estrogen receptor subtype. Intracortical injection of resveratrol (0.1 and 1.0 μM) 10 min prior to 30 min of ischemia followed by 5.5h of reperfusion significantly reduced infarct volume in the prefrontal cortex. This neuroprotective effect was significantly attenuated when resveratrol injection (1.0 μM) was preceded by injection of a selective estrogen receptor α antagonist, 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1N-pyrozole dihydrochloride (MPP) or a selective estrogen receptor beta (ERβ) antagonist, 4-[2-phenyo-5,7-bis(trifluoromrthyl)pyrazolo(1,5-a)pyrimidin-3-yl]phenol (PHTPP). These results provide evidence for rapidly induced neuroprotection mediated by resveratrol activation of either estrogen receptor subtype within the ischemic cortex of rats.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Estrogen Receptor alpha; Estrogen Receptor beta; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Treatment Outcome

Nuclear factor-kappaB (NF-κB) p50/RelA is a key molecule with a dual effect in the progression of ischemic stroke. In harmful ischemia, but not in preconditioning insult, neurotoxic activation of p50/RelA is characterized by RelA-specific acetylation at Lys310 (K310) and deacetylation at other Lys residues. The derangement of RelA acetylation is associated with activation of Bim promoter.. With the aim of producing neuroprotection by correcting altered acetylation of RelA in brain ischemia, we combined the pharmacological inhibition of histone deacetylase (HDAC) 1-3, the enzymes known to reduce global RelA acetylation, and the activation of sirtuin 1, endowed with a specific deacetylase activity on the K310 residue of RelA. To afford this aim, we tested the clinically used HDAC 1-3 inhibitor entinostat (MS-275) and the sirtuin 1 activator resveratrol.. We used the mouse model of transient middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to oxygen glucose deprivation (OGD).. The combined use of MS-275 and resveratrol, by restoring normal RelA acetylation, elicited a synergistic neuroprotection in neurons exposed to OGD. This effect correlated with MS-275 capability to increase total RelA acetylation and resveratrol capability to reduce RelA K310 acetylation through the activation of an AMP-activated protein kinase-sirtuin 1 pathway. The synergistic treatment reproduced the acetylation state of RelA peculiar of preconditioning ischemia. Neurons exposed to the combined drugs totally recovered the optimal histone H3 acetylation. Neuroprotection was reproduced in mice subjected to MCAO and treated with MS-275 (20μg/kg and 200μg/kg) or resveratrol (6800μg/kg) individually. However, the administration of lowest doses of MS-275 (2μg/kg) and resveratrol (68μg/kg) synergistically reduced infarct volume and neurological deficits. Importantly, the treatment was effective even when administered 7h after the stroke onset. Chromatin immunoprecipitation analysis of cortices harvested from treated mice showed that the RelA binding and histone acetylation increased at the Bcl-xL promoter and decreased at the Bim promoter.. Our study reveals that epigenetic therapy shaping acetylation of both RelA and histones may be a promising strategy to limit post-ischemic injury with an extended therapeutic window.

Topics: Acetylation; Animals; Benzamides; Brain; Brain Ischemia; Cell Hypoxia; Disease Models, Animal; Epigenesis, Genetic; Glucose; Histone Deacetylase Inhibitors; Histones; Infarction, Middle Cerebral Artery; Male; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; NF-kappa B; Pyridines; Resveratrol; Sirtuin 1; Stilbenes; Transcription Factor RelA

The present study was undertaken to evaluate whether resveratrol (RSV) modulates membrane lipid composition, as well as on ganglioside profile in ischemia/reperfusion injury.. Global cerebral ischemia was induced by four-vessel occlusion for 10 minutes. RSV (30 mg/kg) or vehicle was intraperitoneally administered to rats 7 days prior to ischemia. Brain structures were homogenized with chloroform/methanol for ganglioside, phospholipids, and cholesterol levels.. RSV significantly prevented the reduction in the total content of gangliosides, phospholipids, and cholesterol in hippocampi and cerebral cortex induced by global cerebral ischemia. Although ischemia/reperfusion decreased ganglioside content, the ganglioside profiles were apparently not modified.. Our experiments suggest that lipid metabolism is important for development of ischemic damage and indicate that RSV treatment 7 days prior to ischemia may prevent membrane lipid loss.

Topics: Animals; Antioxidants; Brain Ischemia; Cholesterol; Chromatography, Thin Layer; Disease Models, Animal; Gangliosidoses; Lipid Metabolism Disorders; Male; Phospholipids; Rats; Rats, Wistar; Resveratrol; Stilbenes

Oxidative stress and inflammation are two important pathological mechanisms involved in cerebral ischemia and reperfusion injury. In pathological conditions such as cerebral infarction, the free radical production is greater than that of elimination by endogenous anti-oxidant system, by this undesirable effect brain is highly injured. Resveratrol is reported to have anti-oxidant and anti-inflammatory, athero-protective activities. Therefore, the aim of the present study is to evaluate the therapeutic potential of resveratrol against cerebral infarction induced by ischemia and reperfusion injury in Wistar rats. Bi-common carotid occlusion followed by 4 h reperfusion model was used to induce cerebral infarction. Percent infarction, oxidative stress markers (malondialdehyde, catalase, superoxide dismutase) and inflammatory markers (myeloperoxidase, TNF-α, IL-6, ICAM-1 and IL-10) were measured. TNF-α, IL-6, IL-10, and intracellular adhesive molecule-I (ICAM-1) levels were quantified by enzyme-linked immunosorbent assay (ELISA). Resveratrol produced significant dose-dependent reduction in percent cerebral infarct volume. At resveratrol 20 mg/kg dose, there was a significant reduction in oxidative stress and inflammatory markers like malondialdehyde, TNF-α, IL-6, myeloperoxidase and ICAM-I and in contrast there was a significant increase in anti-oxidants and anti-inflammatory markers like superoxide dismutase, catalase and IL-10 levels. Resveratrol showed significant cerebroprotective action mediated by anti-oxidant and anti-inflammatory mechanisms.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Brain Ischemia; Cerebral Infarction; Male; Neuroprotective Agents; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Resveratrol; Stilbenes

The main pathophysiology in cerebral ischemia is the structural alteration in the neurovascular unit, coinciding with neurovascular matrix degradation. Among the human matrix metalloproteinases (MMPs), MMP-2 and -9, known as gelatinases, are the key enzymes for degrading type IV collagen, which is the major component of the basal membrane that surrounds the cerebral blood vessel. In the present study, we investigated the effects of resveratrol on cytotoxicity, reactive oxygen species (ROS), and gelatinases (MMP-2 and -9) in human cerebral microvascular endothelial cells exposed to 6 hours of oxygen-glucose deprivation and a subsequent 24 hours of reoxygenation with glucose (OGD/R), to mimic ischemia/reperfusion in vivo. Lactate dehydrogenase increased significantly, in comparison to that in the normoxia group. ROS was markedly increased in the OGD/R group, compared to normoxia. Correspondingly, ROS was significantly reduced with 50 μM of resveratrol. The proMMP-2 activity in the OGD/R group showed a statistically significant increase from the control cells. Resveratrol preconditioning decreased significantly the proMMP-2 in the cells exposed to OGD/R in comparison to that in the OGD/R group. Our results indicate that resveratrol regulates MMP-2 activity induced by OGD/R via its antioxidant effect, implying a possible mechanism related to the neuroprotective effect of resveratrol.

