stilbenes and Stroke

Neurodegenerative diseases (NDDs) are one of the leading causes of death and disability in humans. From a mechanistic perspective, the complexity of pathophysiological mechanisms contributes to NDDs. Therefore, there is an urgency to provide novel multi-target agents towards the simultaneous modulation of dysregulated pathways against NDDs. Besides, their lack of effectiveness and associated side effects have contributed to the lack of conventional therapies as suitable therapeutic agents. Prevailing reports have introduced plant secondary metabolites as promising multi-target agents in combating NDDs. Polydatin is a natural phenolic compound, employing potential mechanisms in fighting NDDs. It is considered an auspicious phytochemical in modulating neuroinflammatory/apoptotic/autophagy/oxidative stress signaling mediators such as nuclear factor-κB (NF-κB), NF-E2-related factor 2 (Nrf2)/antioxidant response elements (ARE), matrix metalloproteinase (MMPs), interleukins (ILs), phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt), and the extracellular regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). Accordingly, polydatin potentially counteracts Alzheimer's disease, cognition/memory dysfunction, Parkinson's disease, brain/spinal cord injuries, ischemic stroke, and miscellaneous neuronal dysfunctionalities. The present study provides all of the neuroprotective mechanisms of polydatin in various NDDs. Additionally, the novel delivery systems of polydatin are provided regarding increasing its safety, solubility, bioavailability, and efficacy, as well as developing a long-lasting therapeutic concentration of polydatin in the central nervous system, possessing fewer side effects.

Topics: Animals; Cognition Disorders; Drug Delivery Systems; Glucosides; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Spinal Cord Injuries; Stilbenes; Stroke

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

Polyphenols have an important protective role against a number of diseases, such as atherosclerosis, brain dysfunction, stroke, cardiovascular diseases, and cancer. Cardiovascular diseases are the number one cause of death worldwide: more people die annually from cardiovascular diseases than from any other cause. The most important behavioural risk factors of heart disease and stroke are unhealthy diet, physical inactivity, tobacco use, and excess alcohol intake. The dietary consumption of polyphenols has shown to be inversely associated with morbidity and mortality by cardio- and cerebrovascular diseases. It is well-known that the protective effects of polyphenols

Topics: Animals; Diet; Humans; Nitric Oxide; Oxidative Stress; Oxidoreductases; Polyphenols; Protective Agents; Quercetin; Resveratrol; Stilbenes; Stroke

The search for molecules capable of restoring altered hippocampal plasticity in psychiatric and neurological conditions is one of the most important tasks of modern neuroscience. It is well established that neural plasticity, such as the ability of the postnatal hippocampus to continuously generate newly functional neurons throughout life, a process called adult hippocampal neurogenesis (AHN), can be modulated not only by pharmacological agents, physical exercise, and environmental enrichment, but also by "nutraceutical" agents. In this review we focus on resveratrol, a phenol and phytoalexin found in the skin of grapes and red berries, as well as in nuts. Resveratrol has been reported to have antioxidant and antitumor properties, but its effects as a neural plasticity inducer are still debated. The current review examines recent evidence implicating resveratrol in regulating hippocampal neural plasticity and in mitigating the effects of various disorders and diseases on this important brain structure. Overall, findings show that resveratrol can improve cognition and mood and enhance hippocampal plasticity and AHN; however, some studies report opposite effects, with resveratrol inhibiting aspects of AHN. Therefore, further investigation is needed to resolve these controversies before resveratrol can be established as a safe coadjuvant in preventing and treating neuropsychiatric conditions.

Topics: Aging; Animals; Disease Models, Animal; Fatigue; Hippocampus; Neurogenesis; Neuronal Plasticity; Resveratrol; Stilbenes; Stress, Physiological; Stroke

Resveratrol, a stilbene formed in many plants in response to various stressors, elicits multiple beneficial effects in vertebrates. Particularly, resveratrol was shown to have therapeutic properties in cancer, atherosclerosis and neurodegeneration. Resveratrol-induced benefits are modulated by multiple synergistic pathways that control oxidative stress, inflammation and cell death. Despite the lack of a definitive mechanism, both in vivo and in vitro studies suggest that resveratrol can induce a neuroprotective state when administered acutely or prior to experimental injury to the CNS. In this review, we discuss the neuroprotective potential of resveratrol in stroke, traumatic brain injury and spinal cord injury, with a focus on the molecular pathways responsible for this protection.

Topics: Animals; Antioxidants; Brain Injuries; Humans; Neuroprotection; Neuroprotective Agents; Resveratrol; Stilbenes; Stroke

Polyphenols are naturally occurring, synthetic or semisynthetic organic compounds that offer a vast array of advanced biomedical applications. The mostly researched polyphenolic compounds are resveratrol and flavanols, notably (-)-epicatechin. The ongoing research on clinically important resveratrol and flavanols has revealed their potentials as extremely efficient drug agents that can be leveraged for new therapeutic designs for combating stroke related injuries, cancer and renal failures. Here, we have highlighted recent developments in this area with an emphasis on the biomedical applications of polyphenols. Also, a perspective on the future research directions has been discussed. We believe that this review would facilitate further research and development of polyphenols as a therapeutic avenue in medical science.

