stilbenes and Encephalitis

Microglial cells play a dual role in the central nervous system as they have both neurotoxic and neuroprotective effects. Uncontrolled and excessive activation of microglia often contributes to inflammation-mediated neurodegeneration. Recently, much attention has been paid to therapeutic strategies aimed at inhibiting neurotoxic microglial activation. Pharmacological inhibitors of microglial activation are emerging as a result of such endeavors. In this review, natural products-based inhibitors of microglial activation will be reviewed. Potential neuroprotective activity of these compounds will also be discussed. Future works should focus on the discovery of novel drug targets that specifically mediate microglial neurotoxicity rather than neuroprotection. Development of new drugs based on these targets may require a better understanding of microglial biology and neuroinflammation at the molecular, cellular, and systems levels.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Benzyl Alcohols; Biological Products; Biphenyl Compounds; Catechin; Catechols; Curcumin; Encephalitis; Fatty Alcohols; Ginsenosides; Glucosides; Microglia; Molecular Structure; Nerve Degeneration; Neuroprotective Agents; Phenyl Ethers; Plant Extracts; Resveratrol; Stilbenes

The 'French Paradox' has been typically associated with moderate consumption of wine, especially red wine. A polyphenol 3,4',5-trihydroxy-trans-stilbene (a member of the non-flavonoids family), better known as resveratrol, has been purported to have many health benefits. A number of these valuable properties have been attributed to its intrinsic antioxidant capabilities, although the potential level of resveratrol in the circulation is likely not enough to neutralize free radical scavenging. The brain and the heart are uniquely vulnerable to hypoxic conditions and oxidative stress injuries. Recently, evidence suggests that resveratrol could act as a signaling molecule within tissues and cells to modulate the expression of genes and proteins. Stimulation of such proteins and enzymes could explain some the intracellular antioxidative properties. The modulation of genes could suffice as an explanation of some of resveratrol's cytoprotective actions, as well as its influence on blood flow, cell death, and inflammatory cascades. Resveratrol stimulation of the expression of heme oxygenase is one example. Increased heme oxygenase activity has led to significant protection against models of in vitro and in vivo oxidative stress injury. Resveratrol could provide cellular resistance against insults; although more work is necessary before it is prescribed as a potential prophylactic in models of either acute or chronic conditions, such as stroke, amyotrophic lateral sclerosis, Parkinson, Alzheimer, and a variety of age-related vascular disorders.

Topics: Animals; Antioxidants; Cerebrovascular Disorders; Encephalitis; Flavonoids; Gene Expression Regulation, Enzymologic; Heme Oxygenase (Decyclizing); Humans; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress; Phenols; Polyphenols; Resveratrol; Stilbenes

Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores.. For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples.. Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels.. Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders.. ClinicalTrials.gov NCT01504854.

Topics: Activities of Daily Living; Adaptive Immunity; Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CCL5; Cognition Disorders; Cytokines; Double-Blind Method; Encephalitis; Female; Fibroblast Growth Factor 2; Follow-Up Studies; Humans; Male; Matrix Metalloproteinase 9; Mental Status Schedule; Peptide Fragments; Resveratrol; Stilbenes; tau Proteins

Early brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms.. A total of 299 male Sprague-Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood-brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI.. We found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 ± 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices.. These results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment.

Topics: Adenine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Blood-Brain Barrier; Brain Edema; Carrier Proteins; Cell Cycle Proteins; Encephalitis; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Gene Expression Regulation; Indoles; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Small Interfering; Signal Transduction; Stilbenes; Subarachnoid Hemorrhage; Sulfonamides; Thiophenes

There is an urge to identify new molecules which can modulate process of epileptogenesis, since currently available drugs act symptomatically and one-third of the patients remain refractory to the disease. Hence, the present study was conducted to evaluate the effects of Resveratrol (RESV) on epileptogenesis in pentylenetetrazole (PTZ)-induced kindling in mice.. Swiss albino mice were administered RESV (10, 20 and 40 mg/kg,p.o) in acute study. On the seventh day animals were subjected to various neurological and neurobehavioral tests viz, Increasing Current Electroshock Test (ICES), PTZ-induced seizures, passive avoidance response, and elevated plus maze test. For the development of kindling PTZ was administered in a dose of 25 mg/kg, i.p. on every alternate day and RESV in all the three doses was administered daily. Seizure score was continuously monitored till the development of kindling and cognition tests were performed in the end of the study. The animals were sacrificed and levels of inflammatory biomarkers viz., IL-1β, interleukin-1 receptor antagonist (IL1-Ra), IL-6, and TNF-α were assessed in the hippocampus and cortex of the kindled animals.. RESV in all three doses increased the seizure threshold to hind limb extension in the ICES test. RESV in all the tested doses suppressed the development of kindling and reduced the levels of IL-1β, IL1-Ra, IL-6, and TNF-α in kindled mice.. RESV suppressed the development of kindling in mice and decreased the levels of inflammatory biomarkers in their hippocampus. RESV modified brain inflammation during epileptogenesis and found to possess nootropic activity in the kindled mice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antioxidants; Avoidance Learning; Cerebral Cortex; Convulsants; Dietary Supplements; Encephalitis; Female; Hippocampus; Inflammation Mediators; Kindling, Neurologic; Male; Maze Learning; Mice; Neurons; Neuroprotective Agents; Pentylenetetrazole; Random Allocation; Resveratrol; Seizures; Stilbenes