Topics: Antioxidants; Brain; Brain Ischemia; Cell Line; Endothelial Cells; Enzyme Precursors; Gelatinases; Glucose; Humans; L-Lactate Dehydrogenase; Matrix Metalloproteinase 2; Microcirculation; Neuroprotective Agents; Oxygen; Reactive Oxygen Species; Reperfusion; Resveratrol; Stilbenes

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.

Topics: Animals; Behavior, Animal; Blood Glucose; Body Weight; Brain Ischemia; Dose-Response Relationship, Drug; Exploratory Behavior; Hippocampus; Male; Maze Learning; Motor Activity; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes

Oxyresveratrol is a potent antioxidant and free-radical scavenger found in mulberry wood (Morus alba L.) with demonstrated protective effects against cerebral ischemia. We analyzed the neuroprotective ability of oxyresveratrol using an in vitro model of stretch-induced trauma in co-cultures of neurons and glia, or by exposing cultures to high levels of glutamate. Cultures were treated with 25 μM, 50 μM or 100 μM oxyresveratrol at the time of injury. Trauma produced marked neuronal death when measured 24 h post-injury, and oxyresveratrol significantly inhibited this death. Microscopic examination of glia suggested signs of toxicity in cultures treated with 100 μM oxyresveratrol, as demonstrated by elevated S-100B protein release and a high proportion of cells with condensed nuclei. Cultures exposed to glutamate (100 μM) for 24 h exhibited ~ 37% neuronal loss, which was not inhibited by oxyresveratrol. These results show that the two pathologies of high glutamate exposure and trauma are differentially affected by oxyresveratrol treatment in vitro. Further studies using oxyresveratrol in trauma models are warranted, as toxicity to glia could be beneficial by inhibiting reactive gliosis, which often occurs after trauma.

Topics: Animals; Antioxidants; Brain Ischemia; Cell Death; Cells, Cultured; Cerebral Cortex; Coculture Techniques; Free Radical Scavengers; Glutamic Acid; Mice; Nerve Growth Factors; Neuroglia; Neurons; Neuroprotective Agents; Plant Extracts; Rats; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Stilbenes; Wounds and Injuries

Considerable evidence has been accumulated to suggests that blocking the inflammatory reaction promotes neuroprotection and shows therapeutic potential for clinical treatment of ischemic brain injury. Consequently, anti-inflammatory therapies are being explored for prevention and treatment of these diseases. Induction of brain tolerance against ischemia by pretreatment with resveratrol has been found to influence expression of different molecules. It remains unclear, however, whether and how resveratrol preconditioning changes expression of inflammatory mediators after subsequent global cerebral ischemia/reperfusion (I/R). Therefore, we investigated the effect of resveratrol pretreatment on NF-κB inflammatory cascade, COX-2, iNOS and JNK levels in experimental I/R. Adult male rats were subjected to 10 min of four-vessel occlusion and sacrificed at selected post-ischemic time points. Resveratrol (30 mg/kg) pretreatment was injected intraperitoneally 7 days prior to I/R induction. We found that resveratrol treatment before insult remarkably reduced astroglial and microglial activation at 7 days after I/R. It greatly attenuated I/R-induced NF-κB and JNK activation with decreased COX-2 and iNOS production. In conclusion, the neuroprotection of resveratrol preconditioning may be due in part to the suppression of the inflammatory response via regulation of NF-κB, COX-2 and iNOS induced by I/R. JNK was also suggested to play a protective role through in neuroprotection of resveratrol, which may also be contributing to reduction in neuroinflammation. The study adds to a growing literature that resveratrol can have important anti-inflammatory actions in the brain.

Topics: Animals; Brain Ischemia; Hippocampus; Inflammation Mediators; Ischemic Preconditioning; Male; Rats; Rats, Wistar; Resveratrol; Stilbenes

Resveratrol, an ingredient in grapes, has been reported to exhibit anti-cancer activity, anti-inflammatory activity, and cardiovascular protection property. Interestingly, resveratrol has been recently reported to have neuroprotective effect. This study reports the neuroprotective effect of a resveratrol derivative, 3-[2-(3,5-dimethoxyphenyl)vinyl]furan (DPVF). This synthetic DPVF conferred more protection than resveratrol against neuronal cell damage induced by oxygen and glucose deprivation in a rat hippocampal slice culture. In addition, DPVF inhibited ATP depletion following oxygen and glucose deprivation in the adult hippocampal slice. Moreover, we found that DPVF is neuroprotective against ischemic damage in rats. DPVF showed potent neuroprotection on a 4-velssel-occusion model and inhibited iron-induced malondialdehyde (MDA) formation in the rat brain tissue. These results demonstrate that DPVF might be a useful agent in reducing ischemic neuronal damage.

Topics: Animals; Brain Ischemia; Cell Death; Disease Models, Animal; Furans; Hippocampus; Neurons; Neuroprotective Agents; Organ Culture Techniques; Rats; Resveratrol; Stilbenes

Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK-3β) and cAMP response element-binding protein (CREB) through phosphatidylinositol 3-kinase (PI3-K)-dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four-vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK-3β and CREB appear to play a critical role in resveratrol neuroprotection through the PI3-K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK-3β and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3-K, compromised the neuroprotective effect of resveratrol and decreased the level of p-Akt, p-GSK-3β and p-CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro-survival states of Akt, GSK-3β and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3-K/Akt signaling pathway, subsequently downregulating expression of GSK-3β and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats.