Topics: Aging; Animals; Anti-Infective Agents; Antioxidants; Catechin; Food Hypersensitivity; Humans; Models, Biological; Neoplasms; Polyphenols; Renal Insufficiency; Resveratrol; Stilbenes; Stroke

Stroke is one of the most common cardiovascular diseases and is known as a leading cause of death in the world. Despite to its high prevalence, there are limited effective therapeutic strategies for stroke till now. However, oxidative stress plays an important role in the pathogenesis of stroke and therefore, antioxidant therapy could be used as a new therapeutic strategy. Among the antioxidants, some natural compounds are very interesting due to their low adverse effects. Resveratrol (3, 5, 4'-trihydroxystilbene) is a natural polyphenolic antioxidant found in grape skin, grape products, and peanuts as well as in red wine. In recent years, much attention has been paid to resveratrol due to its wide range of antioxidant actions. Resveratrol possesses cardioprotective actions through stimulation of nitric oxide production as well as antioxidative and anti-inflammatory effects. Here we review the available literatures on beneficial role of resveratrol on ischemic stroke. We also provide information about chemistry, sources, bioavailability, as well as clinical impacts of resveratrol.

Topics: Animals; Antioxidants; Biological Availability; Humans; Resveratrol; Stilbenes; Stroke

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

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Biological Availability; Brain; Disease Models, Animal; Drug Evaluation, Preclinical; Gerbillinae; Humans; Mice; Neuroprotective Agents; Oxidative Stress; Rats; Resveratrol; Stilbenes; Stroke

Excess production of reactive oxygen species in the brain has been implicated as a common underlying risk factor for the pathogenesis of a number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In recent years, there is considerable interest concerning investigation of antioxidative and anti-inflammatory effects of phenolic compounds from different botanical sources. In this review, we first describe oxidative mechanisms associated with stroke, AD, and PD, and subsequently, we place emphasis on recent studies implicating neuroprotective effects of resveratrol, a polyphenolic compound derived from grapes and red wine. These studies show that the beneficial effects of resveratrol are not only limited to its antioxidant and anti-inflammatory action but also include activation of sirtuin 1 (SIRT1) and vitagenes, which can prevent the deleterious effects triggered by oxidative stress. In fact, SIRT1 activation by resveratrol is gaining importance in the development of innovative treatment strategies for stroke and other neurodegenerative disorders. The goal here is to provide a better understanding of the mode of action of resveratrol and its possible use as a potential therapeutic agent to ameliorate stroke damage as well as other age-related neurodegenerative disorders.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Antioxidants; Cell Death; Humans; Inflammation; Neurodegenerative Diseases; Neuroglia; Neurons; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Resveratrol; Stilbenes; Stroke

Growing evidence from tissue culture, animal, and clinical models suggests that the flavonoid-rich fruits of the North American cranberry and blueberry (Vaccinium spp.) have the potential ability to limit the development and severity of certain cancers and vascular diseases including atherosclerosis, ischemic stroke, and neurodegenerative diseases of aging. The fruits contain a variety of phytochemicals that could contribute to these protective effects, including flavonoids such as anthocyanins, flavonols, and proanthocyanidins; substituted cinnamic acids and stilbenes; and triterpenoids such as ursolic acid and its esters. Cranberry and blueberry constituents are likely to act by mechanisms that counteract oxidative stress, decrease inflammation, and modulate macromolecular interactions and expression of genes associated with disease processes. The evidence suggests a potential role for dietary cranberry and blueberry in the prevention of cancer and vascular diseases, justifying further research to determine how the bioavailability and metabolism of berry phytonutrients influence their activity in vivo.

Topics: Animals; Anthocyanins; Anticarcinogenic Agents; Antioxidants; Atherosclerosis; Blueberry Plants; Flavonoids; Humans; Neoplasms; Phytotherapy; Proanthocyanidins; Stilbenes; Stroke; Triterpenes; Vaccinium macrocarpon; Vascular Diseases

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

Topics: Aging; Animals; Heart Diseases; Humans; Inflammation; Myocardial Infarction; Neoplasms; Protective Agents; Resveratrol; Stilbenes; Stroke

Topics: Arachis; Coronary Disease; Fatty Acids, Monounsaturated; Health Promotion; Humans; Menu Planning; Neoplasms; Phytosterols; Resveratrol; Stilbenes; Stroke

Although recombinant tissue plasminogen activator (r-tPA) is currently the most effective treatment for brain ischemic stroke, the 3-h narrow therapeutic windows severely limits its clinical efficacy. We aim to investigate the effect of resveratrol on improving treatment outcomes of delayed r-tPA administration.. Patients were randomly divided according to their onset-to-treatment time (OTT), as early OTT or delayed OTT. Then, they were either treated with r-tPA + placebo or with r-tPA + resveratrol. Twenty-four hours after the treatment, outcomes were assessed with NIH stroke scale (NIHSS), and plasma levels of MMP-2 and MMP-9 were also examined with ELISA.. In patients receiving delayed r-tPA treatment, co-administration of resveratrol significantly improves their treatment outcomes compared with those receiving placebo, as indicated by improved NIHSS scores. This improved outcome was be caused by resveratrol-induced reduction in plasma levels of both matrix metalloproteinase (MMP)-2 and MMP-9, as a positive correlation was observed between reductions in both MMPs and patient NIHSS scores.. Resveratrol could be potentially administered as an adjuvant with r-tPA treatment, which extends the clinical therapeutic window of r-tPA, therefore improving the outcome of patients receiving late stroke treatment.