Experimental studies have demonstrated that aluminum is an environmental toxin that induces neuroinflammation and the development of Alzheimer's disease.. In this report, we investigated the beneficial effect of a combination of resveratrol and curcumin to reduce aluminum-induced neuroinflammation.. We employed both an in vivo model of aluminum-induced neuroinflammation and an in vitro aluminum stimulated cultured PC-12 cells. Neuroinflammation in rats was assessed by measuring the expression of β-secretase, amyloid-β protein precursor, and γ-subunits (PS-1 and PS-2), along with the inflammatory COX-2, Il-1β, Il-1α, and TNF-α. Furthermore, we measured the expression profiles of neuro-protective Apurinic/apyrimidinic endonuclease 1 (APE1) protein and let-7c microRNA. In parallel, PC-12 cells were treated with 0.5 mM aluminum to induce a neuroinflammation-like state. In addition, curcumin effect, as a selective COX-2 expression inhibitor, was detected in a time course manner.. An overall significant attenuation of the inflammatory markers, as well as a decrease in the amyloidogenic mediators, was observed in resveratrol-curcumin treated rats. The therapeutic effect was also confirmed by transmission electron microscopic analysis of the brain cortexes. APE1 was significantly induced by resveratrol-curcumin combination. Both in vivo and in vitro studies indicated that Let-7c expression is significantly reduced after aluminum stimulation, an effect that was partially suppressed by co-addition of either resveratrol or curcumin and totally restored to the normal level by their combination.. The present study clearly indicates the synergistic and therapeutic effect of a  resveratrol-curcumin combination. We also show that both compounds exert beneficial effect either cooperatively or through differential molecular mechanisms in counteracting aluminum-induced neuroinflammation.

Topics: Acetylcholinesterase; Aluminum Chloride; Aluminum Compounds; Animals; Brain; Catalase; Chlorides; Curcumin; Cyclooxygenase 2; Disease Models, Animal; Drug Combinations; Encephalitis; Glutathione Transferase; Lipid Peroxidation; Male; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase

Microglia are the primary cells that exert immune function in the central nervous system (CNS), and accumulating evidence suggests that microglia act as key players in the initiation of neurodegenerative diseases. It is now well recognized that microglia have functional plasticity and dual phenotypes, proinflammatory M1 and anti-inflammatory M2 phenotypes. Inhibiting the M1 phenotype while stimulating the M2 phenotype has been suggested as a potential therapeutic approach for the treatment of neuroinflammation-related diseases. Resveratrol has been demonstrated to exert anti-inflammatory effects by suppressing M1 microglia activation. However, the role of resveratrol in regulating microglia polarization and the molecular mechanisms involved have not been fully clarified. In this study, we tested whether resveratrol could suppress microglia activation by promoting microglia polarization toward the M2 phenotype via PGC-1α by measuring M1 and M2 markers in vitro and in vivo. Our study demonstrated that resveratrol reduced inflammatory damage and promoted microglia polarization to the M2 phenotype in LPS-induced neuroinflammation. In addition, resveratrol ameliorated LPS-induced sickness behavior in mice. The promoting effects of resveratrol on M2 polarization were attenuated by knocking down PGC-1α. PGC-1α not only suppressed LPS-evoked M1 marker expression by inhibition of NF-κB activity but also increased M2 marker expression by coactivation of the STAT6 and STAT3 pathways. We propose that overexpression PGC-1α by resveratrol could be a potential therapeutic approach to suppress neuroinflammation by regulating microglia polarization.