Topics: Animals; Apoptosis; Brain Ischemia; CA1 Region, Hippocampal; Chromones; Cyclic AMP Response Element-Binding Protein; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Morpholines; Neurons; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Signal Transduction; Stilbenes

Resveratrol has several beneficial effects, including reductions of oxidative stress, inflammatory responses and apoptosis. It has been known that resveratrol is a sirtuin 1 (SIRT1) activator and protective effects of resveratrol are mediated by Akt and mitogen-activated protein kinases. However, it is not examined whether these pathways are regulated by resveratrol in the ischemic brain. Previously, we found that acute resveratrol treatment reduces brain injury induced by transient focal ischemic stroke. In the present study, we defined the signaling pathways modulated by resveratrol in ischemia by examining SIRT1 expression and phosphorylation of Akt, ERK1/2 and p38 in the ischemic cortex. Resveratrol increased expression of SIRT1 and phosphorylation of Akt and p38 but inhibited the increase in phosphorylation of ERK1/2. Gene and protein levels of peroxisome proliferator-activated receptor γ coactivator 1α, a downstream molecule of SIRT1, and mRNA levels of its target genes antioxidative superoxide dismutase 2 and uncoupling protein 2 were elevated. Resveratrol also increased phosphorylation of cyclic AMP-response-element-binding protein and transcription of the anti-apoptotic gene Bcl-2. These results suggest that various neuroprotective actions of resveratrol, including anti-oxidative, anti-apoptotic and inflammatory effects, are mediated via modulation of multiple signaling pathways in the ischemic brain.

Topics: Animals; Base Sequence; Blotting, Western; Brain Ischemia; Cyclic AMP Response Element-Binding Protein; DNA Primers; Fluorescent Antibody Technique; Male; Mice; Mice, Inbred C57BL; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Protein Kinases; Real-Time Polymerase Chain Reaction; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Trans-Activators; Transcription Factors

In this study, we determined the protective potential of trans resveratrol against oxygen-glucose deprivation (OGD) induced reactive oxygen species mediated apoptotic damages in PC12 cells. In vitro model of ischemic cerebral stroke was created by keeping cells in an OGD condition for 6h followed by 24h reoxygenation. Cells received biologically safe doses (5, 10, and 25 μM) of trans resveratrol in the following schedules for 24h prior to OGD; during 6h of OGD; for 24h post OGD and whole treatment group which starts from 24h before OGD and lasted to 24h post OGD. Anti-ischemic potential of trans resveratrol was assessed by measuring the regulation of lipid peroxidation, reactive oxygen species production, glutathione content, and expression (mRNA and protein) of apoptotic markers such as Bax, Bcl(2) and Caspase-3. Hypoxia inducible factor-1α (HIF-1α) was also assessed to correlate the changes with ischemic injuries. Significant (P<0.05) restoration in lipid peroxidation, reactive oxygen species, and glutathione content were observed following the treatment of trans resveratrol in cells receiving OGD and re-oxygenation. Changes induced by trans resveratrol could be correlated well with alterations in the expression of Bax, Bcl(2), Caspase-3 and HIF-1α. These results indicate that trans resveratrol administration attenuates free radical formation and mitochondria mediated apoptosis perhaps by regulating the expressions of Bax, Bcl(2,) and Caspase-3 in PC12 cells receiving OGD and re-oxygenation insult.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Brain Ischemia; Caspase 3; Glucose; Glutathione; Hypoxia-Inducible Factor 1, alpha Subunit; Lipid Peroxidation; Neurons; Neuroprotective Agents; Oxidative Stress; Oxygen; PC12 Cells; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species; Resveratrol; Stilbenes; Transcription, Genetic

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Brain Ischemia; Coronary Disease; Cyclooxygenase Inhibitors; Free Radical Scavengers; Humans; Neuroprotective Agents; Nitric Oxide; Resveratrol; Stilbenes; Stroke; Wine

Oxidative stress damage plays a vital role in cerebral ischemia/reperfusion (I/R) pathogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway can be activated by pharmacological and dietary means to attenuate cellular oxidative stress. Resveratrol, a plant-derived polyphenolic compound, has antioxidant property. Recent studies have demonstrated that resveratrol has protective effects against cerebral I/R injury. However, little is known about its mechanism. Hence, this study identified the neuroprotective effect of resveratrol pretreatment and elucidate the Nrf2/ARE signaling mechanism after focal cerebral I/R injury in rats. Adult male Sprague-Dawley rats were randomly assigned to sham-operated group, ischemia/reperfusion physiological saline-treated group, and ischemia/reperfusion resveratrol-pretreatmented (15 and 30 mg/kg) groups. Rats were pretreatmented with resveratrol or physiological saline of corresponding volume administered intraperitoneally for 7 days before surgery and 30 min before middle cerebral artery occlusion. At 24 h after reperfusion, neurological score, infarct volume, and brain water content were assessed. Oxidative stress was evaluated by malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Pathological changes of brain tissue were observed by HE staining. RT-PCR and Western blot analysed the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). TUNEL staining detected apoptotic cells. The protein expression of Caspase-3 were studied by immunohistochemistry. Resveratrol pretreatment significantly ameliorated neurological scores, reduced infarct volume and brain water content, decreased MDA levels, restored the SOD activity, upregulated the protein and mRNA expression of Nrf2 and HO-1, downregulated the protein expression of caspase-3. TUNEL-positive cells significantly decreased compared with the physiological saline-treated group. HE staining also showed that resveratrol significantly improved neuronal injury. These results showed that resveratrol pretreatment had neuroprotective effects on cerebral I/R injury. This neuroprotective effect is likely exerted by upregulated expression of transcription factor Nrf2 and HO-1 to ameliorate oxidative damage, decreased the protein expression of caspase-3. Our finding is important for understanding the neuroprotective mechanism of resveratrol and promoting its clinical the

Topics: Animals; Antioxidants; Brain Ischemia; Caspase 3; DNA Fragmentation; Down-Regulation; Heme Oxygenase-1; Infarction, Middle Cerebral Artery; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Up-Regulation

Neuroprotective effects of parthenocissin A (PA), a novel antioxidant and free radical scavenger, were studied in a transient middle cerebral artery (MCA) occlusion model in rats for the first time. The animals were treated intraperitoneally with PA at 2.5, 5 or 10 mg/kg, for both 30 min before MCA occlusion and 6 h after reperfusion. The MCA was occluded for 1 h in anesthetized Sprague-Dawley rats. Compared with vehicle-treated controls, MCA occluded animals treated with PA showed dose-dependent reductions in brain infarction size with improved neurological and motor outcome. Biomedical assay showed that the PA treatment suppressed lipid peroxidation and restored superoxide dismutase (SOD) activity in brain tissue. In addition, the ischemia/reperfusion (I/R) induced elevation of nitric oxide (NO) production and nitric oxide synthase (NOS) activity in brain tissue was also inhibited. Thus, PA demonstrated a neuroprotective effect in the I/R model and the beneficial effects of the compound may result from the reduction of oxidative stress and the inhibition of NO production induced by I/R. The neuroprotective effects of PA have highlighted the potential use of stilbene oligomers in stroke therapy.