Topics: Aged; Antioxidants; Female; Fibrinolytic Agents; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Resveratrol; Stilbenes; Stroke; Time Factors; Tissue Plasminogen Activator; Treatment Outcome

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

Vascular dysfunction is correlated to the incidence and severity of Alzheimer's disease. In a mouse model of Alzheimer's disease (APP/PS1) using in vivo, time-lapse, multiphoton microscopy, we found that occlusions of the microvasculature alter amyloid-beta (Aβ) plaques. We used several models of vascular injury that varied in severity. Femtosecond laser-induced occlusions in single capillaries generated a transient increase in small, cell-sized, Aβ deposits visualized with methoxy-X04, a label of fibrillar Aβ. After occlusions of penetrating arterioles, some plaques changed morphology, while others disappeared, and some new plaques appeared within a week after the lesion. Antibody labeling of Aβ revealed a transient increase in non-fibrillar Aβ one day after the occlusion that coincided with the disappearance of methoxy-X04-labeled plaques. Four days after the lesion, anti-Aβ labeling decreased and only remained in patches unlabeled by methoxy-X04 near microglia. Histology in two additional models, sparse embolic occlusions from intracarotid injections of beads and infarction from photothrombosis, demonstrated increased labeling intensity in plaques after injury. These results suggest that microvascular lesions can alter the deposition and clearance of Aβ and confirm that Aβ plaques are dynamic structures, complicating the interpretation of plaque burden as a marker of Alzheimer's disease progression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Arterioles; Female; Immunohistochemistry; Intracranial Thrombosis; Male; Mice; Mice, Transgenic; Microglia; Microscopy, Fluorescence, Multiphoton; Microvessels; Plaque, Amyloid; Stilbenes; Stroke

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

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA contributing to protect the blood-brain barrier (BBB) after stroke. We searched for small molecules that may up-regulate MALAT1 and focused on polydatin (PD), a natural product, as a possible candidate. PD enhanced MALAT1 gene expression in rat brain microvascular endothelial cells, reducing cell toxicity and apoptosis after oxygen and glucose deprivation (OGD). These effects correlated with reduction of inflammatory factors and enhancement of expression of BBB markers. We found opposite changes after MALAT1 silencing. We determined that C/EBPβ is a key transcription factor for PD-mediated MALAT1 expression. PPARγ activity is involved in MALAT1 protective effects through its coactivator PGC-1α and the transcription factor CREB. This suggests that PD activates the MALAT1/CREB/PGC-1α/PPARγ signaling pathway to protect endothelial cells against ischemia. PD administration to rats subjected to brain ischemia by transient middle cerebral artery occlusion (tMCAO) reduced cerebral infarct volume and brain inflammation, protected cerebrovascular endothelial cells and BBB integrity. These effects correlated with increased expression of MALAT1, C/EBPβ, and PGC-1α. Our results strongly suggest that the beneficial effects of PD involve the C/EBPβ/MALAT1/CREB/PGC-1α/PPARγ pathway, which may provide a novel therapeutic strategy for brain ischemic stroke.

Topics: Animals; Base Sequence; Blood-Brain Barrier; Brain; CCAAT-Enhancer-Binding Protein-beta; Cyclic AMP Response Element-Binding Protein; Glucosides; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Infarction, Middle Cerebral Artery; Microvessels; Models, Biological; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Rats, Sprague-Dawley; RNA, Long Noncoding; Stilbenes; Stroke; Time Factors

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

Topics: Acetylation; Animals; Bcl-2-Like Protein 11; Disease Models, Animal; Drug Synergism; Histone Deacetylase Inhibitors; Histones; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Promoter Regions, Genetic; Protein Binding; Resveratrol; Stilbenes; Stroke; Transcription Factor RelA; Valproic Acid

Stroke is a leading cause of mortality worldwide, as well as a source of long-term disabilities and huge socioeconomic costs. This study investigates the effects of resveratrol, an antioxidant supplement, on blood pressure, weight status, glucose, and lipid profile in patients who had a stroke in the last 12 months. Two hundred and twenty-eight patients were divided into three groups: group I received only allopathic treatment (control group), while groups II and III received allopathic treatment with a daily supplementation of oral resveratrol (100 and 200 mg, resp.) for 12 months. In all groups, the changes of the studied parameters were monitored at 6 and 12 months from the initial evaluation. In groups II and III, resveratrol induced significant changes (

Topics: Anti-Inflammatory Agents, Non-Steroidal; Dietary Supplements; Female; Humans; Male; Resveratrol; Stilbenes; Stroke