Topics: Animals; Cell Line, Tumor; Cell Polarity; Encephalitis; Humans; Mice; Microglia; Neuroprotective Agents; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; 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

Oxidative stress events have been implicated to occur and facilitate multiple failure modes of intracortical microelectrodes. The goal of the present study was to evaluate the ability of a sustained concentration of an anti-oxidant and to reduce oxidative stress-mediated neurodegeneration for the application of intracortical microelectrodes.. Non-functional microelectrodes were implanted into the cortex of male Sprague Dawley rats for up to sixteen weeks. Half of the animals received a daily intraperitoneal injection of the natural anti-oxidant resveratrol, at 30 mg kg(-1). The study was designed to investigate the biodistribution of the resveratrol, and the effects on neuroinflammation/neuroprotection following device implantation.. Daily maintenance of a sustained range of resveratrol throughout the implantation period resulted in fewer degenerating neurons in comparison to control animals at both two and sixteen weeks post implantation. Initial and chronic improvements in neuronal viability in resveratrol-dosed animals were correlated with significant reductions in local superoxide anion accumulation around the implanted device at two weeks after implantation. Controls, receiving only saline injections, were also found to have reduced amounts of accumulated superoxide anion locally and less neurodegeneration than controls at sixteen weeks post-implantation. Despite observed benefits, thread-like adhesions were found between the liver and diaphragm in resveratrol-dosed animals.. Overall, our chronic daily anti-oxidant dosing scheme resulted in improvements in neuronal viability surrounding implanted microelectrodes, which could result in improved device performance. However, due to the discovery of thread-like adhesions, further work is still required to optimize a chronic anti-oxidant dosing regime for the application of intracortical microelectrodes.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Chronic Disease; Electrodes, Implanted; Electroencephalography; Encephalitis; Injections, Intraperitoneal; Male; Microelectrodes; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Treatment Outcome

Chronic alcohol intake is known to induce permanent cognitive deficits along with enhanced oxidative-nitrosative stress and activation of neuroinflammatory cascade. In the present study, we investigated the protective effect of resveratrol, a natural polyphenolic phytoalexin against chronic alcohol-induced cognitive dysfunction and neuroiflammatory cascade in the brain of adult rats chronically administered ethanol. Male Wistar rats were adminstered ethanol (10g/kg; oral gavage) for ten weeks and treated with resveratrol (5, 10 and 20mg/kg) for the same duration. Ethanol-exposed rats showed impaired spatial navigation in the Morris water maze test and poor retention in the elevated plus maze task which was coupled with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, cytokines (TNF-alpha and IL-1beta), NF-kappa β and caspase-3 levels in different brain regions (cerebral cortex and hippocampus) of ethanol-treated rats. Co-administration with resveratrol significantly and dose-dependently prevented all the behavioral, biochemical and molecular deficits. Correlatively, the results of the present study revealed that treatment with resveratrol significantly prevented cognitive deficits induced by chronic ethanol exposure not only by modulating oxido-nitrosative stress but also by attenuating the enhanced levels of pro-inflammatory cytokines (TNF-α and IL-1β), NF-kβ and caspase-3 in different brain regions of ethanol treated rats. Therefore, mechanism underlying the neuroprotective effects of resveratrol observed in our study may be due to its antioxidant, anti-inflammatory and neuromodulating activities.

Topics: Acetylcholinesterase; Animals; Antioxidants; Anxiety; Catalase; Central Nervous System Depressants; Cognition Disorders; Encephalitis; Ethanol; Glutathione; Interleukin-1beta; Lipid Peroxidation; Male; Maze Learning; Memory; Motor Activity; NF-kappa B; Nitrites; Oxidative Stress; Rats; Rats, Wistar; Reactive Nitrogen Species; Resveratrol; Stilbenes; Stress, Physiological; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Resveratrol, a natural polyphenolic compound, has attracted considerable interest for its anti-inflammatory and neuroprotective properties. However, the biological effects of resveratrol appear strongly limited because it is photosensitive, easily oxidized, and has unfavorable pharmacokinetics. The present study aimed to elucidate the effect of resveratrol on Abeta-triggered neuroinflammation by comparing the effects of free resveratrol (RSV) treatment with those of treatment with resveratrol-loaded lipid-core nanocapsules (RSV-LNC). Organotypic hippocampal cultures were stimulated by Abeta1-42 with or without different concentrations of RSV or RSV-LNC. We found that Abeta triggered a harmful neuroinflammation process in organotypic hippocampal cultures. Pre- and co-treatments with RSV-LNC were able to protect cultures against ROS formation and cell death induced by Abeta, possibly through sustained blocking of TNF-alpha, IL-1beta, and IL-6 release. Furthermore, RSV-LNC was able to increase IL-10 release even in the presence of Abeta and prevent or decrease both glial and JNK activation. On the other hand, both pre- and co-treatment with RSV exhibited a lower ability to prevent or decrease neuroinflammation, ROS formation, and cell death, and failed to increase IL-10 release. Our findings suggest that modulation of neuroinflammation through a combination of resveratrol and a lipid-core nanocapsule-based delivery system might represent a promising approach for preventing or delaying the neurodegenerative process triggered by Abeta. The results open new vistas to the interplay between inflammation and amyloid pathology.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Cells, Cultured; Drug Synergism; Encephalitis; Hippocampus; Inflammation; Lipids; Male; Nanocapsules; Neurons; Rats; Rats, Wistar; Reactive Oxygen Species; Resveratrol; Stilbenes