Topics: Animals; Brain; Brain Ischemia; Cerebral Infarction; Free Radical Scavengers; Indenes; Infarction, Middle Cerebral Artery; Lipid Peroxidation; Male; Molecular Structure; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats; Reperfusion Injury; Resorcinols; Stilbenes; Superoxide Dismutase; Vitaceae

To evaluate the protective effect of polydatin on a PC12 cell model of oxygen and glucose deprivation (OGD).. A pheochromocytoma cell injury model was induced by OGD to simulate the cerebral ischemic changes. The protective effects of polydatin were investigated in this model.. Polydatin treatment significantly enhanced the cell viability and reduced the levels of lactate dehydrogenase, nitric oxide and the malondialdehyde of the pheochromocytoma cells as compared with the OGD group. Polydatin also increased the activity of superoxide dismutase in the cells.. Polydatin offers protective effect against OGD-induced injury in pheochromocytoma cells.

Topics: Animals; Brain Ischemia; Cell Survival; Glucose; Glucosides; L-Lactate Dehydrogenase; Malondialdehyde; Nitric Oxide; Oxygen; PC12 Cells; Protective Agents; Rats; Stilbenes; Superoxide Dismutase

We defined whether resveratrol administration during the acute phase of ischemic stroke reduces brain injury in mice. Infarct volumes were decreased significantly in both sexes with different doses of resveratrol (5mg/kg for males and 1mg/kg for females) administered 3h after ischemic stroke. Administration of resveratrol 6h after insult was also effective to decrease infarct volumes. Resveratrol suppressed expressions of IL-1β and TNF-α, microglial activation, and ROS production in the ischemic cortex. The findings suggest that the suppression of inflammation is partly associated with the neuroprotective effects of resveratrol, and resveratrol can be developed as a therapeutic drug for acute ischemic stroke.

Topics: Acute Disease; Animals; Brain Infarction; Brain Ischemia; Disease Models, Animal; Dose-Response Relationship, Immunologic; Female; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Reactive Oxygen Species; Resveratrol; Stilbenes; Stroke

To investigate the effects of terahydroxy stilbene glucoside (TSG) on neurological deficits, the expressions of nerve growth factor (NGF) and growth associated protein43 (GAP43) in rats after Cerebral Ischemia-reperfusion.. 96 Sprague-Dawley male rats were divided into four groups (n = 24): control group, ischemia-reperfusion (I/R) model group, low dose TSG (60 mg/kg) group and high dose TSG (120 mg/kg) group. After 6 days' administration of TSG or natural saline (model group), reversible middle cerebral artery occlusion (MCAO) model was established by intraluminal suture technique. Rats in control group were operated while middle cerebral artery were not blocked. At 6, 24, 48 h and 7 d after reperfusion, behavior test was used to evaluate the neurological deficiency of each group. The expressions of NGF and GAP-43 in the cortex were measured by immunohistochemical method.. Compared with model group, both dose of TSG could decrease the grade of the rat neurological defects except at 6 h of ter reperfusion and increase the protein expressions of NGF and GAP-43 after reperfusion.. TSG can improve the neurological function through increasing the expressions of NGF and GAP-43 of cerebral ischemia-reperfusion rats.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Disease Models, Animal; GAP-43 Protein; Glucosides; Immunohistochemistry; Infarction, Middle Cerebral Artery; Male; Nerve Growth Factor; Neuroprotective Agents; Polygonaceae; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stilbenes

Free radicals are known to cause secondary neuronal damage in cerebral ischemia/reperfusion (I/R). We investigated here the neuroprotective effect of resveratrol, a potent antioxidant present in grape seed, against cerebral I/R-induced mitochondrial dysfunctions in hippocampus. Transient rat middle cerebral artery occlusion (MCAO) model of brain ischemia was used to induce brain infarction. Resveratrol (10(-7) g/kg) was given twice intravenously: 15 min pre-occlusion and at the time of reperfusion (2 h post-occlusion). Resveratrol significantly restored ATP content and the activity of mitochondrial respiratory complexes in resveratrol treated group which were severely altered in MCAO group. Western blot analysis showed a marked decrease in cytochrome c release as a result of resveratrol treatment. Electrophoretic migration of hippocampal genomic DNA showed a marked decrease in DNA fragmentation after resveratrol treatment. Notably, expression of Hsp70 and metallothionein (MT) was significantly higher in MCAO group but their expression was more significant in resveratrol treated group. The status of mitochondrial glutathione (GSH), glucose 6-phosphate dehydrogenase (G6-PD) and serum lactate dehydrogenase (LDH) was restored by resveratrol treatment with a significant decrease in mitochondrial lipid peroxidation (LPO), protein carbonyl and intracellular H(2)O(2) content. Resveratrol significantly improved neurological deficits assessed by different scoring methods. Also, the brain infarct volume and brain edema were significantly reduced. Histological analysis of CA1 hippocampal region revealed that resveratrol treatment diminished intercellular and pericellular edema and glial cell infiltration. The findings of this study highlight the ability of resveratrol in anatomical and functional preservation of ischemic neurovascular units and its relevance in the treatment of ischemic stroke.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Brain Ischemia; Cell Death; Cytochromes c; DNA Fragmentation; Glucosephosphate Dehydrogenase; Glutathione; Hippocampus; HSP70 Heat-Shock Proteins; Hydrogen Peroxide; Infarction, Middle Cerebral Artery; Lactate Dehydrogenases; Lipid Peroxidation; Male; Metallothionein; Mitochondria; Neuroprotective Agents; Protein Carbonylation; Rats; Rats, Wistar; Resveratrol; Stilbenes