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

Dysfunction of energy metabolism can be a significant and fundamental pathophysiological basis for strokes. In studies of both humans and rodents, resveratrol, a natural polyphenol, has been reported to provide protection from cerebral ischemic injury by regulating expression of silent mating type information regulation 2 homolog 1 (SIRT1). However, direct evidence demonstrating that resveratrol exerts neuroprotection from cerebral ischemia injury by decreasing energy consumption is still lacking. Therefore, the aim of this study was to elucidate the mechanisms and signaling pathways through which resveratrol regulates energy metabolism in the ischemic brain, and to identify potential targets of resveratrol. ATP levels in brain tissues were detected by high performance liquid chromatography. SIRT1 and the phosphorylation of adenosine-monophosphate-activated protein kinase (P-AMPK) expressiones were evaluated by western blot. Levels of phosphodiesterase (PDEs) and cAMP were quantitated by real-time PCR and ELISA, respectively. Results showed that resveratrol significantly reduced the harmful effects of cerebral ischemic injury in vivo. Moreover, levels of ATP, p-AMPK, SIRT1, and cAMP were increased by resveratrol and PDE inhibitors. In conclusion, our findings indicate that resveratrol provides neuroprotection by inhibiting PDEs and regulating the cAMP/AMPK/SIRT1 pathway, which reduces ATP energy consumption during ischemia.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Brain; Brain Infarction; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation; Male; Neuroprotective Agents; Phosphoric Diester Hydrolases; Phosphorylation; Rats; Rats, Sprague-Dawley; Resveratrol; Rolipram; Signal Transduction; Sirtuin 1; Stilbenes; Stroke

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

Redox imbalance in the brain significantly contributes to ischemic stroke pathogenesis, but antioxidant therapies have failed in clinical trials. Activation of endogenous defense mechanisms may provide better protection against stroke-induced oxidative injury. TXNIP (thioredoxin-interacting protein) is an endogenous inhibitor of thioredoxin (TRX), a key antioxidant system. We hypothesize that TXNIP inhibition attenuates redox imbalance and inflammation and provides protection against a clinically relevant model of embolic stroke. Male TXNIP-knockout (TKO), wild-type (WT), and WT mice treated with a pharmacological inhibitor of TXNIP, resveratrol (RES; 5 mg/kg body weight), were subjected to embolic middle cerebral artery occlusion (eMCAO). Behavior outcomes were monitored using neurological deficits score and grip strength meter at 24 h after eMCAO. Expression of oxidative, inflammatory, and apoptotic markers was analyzed by Western blot, immunohistochemistry, and slot blot at 24 h post-eMCAO. Our result showed that ischemic injury increases TXNIP in WT mice and that RES inhibits TXNIP expression and protects the brain against ischemic damage. TKO and RES-treated mice exhibited a 39.26 and 41.11 % decrease in infarct size and improved neurological score and grip strength compared to WT mice after eMCAO. Furthermore, the levels of TRX, nitrotyrosine, NOD-like receptor protein (NLRP3), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and activations of caspase-1, caspase-3, and poly-ADP-ribose polymerase (PARP) were significantly (P < 0.05) attenuated in TKO and RES-treated mice. The present study suggests that TXNIP is contributing to acute ischemic stroke through redox imbalance and inflammasome activation and inhibition of TXNIP may provide a new target for therapeutic interventions. This study also affirms the importance of the antioxidant effect of RES on the TRX/TXNIP system.

Topics: Animals; Carrier Proteins; Drug Delivery Systems; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Resveratrol; Stilbenes; Stroke; Thioredoxins; Thromboembolism

Ischemic stroke is particularly susceptible to free radicals mediated secondary neuronal damage, especially mitochondrial dysfunction. Malibatol A (MA), a novel resveratrol oligomer, has shown potential antioxidant property in vitro. But little is known about its effect on central nervous system (CNS) in vivo. In the present study, the effect of MA was evaluated in focal cerebral ischemia induced by right middle cerebral artery occlusion (MCAO) in mice. MA at the dose of 20 mg/kg was administered by caudal-vein injection within 15 min after reperfusion. At 24 h after cerebral ischemia/reperfusion (I/R) injury, ameliorated neurological scores and reduced infarct volume was observed in MA treated group. Also, MA treatment restored the increased levels of reactive oxygen species (ROS), 3-Nitrotyrosine (3-NT), and 4-Hydroxynonenal (4-HNE) induced by MCAO. The activities of respiratory enzyme complex I, III and mitochondrial transmembrane potential (Δm) were effectively preserved compared with MCAO group through MA treatment. Western blot analysis showed a marked increase in Bcl-2 and decrease in Bax expression after MA treatment as compared with MCAO group. Moreover, MA treatment prevented release of cytochrome c from mitochondria into cytoplasm and blunted activities of caspase-9 and caspase-3. Collectively, the present study indicates that MA can ameliorate MCAO-induced mitochondrial dysfunction, and this might partially contribute to its protective effect on brain damage after 24 h of I/R injury.

Topics: Animals; Brain Injuries; Male; Mice; Mice, Inbred ICR; Mitochondria; Neuroprotective Agents; Stilbenes; Stroke