Following a mild traumatic brain injury (TBI) event, the secondary brain injury that persists after the initial blow to the head consists of excitotoxicity, decreased cerebral glucose levels, oxidant injury, mitochondrial dysfunction, inflammation, and neuronal cell death. To date, there are no effective interventions used at decreasing secondary brain injury after mild TBI.. In this study, male mice were treated with either placebo or resveratrol (100 mg/kg) at 5 minutes and 12 hours after mild TBI. The mice were injured using the controlled cortical impact device. In this closed-head model, a midline incision was made to access the skull and the impactor tip was aligned on the sagittal suture midway between the bregma and lambda sutures. The mice were injured at a depth of 2.0 mm, velocity of 4 m/s, and a delay time of 100 milliseconds. At 72 hours following injury, the animals were intracardially perfused with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for microglial activation (Iba1). In addition, using the enzyme-linked immunosorbent assay, tissue levels of interleukin 6 (IL-6) and IL-12 were measured in the cerebral cortex and hippocampus.. In this study, we found that in the placebo treatment group, there was a significant increase in Iba1 staining in the brain. The levels of microglial activation was reduced by resveratrol in the cerebral cortex (p < 0.001), corpus callosum (p < 0.001), and dentate gyrus (p < 0.005) brain regions after mild TBI. In addition to Iba1, resveratrol decreased the brain levels of IL-6 (p < 0.0001) and IL-12 (p < 0.004), which were observed in the hippocampus of the placebo group. In our model, no increase of IL-6 or IL-12 was observed in the cerebral cortex following TBI.. Resveratrol given acutely after TBI results in a decrease in neuroinflammation. These results suggest that resveratrol may be beneficial in reducing secondary brain injury after experiencing a mild TBI.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain Injuries; Disease Models, Animal; Encephalitis; Enzyme-Linked Immunosorbent Assay; Hippocampus; Interleukin-12; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Microglia; Resveratrol; Stilbenes

Neuroinflammatory responses are triggered by diverse ethiologies and can provide either beneficial or harmful results. Microglial cells are the major cell type involved in neuroinflammation, releasing several mediators, which contribute to the neuronal demise in several diseases including cerebral ischemia and neurodegenerative disorders. Attenuation of microglial activation has been shown to confer protection against different types of brain injury. Recent evidence suggests that resveratrol has anti-inflammatory and potent antioxidant properties. It has been also shown that resveratrol is a potent inhibitor of cyclooxygenase (COX)-1 activity. Previous findings have demonstrated that this compound is able to reduce neuronal injury in different models, both in vitro and in vivo. The aim of this study was to examine whether resveratrol is able to reduce prostaglandin E2 (PGE2) and 8-iso-prostaglandin F2alpha (8-iso-PGF2 alpha) production by lipopolysaccharide (LPS)-activated primary rat microglia.. Primary microglial cell cultures were prepared from cerebral cortices of neonatal rats. Microglial cells were stimulated with 10 ng/ml of LPS in the presence or absence of different concentrations of resveratrol (1-50 microM). After 24 h incubation, culture media were collected to measure the production of PGE2 and 8-iso-PGF2 alpha using enzyme immunoassays. Protein levels of COX-1, COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) were studied by Western blotting after 24 h of incubation with LPS. Expression of mPGES-1 at the mRNA level was investigated using reverse transcription-polymerase chain reaction (RT-PCR) analysis.. Our results indicate that resveratrol potently reduced LPS-induced PGE2 synthesis and the formation of 8-iso-PGF2 alpha, a measure of free radical production. Interestingly, resveratrol dose-dependently reduced the expression (mRNA and protein) of mPGES-1, which is a key enzyme responsible for the synthesis of PGE2 by activated microglia, whereas resveratrol did not affect the expression of COX-2. Resveratrol is therefore the first known inhibitor which specifically prevents mPGES-1 expression without affecting COX-2 levels. Another important observation of the present study is that other COX-1 selective inhibitors (SC-560 and Valeroyl Salicylate) potently reduced PGE2 and 8-iso-PGF2 alpha production by LPS-activated microglia.. These findings suggest that the naturally occurring polyphenol resveratrol is able to reduce microglial activation, an effect that might help to explain its neuroprotective effects in several in vivo models of brain injury.

Topics: Animals; Animals, Newborn; Antioxidants; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Down-Regulation; Encephalitis; Free Radical Scavengers; Free Radicals; Gliosis; Inflammation Mediators; Lipopolysaccharides; Microglia; Oxidative Stress; Rats; Resveratrol; Stilbenes