Neurons require large amounts of energy to support their survival and function, and are therefore susceptible to excitotoxicity, a form of cell death involving bioenergetic stress that may occur in several neurological disorders including stroke and Alzheimer's disease. Here we studied the roles of NAD(+) bioenergetic state, and the NAD(+)-dependent enzymes SIRT1 and PARP-1, in excitotoxic neuronal death in cultured neurons and in a mouse model of focal ischemic stroke. Excitotoxic activation of NMDA receptors induced a rapid decrease of cellular NAD(P)H levels and mitochondrial membrane potential. Decreased NAD(+) levels and poly (ADP-ribose) polymer (PAR) accumulation in nuclei were relatively early events (<4 h) that preceded the appearance of propidium iodide- and TUNEL-positive cells (markers of necrotic cell death and DNA strand breakage, respectively) which became evident by 6 h. Nicotinamide, an NAD(+) precursor and an inhibitor of SIRT1 and PARP1, inhibited SIRT1 deacetylase activity without affecting SIRT1 protein levels. NAD(+) levels were preserved and PAR accumulation and neuronal death induced by excitotoxic insults were attenuated in nicotinamide-treated cells. Treatment of neurons with the SIRT1 activator resveratrol did not protect them from glutamate/NMDA-induced NAD(+) depletion and death. In a mouse model of focal cerebral ischemic stroke, NAD(+) levels were decreased in both the contralateral and ipsilateral cortex 6 h after the onset of ischemia. Stroke resulted in dynamic changes of SIRT1 protein and activity levels which varied among brain regions. Administration of nicotinamide (200 mg/kg, i.p.) up to 1 h after the onset of ischemia elevated brain NAD(+) levels and reduced ischemic infarct size. Our findings demonstrate that the NAD(+) bioenergetic state is critical in determining whether neurons live or die in excitotoxic and ischemic conditions, and suggest a potential therapeutic benefit in stroke of agents that preserve cellular NAD(+) levels. Our data further suggest that, SIRT1 is linked to bioenergetic state and stress responses in neurons, and that under conditions of reduced cellular energy levels SIRT1 enzyme activity may consume sufficient NAD(+) to nullify any cell survival-promoting effects of its deacetylase action on protein substrates.

Topics: Animals; Antioxidants; Brain Ischemia; Cell Death; Cells, Cultured; Male; Mice; Mice, Inbred C57BL; NAD; Neurons; Neuroprotective Agents; Neurotoxins; Niacinamide; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

Resveratrol is a natural polyphenol found in grapes and wine and has been associated with protective effects against cardiovascular diseases. In vitro, both resveratrol preconditioning (RPC) and ischemic preconditioning (IPC) require activation of sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, to induce neuroprotection against cerebral ischemia. In the present study, we tested two hypotheses: (a) that neuroprotection against cerebral ischemia can be induced by RPC in vivo; and (b) that RPC neuroprotection involves alterations in mitochondrial function via the SIRT1 target mitochondrial uncoupling protein 2 (UCP2). IPC was induced by 2 min of global ischemia (temporary bilateral carotid artery occlusion with hypotension), and RPC, by i.p. injection of resveratrol at 10, 50 and 100 mg/kg dosages. Forty-eight hours later, we compared the neuroprotective efficacy of RPC and IPC in vulnerable cornu ammonis 1 hippocampal pyramidal neurons using a rat model of asphyxial cardiac arrest (ACA). SIRT1 activity was measured using a SIRT1-specific fluorescent enzyme activity assay. In hippocampal mitochondria isolated 48 h after IPC or RPC, we measured UCP2 levels, membrane potential, respiration, and the mitochondrial ATP synthesis efficiency (ADP/O ratio). Both IPC and RPC induced tolerance against brain injury induced by cardiac arrest in this in vivo model. IPC increased SIRT1 activity at 48 h, while RPC increased SIRT1 activity at 1 h but not 48 h after treatment in hippocampus. Resveratrol significantly decreased UCP2 levels by 35% compared to sham-treated rats. The SIRT1-specific inhibitor sirtinol abolished the neuroprotection afforded by RPC and the decrease in UCP2 levels. Finally, RPC significantly increased the ADP/O ratio in hippocampal mitochondria reflecting enhanced ATP synthesis efficiency. In conclusion, in vivo resveratrol pretreatment confers neuroprotection similar to IPC via the SIRT1-UCP2 pathway.

Topics: Adenosine Triphosphate; Animals; Asphyxia; Benzamides; Brain Ischemia; Carotid Artery Diseases; Disease Models, Animal; Heart Arrest; Hippocampus; Hypotension; Ion Channels; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Proteins; Naphthols; Neuroprotective Agents; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Respiration; Resveratrol; Signal Transduction; Sirtuin 1; Sirtuins; Stilbenes; Uncoupling Protein 2

Resveratrol, a natural polyphenolic compound, is found in a few edible materials and is well known for its phytoestrogenic and antioxidant properties. A growing body of in vivo and in vitro evidence indicates that resveratrol has protective effect on cerebral ischemic stroke. Here, we review the effect of resveratrol on cerebral ischemic stroke, and propose a possible mechanism. During acute phases after stroke, resveratrol preconditioning suppresses matrix metalloprotease-9 activity to ameliorate blood-brain barrier disruption, edema formation and neuronal cell death caused by ischemia and reperfusion. But during delayed phases after stroke, resveratrol preconditioning conduces to cerebral angiogenesis and brain regeneration through increasing matrix metalloprotease-9 activity and expression. Resveratrol's effect on matrix metalloprotease-9 is distinguishing in different phases because of temporal and spatial redistribution of matrix metalloprotease-9 within the cells of the neurovascular unit after cerebral ischemia. This paper also hypothesizes that resveratrol treatment after cerebral ischemia might be beneficial for cerebral angiogenesis and brain regeneration during delayed phases after stroke.

Topics: Blood-Brain Barrier; Brain Ischemia; Humans; Matrix Metalloproteinase 9; Models, Neurological; Neovascularization, Pathologic; Resveratrol; Stilbenes; Vasodilator Agents

Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural phytoalexin found in grape skin, and has been suggested to be an antioxidant agent, an anticancer agent and a cardioprotective agent. In particular, recent experimental evidence has demonstrated that resveratrol exhibits neuroprotective effects in various assay systems. During the study on the resveratrol derivatives, we found that (4-methoxybenzylidene)-(3-methoxyphenyl)amine (MBMPA), which has blocked free phenolic groups, strongly protects neuronal cells against ischemic damage on a higher activity than resveratrol. The MBMPA potently reduced the level of neuronal cell death in an oxygen and glucose deprivation-exposed rat organotypic hippocampal slice culture. In addition, ATP depletion following the onset of oxygen and glucose deprivation in an adult hippocampal slice was blocked by the MBMPA treatment. These results suggest that MBMPA has a neuroprotective effect on an in vitro ischemia model, and may be useful for treating stroke.