Resveratrol has been shown to mimic the beneficial effects of dietary restriction (DR). We previously reported that DR delays stroke onset and extends the lifespan in Stroke-Prone Spontaneously Hypertensive rats (SHRSP). Therefore, we examined whether resveratrol mimics DR and delays stroke onset in SHRSP.. Cerebrovascular endothelial cells (CVECs) from SHRSP were treated with resveratrol, and the inflammatory gene expression levels and NFκB protein levels were measured. In order to address the effects of resveratrol in vivo, SHRSP (male, 10 weeks of age) were fed an experimental diet containing several doses of resveratrol (0 - 0.05% (w/w)), after which we measured the plasma cytokine levels and examined the stroke onset and lifespan.. Treatment with resveratrol (100 μM, 24 hours) in CVECs from SHRSP significantly decreased the interleukin (IL)-1β-induced monocyte chemoattractant protein-1 (MCP-1) mRNA expression levels and p50 and p65 protein levels in the nuclear fraction. When the SHRSP were fed a diet containing resveratrol for one week, the resveratrol treatment did not affect the plasma lipid and glucose levels, body weight or weight of each tissue. Resveratrol slightly, but not significantly, decreased the plasma levels of IL-1β and MCP-1 compared with that observed in the control group. In addition, resveratrol decreased the IL-1β and MCP-1 mRNA expression levels in the brain versus the control animals. However, no doses of resveratrol delayed stroke onset or extended the lifespan in SHRSP.. In this study, resveratrol did not delay stroke onset in SHRSP, although it partially suppressed systemic and cerebral inflammation. These results suggest that resveratrol does not mimic the beneficial effects of DR on stroke in vivo.

Topics: Adenylate Kinase; Animals; Antioxidants; Blood Glucose; Blood Pressure; Body Weight; Cerebrovascular Circulation; Chemokine CCL2; Endothelial Cells; Inflammation; Interleukin-1beta; Male; Rats; Rats, Inbred SHR; Resveratrol; Signal Transduction; Stilbenes; Stroke

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

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

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

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

Resveratrol has a neuroprotective effect against cerebral ischemia. The objective of this study was to identify proteins that are differentially expressed in the cerebral cortex of vehicle- and resveratrol-treated animals during ischemic injury. Focal cerebral ischemia was induced as middle cerebral artery occlusion (MCAO) in male rats. Rats were treated with vehicle or resveratrol before MCAO, and cerebral cortex was collected 24 hr after MCAO. Cerebral cortex proteins were identified by two-dimensional gel electrophoresis and mass spectrometry. Several proteins were identified as differentially expressed between vehicle- and resveratrol-treated animals. Among these proteins, expression of peroxiredoxin-5, isocitrate dehydrogenase [NAD(+)], apolipoprotein A-I and ubiquitin carboxy terminal hydrolase L1 was decreased in the vehicle-treated group, whereas resveratrol attenuated the injury-induced decrease in expression of these proteins. However, expression of collapsing response mediator protein 2 was increased in the vehicle-treated group, whereas resveratrol prevented the injury-induced increase in the expression of this protein. These findings suggest that resveratrol modulates the expression of various proteins that associated with oxidative stress and energy metabolism in focal cerebral ischemia.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Male; Proteomics; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Stroke; Transcriptome

Polyphenol resveratrol (RSV) has been associated with Silent Information Regulator T1 (SIRT1) and AMP-activated protein kinase (AMPK) metabolic stress sensors and probably responds to the intracellular energy status. Our aim here was to investigate the neuroprotective effects of RSV and its association with SIRT1 and AMPK signaling in recurrent ischemia models. In this study, elderly male Wistar rats received a combination of two mild transient middle cerebral artery occlusions (tMCAOs) as an in vivo recurrent ischemic model. Primary cultured cortical neuronal cells subjected to combined oxygen-glucose deprivation (OGD) were used as an in vitro recurrent ischemic model. RSV administration significantly reduced infarct volumes, improved behavioral deficits and protected neuronal cells from cell death in recurrent ischemic stroke models in vivo and in vitro. RSV treatments significantly increased the intracellular NAD(+) /NADH ratio, AMPK and SIRT1 activities, decreased energy assumption and restored cell energy ATP level. SIRT1 and AMPK inhibitors and specific small interfering RNA (siRNA) for SIRT1 and AMPK significantly abrogated the neuroprotection induced by RSV. AMPK-siRNA and inhibitor decreased SIRT1 activities; however, SIRT1-siRNA and inhibitor had no impact on phospho-AMPK (p-AMPK) levels. These results indicated that the neuroprotective effects of RSV increased the intracellular NAD(+) /NADH ratio as well as AMPK and SIRT1 activities, thereby reducing energy ATP requirements during ischemia. SIRT1 is a downstream target of p-AMPK signaling induced by RSV in the recurrent ischemic stroke model.

Topics: Age Factors; AMP-Activated Protein Kinases; Animals; Cerebral Cortex; Diet; Energy Metabolism; Enzyme Inhibitors; Infarction, Middle Cerebral Artery; Male; NAD; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Resveratrol; RNA, Small Interfering; Signal Transduction; Sirtuin 1; Stilbenes; Stroke

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

Accumulating evidence shows that post-ischemic inflammation originated by Toll-like receptors (TLR) plays critical roles in ischemic stroke. However, the functions of other innate immune receptors are poorly understood in cerebral ischemia. Macrophage-inducible C-type lectin, Mincle, is one of the innate immune receptor C-type lectin-like receptor (CLR) to response against dying cells. In the present study, we showed that Mincle, its ligand SAP130, and its downstream phospho-Syk/Syk were upregulated after ischemia, and that Mincle is expressed in immune and non-immune cells in the ischemic brains of mice and human. We treated mice with piceatannol, a Syk inhibitor, and consequently the infarct volume and swelling were suppressed by piceatannol. The levels of phospho-Syk, MMP9 and ICAM-1 were downregulated, and the level of Claudin5 was uplegurated in piceatannol-treated groups. These data indicate that innate immune system, such as Mincle and Syk plays a pivotal role in the pathogenesis after the ischemia and reperfusion.