Topics: Adenosine Triphosphate; Aniline Compounds; Animals; Benzyl Compounds; Brain Ischemia; Cell Hypoxia; Cell Survival; Dose-Response Relationship, Drug; Glucose; Hippocampus; Neurons; Neuroprotective Agents; Organ Culture Techniques; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Topics: Angiogenesis Inhibitors; Animals; Brain; Brain Ischemia; Humans; Models, Cardiovascular; Models, Neurological; Neovascularization, Physiologic; Reperfusion Injury; Resveratrol; Stilbenes

Topics: Animals; Antioxidants; Brain Ischemia; DNA, Mitochondrial; Flavonoids; Humans; Hypoxia; Mice; Mitochondria; Models, Biological; Phenols; Polyphenols; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Stilbenes; Stroke

Our prior study showed that resveratrol could suppress infarct volume and exert neuroprotective effect on rats subjected to focal cerebral ischemia (FCI) injury. Recently, it has been reported in some literature that resveratrol protects the spinal cord, kidney, and heart from ischemia-reperfusion injury through upregulation of nitric oxide (NO). Therefore, this study was designed to investigate the role of nitric oxide on the neuroprotective mechanisms of resveratrol on rats after FCI injury.. The FCI injury was induced by the middle cerebral artery (MCA) occlusion for 1 hour and then a 24-hour reperfusion followed in the anesthetized Long-Evans rats. Resveratrol was intravenously injected after 1 hour MCA occlusion.. Treatment of resveratrol (0.1 and 1 microg/kg) decreased the lactate dehydrogenase (LDH) in plasma and malondialdehyde (MDA) in FCI injury brain tissue, whereas the level of NO in plasma was increased. In addition, resveratrol downregulated protein and mRNA expression of inducible nitric oxide synthase (iNOS), and upregulated protein and mRNA expression of endothelial nitric oxide synthase (eNOS), while the expression of protein and mRNA of neuronal nitric oxide synthase (nNOS) was unchanged. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, the nonselective NOS inhibitor) or L-N(5)-(1-iminoethyl)-ornithine (L-NIO, the eNOS selective inhibitor) completely blocked the effect of resveratrol in decreasing infarction volumes.. This study demonstrated the important role of NO in the neuroprotective effect of resveratrol in FCI injury.

Topics: Animals; Brain; Brain Ischemia; Carotid Arteries; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Infarction, Middle Cerebral Artery; L-Lactate Dehydrogenase; Ligation; Male; Malondialdehyde; Middle Cerebral Artery; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Ornithine; Rats; Rats, Long-Evans; Resveratrol; RNA, Messenger; Stilbenes; Up-Regulation

To investigate the protective effects of resveratrol on inflammatory process induced by focal cerebral ischemia-reperfusion in rats.. Rats were pretreated with resvreratrol at the dose of 10, 20, 40 mg kg(-1) for 7 days and then subjected to cerebral ischemia/reperfusion induced by a middle cerebral artery occlusion (MCAO). The infarct volume and the neurological deficit were determined by the method of TTC (2, 3, 5-triphenylterazolium chloride) staining and Longa's score. The permeability of blood-brain barrier (BBB) was evaluated by measurement of the evans blue (EB) content in the brain with spectrophotometer. The content of interleukin-lbeta, interleukin-6 (IL-6, IL-1beta) in serum and tumor necrosis factor-alpha (TNF-alpha), myeloperoxidase (MPO) in brain were determined by radio-immunoassay and ELISA assay.. Resveratrol reduced infarct volume, ameliorated the neurological deficit and the permeability of BBB, the content of IL-6, IL-1beta in serum and TNF-alpha, MPO activity in brain tissue also were significantly decreased.. These results showed that resveratrol had protective effects on cerebral injury by inhibiting the releasing of the inflammatory mediators after ischemia/reperfusion injury.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Ischemia; Infarction, Middle Cerebral Artery; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Male; Neuroprotective Agents; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Resveratrol is a natural phytoestrogen and possesses many biological functions such as anti-inflammatory activity and protection against atherosclerosis and myocardial infraction. The present study was carried out to elucidate the neuroprotective effect and possible mechanism of resveratrol on cerebral ischemia-induced hippocampus neuron loss. Sixty adult male rats underwent general anesthesia (urethane, 1.4 g/kg, i.p.) and were divided into three groups: sham operation, ischemia treatment, and ischemia combined with resveratrol administration (20 mg/kg, i.v.). The carotid artery was bilaterally ligated to induce cerebral ischemia. Microdialysis and high-performance liquid chromatography were used to analyze dihydroxybenzoic acid (DHBA) that reflected the hippocampal hydroxyl radical level. Hippocampal nitric oxide was assayed among different groups. During cerebral ischemia, the hydroxyl radical levels were elevated in rats and animals displayed severe neuronal loss. A single dose of resveratrol significantly increased the nitric oxide level and decreased the hydroxyl radical level. The reduction of cerebral blood flow and neuronal loss were also attenuated by resveratrol treatment. The results demonstrated that a single infusion of resveratrol could elicit neuroprotective effects on cerebral ischemia-induced neuron damage through free radical scavenging and cerebral blood elevation due to NO release.

Topics: Animals; Blood Pressure; Brain Ischemia; Free Radical Scavengers; Heart Rate; Hippocampus; Male; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase

Neuronal death associated with cerebral ischemia and hypoglycemia is related to increased release of excitatory amino acids (EAA) and energy failure. The intrahippocampal administration of the glycolysis inhibitor, iodoacetate (IOA), induces the accumulation of EAA and neuronal death. We have investigated by microdialysis the role of exocytosis, glutamate transporters and volume-sensitive organic anion channel (VSOAC) on IOA-induced EAA release. Results show that the early component of EAA release is inhibited by riluzole, a voltage-dependent sodium channel blocker, and by the VSOAC blocker, tamoxifen, while the early and late components are blocked by the glutamate transport inhibitors, L-trans-pyrrolidine 2,4-dicarboxylate (PDC) and DL-threo-beta-benzyloxyaspartate (DL-TBOA); and by the VSOAC blocker 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS). Riluzole, DL-TBOA and tamoxifen did not prevent IOA-induced neuronal death, while PDC and DNDS did. The VSOAC blockers 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) and phloretin had no effect either on EAA efflux or neuronal damage. Results suggest that acute inhibition of glycolytic metabolism promotes the accumulation of EAA by exocytosis, impairment or reverse action of glutamate transporters and activation of a DNDS-sensitive mechanism. The latest is substantially involved in the triggering of neuronal death. To our knowledge, this is the first study to show protection of neuronal death by DNDS in an in vivo model of neuronal damage, associated with deficient energy metabolism and EAA release, two conditions involved in some pathological states such as ischemia and hypoglycemia.

Topics: Animals; Aspartic Acid; Brain Ischemia; Cell Death; Energy Metabolism; Excitatory Amino Acids; Exocytosis; Extracellular Fluid; Glycolysis; Hippocampus; Male; Microdialysis; Nerve Degeneration; Nitrobenzoates; Phloretin; Rats; Rats, Wistar; Riluzole; Stilbenes; Tamoxifen; Vesicular Glutamate Transport Proteins; Voltage-Dependent Anion Channels

Zinc neurotoxicity has been demonstrated in ischemic, seizure, hypoglycemic, and trauma-induced neuronal death where Zn(2+) is thought to be synaptically released and taken up in neighbouring neurons, reaching toxic concentrations. We previously demonstrated that toxicity of extracellular Zn(2+) depended on entry, elevation in intracellular free Zn(2+) ([Zn(2+)](i)), a reduction in NAD(+) and ATP levels, and dysfunction of glycolysis and cellular metabolism. We suggested that PARP-1 activation alone can not explain this loss of neuronal NAD(+). NAD(+) was recently demonstrated to permeate neurons and glia, and we have now shown that exogenous NAD(+) can reduce Zn(2+) neurotoxicity, and 3-acetylpyridine, which generates inactive NAD(+), potentiated Zn(2+) neurotoxicity. Sirtinol and 2-hydroxynaphthaldehyde, inhibitors of the sirtuin pathway (SIRT proteins are NAD(+)-catabolic protein deacetylases), attenuated both acute and chronic Zn(2+) neurotoxicity. Resveratrol and fisetin (sirtuin activators) potentiated NAD(+) loss and Zn(2+) neurotoxicities. Furthermore, neuronal cultures derived from the Wld(s) mouse, which overexpress the NAD(+) synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT-1), had reduced sensitivity to Zn(2+) neurotoxicity. Finally, nicotinamide was demonstrated to attenuate CA1 neuronal death after 10 min of global ischemia in rat even if administered 1 h after the insult. Together with previous data, these results further implicate NAD(+) levels in Zn(2+) neurotoxicity.

Topics: Aldehydes; Animals; Antioxidants; Brain Ischemia; Cells, Cultured; Flavonoids; Flavonols; Ion Channels; Male; Mitochondria; NAD; Naphthalenes; Neural Conduction; Neurotoxicity Syndromes; Neurotoxins; Niacinamide; Pyridines; Rats; Rats, Long-Evans; Resveratrol; Signal Transduction; Sirtuins; Stilbenes; Transcriptional Activation; Zinc

Oxidative stress is one of the major pathological factors in the cascade that leads to cell death in cerebral ischemia. Here, we investigated the neuroprotective effect of a naturally occurring antioxidant, oxyresveratrol, to reduce brain injury after cerebral stroke. We used the transient rat middle cerebral artery occlusion (MCAO) model of brain ischemia to induce a defined brain infarction. Oxyresveratrol was given twice intraperitoneally: immediately after occlusion and at the time of reperfusion. Oxyresveratrol (10 or 20 mg/kg) significantly reduced the brain infarct volume by approximately 54% and 63%, respectively, when compared to vehicle-treated MCAO rats. Also, the neurological deficits as assessed by different scoring methods improved in oxyresveratrol-treated MCAO rats. Histological analysis of apoptotic markers in the ischemic brain area revealed that oxyresveratrol treatment diminished cytochrome c release and decreased caspase-3 activation in MCAO rats. Also, staining for apoptotic DNA showed that the number of apoptotic nuclei in ischemic brain was reduced after oxyresveratrol treatment as compared to the vehicle-treated MCAO rats. This dose-dependent neuroprotective effect of oxyresveratrol in an in vivo stroke model demonstrates that this drug may prove to be beneficial for a therapeutic strategy to limit brain injury in acute brain ischemia.

Topics: Analysis of Variance; Animals; Brain Ischemia; Cell Death; Cerebral Cortex; Cerebral Infarction; Cytochromes c; Disease Models, Animal; DNA Fragmentation; Dose-Response Relationship, Drug; Epoprostenol; Immunohistochemistry; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Microtubule-Associated Proteins; Mitochondria; Neurologic Examination; Neurons; Neuroprotective Agents; Phosphopyruvate Hydratase; Plant Extracts; Rats; Rats, Wistar; Stilbenes; Time Factors

To study the effect of resveratrol on cerebral infarct volume, cerebral edema as well as the expression of nuclear fac for (NF-kappaB) p65 in the experimental permanent middle cerebral artery occlusion.. A middle cerebral artery occlusion model was constructed in 20 Wistar rats with Longa's method. Then the 20 rats were divided into 4 groups: control group, and 3 resveratrol groups (resveratrol of the concentrations of 10(-8) g/kg, 10(-7) g/kg, and 10(-6) g/kg were injected intravenously) (group 1- 4). The area of infarct was examined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The water content was calculated by dry and wet weight method. The expression of NF-kappaB p65 was investigated with immunohistochemistry.. The ischemic volume was 241 +/- 36, 222 +/- 39, 126 +/- 16, and 128 +/- 19 * in the groups 1 - 4 respectively, and the volume ratio was 0.49 +/- 0.04, 0.47 +/- 0.04, 27 +/- 0.02, and 0.43 +/- 0.02 respectively. The brain water content was 83.5% +/- 1.5%, 82.9% +/- 1.4%, 79.5% +/- 1.5%, and 79.9% +/- 1.4% in groups 1 - 4 with a significant difference between 10(-7) g/kg resveratrol group and pure ischemia group and 10(-6) g/kg resveratrol group and pure ischemia group (both P < 0.05). NF-kappaB p65 was not expressed in the normal control group and sham operation group, and was expressed 2 hours after pure ischemia. The expression of NF-kappaB p65 positive cells was the most significant 12 hours after the pure ischemia and began to decrease 24 hours after ischemia.. Resveratrol has a neuroprotective effect on the ischemic brain. This effect is related to the inhabitation of expression of NF-kappaB p65.