Topics: Animals; Brain; Down-Regulation; Humans; Immunity, Innate; In Vitro Techniques; Intercellular Adhesion Molecule-1; Intracellular Signaling Peptides and Proteins; Ischemia; Lectins, C-Type; Male; Matrix Metalloproteinase 9; Membrane Proteins; Mice; Protective Agents; Protein-Tyrosine Kinases; Stilbenes; Stroke; Syk Kinase; Up-Regulation

Resveratrol may be a powerful way of protecting the brain against a wide variety of stress and injury. Recently, it has been proposed that resveratrol not only reduces brain injury but also promotes recovery after stroke. But the underlying mechanisms are unclear. Here, we tested the hypothesis that resveratrol promotes angiogenesis in cerebral endothelial cells and dissected the signaling pathways involved. Treatment of cerebral endothelial cells with resveratrol promoted proliferation, migration, and tube formation in Matrigel assays. Consistent with these pro-angiogenic responses, resveratrol altered endothelial morphology resulting in cytoskeletal rearrangements of β-catenin and VE-cadherin. These effects of resveratrol were accompanied by activation of phosphoinositide 3 kinase (PI3-K)/Akt and Mitogen-Activated Protein Kinase (MAPK)/ERK signaling pathways that led to endothelial nitric oxide synthase upregulation and increased nitric oxide (NO) levels. Subsequently, elevated NO signaling increased vascular endothelial growth factor and matrix metalloproteinase levels. Sequential blockade of these signaling steps prevented resveratrol-induced angiogenesis in cerebral endothelial cells. These findings provide a mechanistic basis for the potential use of resveratrol as a candidate therapy to promote angiogenesis and neurovascular recovery after stroke.

Topics: Angiogenesis Inducing Agents; Anti-Inflammatory Agents, Non-Steroidal; Antigens, CD; Brain; Cadherins; Endothelial Cells; Humans; MAP Kinase Signaling System; Metalloproteases; Nitric Oxide; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Resveratrol; Stilbenes; Stroke; Vascular Endothelial Growth Factor A

Despite increased risk of a recurrent stroke following a minor stroke, information is minimal regarding the interaction between injurious mild cerebral ischemic episodes and the possible treatments which might be effective. The aim of the current study was to investigate recurrent ischemic stroke and whether resveratrol, a nutritive polyphenol with promising cardio- and neuro- protective properties, could ameliorate the associated brain damage. Experiments in adult rats demonstrated that a mild ischemic stroke followed by a second mild cerebral ischemia exacerbated brain damage, and, daily oral resveratrol treatment after the first ischemic insult reduced ischemic cell death with the recurrent insult (P<0.002). Further investigation demonstrated reduction of both inflammatory changes and markers of oxidative stress in resveratrol treated animals. The protection observed with resveratrol treatment could not be explained by systemic effects of resveratrol treatment including effects either on blood pressure or body temperature measured telemetrically. Investigation of resveratrol effects on the blood-brain barrier in vivo demonstrated that resveratrol treatment reduced blood-brain barrier disruption and edema following recurrent stroke without affecting regional cerebral blood flow. Investigation of the mechanism in primary cell culture studies demonstrated that resveratrol treatment significantly protected endothelial cells against an in vitro 'ischemia' resulting in improved viability against oxygen and glucose deprivation (39.6 ± 6.6% and 81.3 ± 9.5% in vehicle and resveratrol treated cells, respectively). An inhibition of nitric oxide synthesis did not prevent the improved cell viability following oxygen glucose deprivation but SIRT-1 inhibition with sirtinol partially blocked the protection (P<0.001) suggesting endothelial protection is to some extent SIRT-1 dependent. Collectively, the results support that oral resveratrol treatment provides a low risk strategy to protect the brain from enhanced damage produced by recurrent stroke which is mediated in part by a protective effect of resveratrol on the endothelium of the cerebrovasculature.

Topics: Administration, Oral; Animals; Biomarkers; Blood Gas Analysis; Blood Pressure; Blood-Brain Barrier; Body Temperature; Brain; Cell Death; Cell Hypoxia; Cerebrovascular Circulation; Endothelial Cells; Endothelium, Vascular; Glucose; Heart Rate; Inflammation; Liver; Nitrosation; Oxidation-Reduction; Oxygen; Rats; Recurrence; Resveratrol; Stilbenes; Stress, Physiological; Stroke; Treatment Outcome

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

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

It has been reported recently that resveratrol preconditioning can protect the brain from ischemia-reperfusion injury. However, it was unclear whether resveratrol administration after stroke was beneficial to the delayed phases after focal cerebral ischemia injury. This study investigated the effects and possible protective mechanism of resveratrol on the delayed phase after focal cerebral ischemia injury in mice.. Mice were randomly assigned to five groups according to the time of administration of resveratrol. Control group mice received a corresponding volume of saline solution (0.9% NaCl) containing 20% hydroxypropyl h-cyclodextrin by gavage and were exposed to middle cerebral artery (MCA) occlusion and reperfusion injury. The treatment groups received resveratrol (50 mg/kg/d, gavage) until day 7. Ischemia group mice received their first dose 5 minutes before MCA ischemia, reperfusion group mice received their first dose 5 minutes before MCA reperfusion, first-day, group mice received their first dose 24 hours after MCA reperfusion, and third-day group mice received their first dose at 72 hours after MCA reperfusion. Brain injury was evaluated by triphenyltetrazolium chloride staining and neurologic examination 7 days after reperfusion. The microvascular cell number was examined with immunohistochemistry staining. Effect of resveratrol on matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) gene expression was investigated with reverse transcriptase-polymerase chain reaction and Western blot.. The mean neurologic scores and infarct volumes of the ischemia and reperfusion groups were lower than that of the control group at 7 days after MCA reperfusion (P < .05). Immunohistochemistry staining showed significantly less reduction in the number of microvessels in the cortical area of mice of the ischemia and reperfusion groups compared with controls. The ischemic hemispheres of the ischemia and reperfusion groups showed significantly (P < .05) elevated levels of protein of MMP-2 and VEGF.. Resveratrol administration by gavage provided an important neuroprotective effect on focal cerebral ischemic injury in the delayed phase. The elevated MMP-2 and VEGF levels might be important in the neuroprotective effect of resveratrol administration by inducing angiogenesis.

Topics: Angiogenic Proteins; Animals; Blotting, Western; Brain; Coloring Agents; Disease Models, Animal; Drug Administration Schedule; Immunohistochemistry; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred BALB C; Microcirculation; Motor Activity; Neovascularization, Physiologic; Neuroprotective Agents; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Stroke; Tetrazolium Salts; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A

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

Stroke is one of the leading causes of mortality; however, its treatment remains obscure and largely empirical. Since matrix metalloproteinase 9 (MMP-9) has been postulated to be the major contributor of neuronal injury during reperfusion, inhibition of MMP-9 could be a potential approach in maintaining the viability of neurons. Trans-resveratrol (resveratrol), a polyphenolic compound has recently been shown to have neuroprotective activity against cerebral ischemia. Therefore, the aim of the present study was to evaluate the effect of resveratrol on MMP-9 induced by cerebral ischemia-reperfusion in vivo. Male Balb/C mice were treated with resveratrol for 7 days (50 mg/kg, gavage). Thereafter, middle cerebral artery occlusion (MCAo) was performed for 2 h with the help of intraluminal thread. Drug-treated mice showed improvement in necrotic changes in cortex and basal ganglia. Detection of MMP-9 activity and gene expression was performed at various time points after MCAo. The elevated levels of MMP-9 were significantly attenuated in the resveratrol-treated mice as compared to the vehicle MCAo mice. The study suggests that resveratrol has protective effects against acute ischemic stroke, which could be attributed to its property against MMP-9. Thus, resveratrol may be a potential agent for the treatment of neuronal injury associated with stroke.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cerebral Cortex; Disease Models, Animal; Gene Expression; Ischemic Attack, Transient; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Stroke

Topics: Alcohol Drinking; Animals; Antioxidants; Arteriosclerosis; Cohort Studies; Cricetinae; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Flavonoids; Follow-Up Studies; Gene Expression Regulation; Humans; Male; Middle Aged; Myocardial Infarction; Phenols; Phytotherapy; Polyphenols; Rabbits; Resveratrol; Risk; Stilbenes; Stroke; Wine

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors which belong to the nuclear receptor family. We examined whether PPARalpha agonists and resveratrol, a polyphenol contained in grapes, protect the brain against ischemia. To investigate whether resveratrol activates PPARs, we performed a cell-based transfection activity assay using luciferase reporter plasmid. PPARalpha and PPARgamma were activated by resveratrol in primary cortical cultures and vascular endothelial cells. Resveratrol (20 mg/kg, 3 days) reduced infarct volume by 36% at 24 h after middle cerebral artery occlusion in wild-type mice. The PPARalpha agonists fenofibrate (30 mg/kg, 3 days) and Wy-14643 (30 mg/kg, days) exerted similar brain protection. However, resveratrol and fenofibrate failed to protect the brain in PPARalpha knockout mice. The data indicate that PPARalpha agonists protect the brain through PPARalpha.

Topics: Animals; Brain; Cattle; Dose-Response Relationship, Drug; Fenofibrate; Haplorhini; Humans; Mice; Mice, Knockout; Receptors, Cytoplasmic and Nuclear; Resveratrol; Stilbenes; Stroke; Transcription Factors

Free radicals have been implicated in neuronal injury during ischemia reperfusion in stroke. Trans resveratrol, a potent antioxidant, polyphenolic compound found in grapes and wines has recently been shown to have neuroprotective activity against oxidative stress in in vitro studies. In the present study the effect of chronic treatment of trans resveratrol was evaluated in focal ischemia induced by middle cerebral artery [MCA] occlusion in rats. Male Wistar rats were pretreated with trans resveratrol 20 mg/kg i.p. for 21 days and were subjected to focal ischemia by occlusion of MCA using intraluminal thread. After two hours of MCA occlusion reperfusion was allowed by retracting the thread. Animals were assessed for motor performance after 24 hours and subsequently rats were sacrificed for estimation of markers of oxidative stress [malondialdehyde [MDA] and reduced glutathione] and for evaluation of volume of infarction. Control group received vehicle and similar protocol was followed. Significant motor impairment, with elevated levels of MDA and reduced glutathione was observed in the vehicle treated MCA occluded rats. Treatment with trans resveratrol prevented motor impairment, rise in levels of MDA and reduced glutathione and also significantly decreased the volume of infarct as compared to control. The study provides first evidence of effectiveness of trans resveratrol in focal ischemia most probably by virtue of its antioxidant property.