Topics: Animals; Brain Edema; Brain Ischemia; Male; Neuroprotective Agents; NF-kappa B; Rats; Rats, Wistar; Resveratrol; Stilbenes; Transcription Factor RelA

Increased oxidative stress has been implicated in the mechanisms of delayed neuronal cell death (DND) following cerebral ischemic insult. In this study, we investigated whether resveratrol, a polyphenolic antioxidant enriched in grape, may ameliorate ischemia-induced neuron cell death. Mongolian gerbils were divided into three groups, namely, sham control, ischemia and ischemia treated with resveratrol. Transient global cerebral ischemia was induced by occlusion of both common carotid arteries (CCA) for 5 min. Resveratrol was injected i.p. (30 mg/kg body weight), either during or shortly after CCA occlusion, and again at 24 h after ischemia. Cerebral blood flow was monitored before and during CCA occlusion using a laser Doppler flowmeter. Brain sections were immuno-stained for neurons, astrocytes and microglial cells. A time course study was also carried out to assess the bioavailability of resveratrol in serum, liver and brain using high performance liquid chromatography (HPLC). Morphometric measurements indicated extensive DND in the hippocampal CA1 region 4 days after ischemia and that neuron cell death was marked by the increase in reactive astrocytes and microglial cells. Administration of resveratrol, either during or after CCA occlusion, significantly (P<0.05) decreased DND as well as glial cell activation. Analysis of resveratrol after i.p. injection indicated its presence in serum, liver and brain with peak activity at 1, 4 and 4 h, respectively. This study demonstrated for the first time that resveratrol, a polyphenolic antioxidant, can cross the blood-brain barrier and exert protective effects against cerebral ischemic injury.

Topics: Animals; Brain Ischemia; Cell Death; Gerbillinae; Hippocampus; Male; Neuroglia; Neurons; Reperfusion Injury; Resveratrol; Stilbenes

Resveratrol is found in a wide variety of plant species. It is present in the seeds and skin of grapes and constitutes one of the major components of red wine. This study was undertaken to evaluate whether resveratrol could effectively suppress infarct size from the damaging effects of focal cerebral ischemia. The middle cerebral artery was occluded for 1 hr and 24 hr reperfusion in anesthetized Long-Evans rats. In pretreatment or treatment groups, resveratrol, at dosages of 10(-6), 10(-7), 10(-8) and 10(-9) g/kg, was intravenous injected 15 minutes before middle cerebral artery (MCA) occlusion or when the common carotid arteries clips were removed respectively. Pretreatment or treatment of resveratrol (10(-6), 10(-7), 10(-8) and 10(-9) g/kg) did not produce any changes in pH, blood gases, heart rate or mean arterial blood pressure, but it significantly reduced the total volume of infarction at the doses 10(-6) and 10(-7) g/kg. Our study suggests resveratrol is a potent neuroprotective agent in focal cerebral ischemia. Its beneficial effects may be related to its anti-platelet aggregation activity, vasodilating effect, antioxidant property or by all mechanisms together.

Topics: Animals; Blood Gas Analysis; Brain Ischemia; Dose-Response Relationship, Drug; Hemodynamics; Hydrogen-Ion Concentration; Infarction, Middle Cerebral Artery; Ligation; Male; Rats; Rats, Long-Evans; Resveratrol; Stilbenes; Vasodilator Agents

The antioxidant compound trans-resveratrol, is found in substantial amount in several types of red wine and is considered one of the substances responsible for the lower incidence of coronary heart diseases among regular consumers of such wines, an effect also known as the French paradox. It has also been proposed that resveratrol may have beneficial effects against neurodegenerative diseases. We report here that chronic administration of resveratrol to young-adult rats, significantly protects from the damage caused by systemic injection of the excitotoxin kainic acid, in the olfactory cortex and the hippocampus. The same treatment, however, is not able to give any significant protection in an ex vivo model of simulated ischemia on hippocampal slices in vitro. This first evidence of a partial neuroprotective action of chronic administration of resveratrol in vivo, suggests that other models of neurodegenerative injury, and in particular of excitotoxic brain damage, should be investigated in order to assess the potentiality for resveratrol to be used as a pharmacological tool for neuroprotection.

Topics: Animals; Antioxidants; Brain; Brain Ischemia; Excitatory Amino Acid Agonists; Glutamate Decarboxylase; Hippocampus; In Vitro Techniques; Kainic Acid; Male; Neuroprotective Agents; Olfactory Pathways; Rats; Rats, Wistar; Resveratrol; Stilbenes; Wine

Increased activation of excitatory amino acid (EAA) receptors is considered a major cause of neuronal damage. Possible sources and mechanisms of ischemia-induced EAA release were investigated pharmacologically with microdialysis probes placed bilaterally in rat striatum.. Forebrain ischemia was induced by bilateral carotid artery occlusion and controlled hypotension in halothane-anesthetized rats. During 30 minutes of ischemia, microdialysate concentrations of glutamate and aspartate were measured in the presence of a nontransportable blocker of the astrocytic glutamate transporter GLT-1, dihydrokinate (DHK), or an anion channel blocker, 4,4'-dinitrostilben-2,2'-disulfonic acid (DNDS), administered separately or together through the dialysis probe.. In control striata during ischemia, glutamate and aspartate concentrations increased 44+/-13 (mean+/-SEM) times and 19+/-5 times baseline, respectively, and returned to baseline values on reperfusion. DHK (1 mmol/L in perfusate; n=8) significantly attenuated EAA increases compared with control (glutamate peak, 9. 6+/-1.7 versus control, 15.4+/-2.6 pmol/ microL). EAA levels were similarly decreased by 10 mmol/L DHK. DNDS (1 mmol/L; n=5) also suppressed EAA peak increases (glutamate peak, 5.8+/-1.1 versus control, 10.1+/-0.7 pmol/ microL). At a higher concentration, DNDS (10 mmol/L; n=7) further reduced glutamate and aspartate release and also inhibited ischemia-induced taurine release. Together, 1 mmol/L DHK and 10 mmol/L DNDS (n=5) inhibited 83% of EAA release (glutamate peak, 2.7+/-0.7 versus control, 10.9+/-1.2 pmol/ microL).. These findings support the hypothesis that both cell swelling-induced release of EAAs and reversal of the astrocytic glutamate transporter are contributors to the ischemia-induced increases of extracellular EAAs in the striatum as measured by microdialysis.

Topics: Amino Acid Transport System X-AG; Animals; Aspartic Acid; ATP-Binding Cassette Transporters; Biological Transport; Blood Flow Velocity; Brain Ischemia; Cerebrovascular Circulation; Chromatography, High Pressure Liquid; Corpus Striatum; Drug Therapy, Combination; Glutamic Acid; Ion Pumps; Kainic Acid; Male; Microdialysis; Rats; Rats, Sprague-Dawley; Stilbenes