Topics: Animals; Brain; Disease Models, Animal; Drug Administration Schedule; Free Radicals; Hand Strength; Ischemic Attack, Transient; Male; Malondialdehyde; Middle Cerebral Artery; Motor Activity; Muscle, Skeletal; Oxidative Stress; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Reference Values; Reperfusion Injury; Resveratrol; Stilbenes; Stroke; Time Factors

Advanced glycation end-products (AGEs) of plasma proteins and/or matrix proteins are candidate mediators for various vascular complications such as atherosclerosis. We previously reported a significantly larger accumulation of AGEs of the aorta in stroke-prone spontaneously hypertensive rats (SHRSP) than in age-matched Wistar-Kyoto rats (WKY). In this study, we examined the effects of AGEs on vascular smooth muscle cells (VSMC) from SHRSP and WKY rats. We also studied the in vitro effects of resveratrol (3, 4',5-trihydroxystilbene), a natural phytestrogen, on VSMC proliferation, DNA synthesis, and collagen synthesis activity in SHRSP-VSMC. AGEs accelerated the proliferation of SHRSP- or WKY-VSMC in a time- and dose-dependent manner. VSMC from SHRSP were more sensitive to AGEs than VSMC from normotensive WKY. AGEs also significantly increased DNA synthesis and prolyl hydroxylase activity, a marker for collagen synthesis, in SHRSP-VSMC. AGEs-induced increases in TGF-beta1 mRNA in SHRSP-VSMC were significantly greater than in WKY-VSMC. Resveratrol inhibited AGEs-stimulated proliferation, DNA synthesis, and prolyl hydroxylase activity in SHRSP-VSMC in a dose-dependent manner. ICI 182780, a specific estrogen receptor antagonist, partly blocked the inhibitory effects of resveratrol on AGEs-stimulated proliferation, DNA synthesis, and prolyl hydroxylase activity. Resveratrol significantly inhibited AGEs-induced TGF-beta1 mRNA increases in a dose-dependent manner. Thus, resveratrol may confer protective effects on the cardiovascular system by attenuating vascular remodeling and may be clinically useful as a safer substitute for feminizing estrogens in preventing cardiovascular disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Division; Cells, Cultured; Collagen; DNA; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Fulvestrant; Glycation End Products, Advanced; Male; Muscle, Smooth, Vascular; Polymerase Chain Reaction; Procollagen-Proline Dioxygenase; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Estrogen; Resveratrol; Stilbenes; Stroke; Time Factors; Transforming Growth Factor beta

A recent study demonstrated that reactive oxygen species (ROS) were involved in the maintenance of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). However, the role of oxidative stress in hypertension and its related diseases in SHRSP remains unknown. To determine whether phytoestrogens attenuate oxidative DNA damage in vascular smooth muscle cells (VSMC) from SHRSP and Wistar-Kyoto (WKY) rats, we investigated the effect of daidzein, genistein and resveratrol on oxidative DNA damage in VSMC, induced by advanced glycation end-products (AGEs).. VSMC were treated with AGEs in the presence or absence of phytoestrogens for the indicated time. Cellular degeneration induced by AGEs was characterized in terms of intracellular oxidant levels, intracellular total glutathione (GSH) levels, mRNA expression for gamma-glutamylcysteine synthetase (GCS), and a new marker of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG) contents.. AGEs stimulated 8-OHdG formation in VSMC in a time- and dose-dependent manner. We also confirmed that VSMC from SHRSP were more vulnerable to oxidative stress induced by AGEs, than VSMC from WKY rats. Daidzein, genistein or resveratrol reduced AGEs-induced 8-OHdG formation in a dose-dependent manner. The preventive effects of phytoestrogens on 8-OHdG formation remarkably paralleled changes in the intracellular oxidant levels in VSMC following AGEs treatment. We further demonstrated that phytoestrogens increase intracellular total GSH level in VSMC. Increased GSH synthesis was due to enhanced expression of the rate-limiting enzyme for GSH synthesis, GCS. Phytoestrogens-stimulated total GSH level in VSMC could lead to decreased intracellular oxidant levels, and thus prevent oxidative DNA damage, induced by AGEs. The phytoestrogens are powerful antioxidants able to interfere with AGEs-mediated oxidative DNA damage of VSMC, and are potentially useful against vascular diseases where ROS are involved in hypertension.

Topics: Animals; Base Sequence; Cells, Cultured; DNA Damage; DNA Primers; Estrogens, Non-Steroidal; Genistein; Glutathione; Glutathione Peroxidase; Glycation End Products, Advanced; Hypertension; Isoflavones; Muscle, Smooth, Vascular; Oxidation-Reduction; Oxidative Stress; Phytoestrogens; Plant Preparations; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Resveratrol; RNA, Messenger; Stilbenes; Stroke