Inflammatory Mediators In Brain Research Articles

Chronic Treatment with Nigella sativa Oil Exerts Antimanic Properties and Reduces Brain Inflammation in Rats.

Nigella sativa (NS) is a native herb consumed habitually in several countries worldwide, possessing manifold therapeutic properties. Among them, anti-inflammatory features have been reported, presumably relating to mechanisms involved in the nuclear factor kappa-B pathway, among others. Given the observed association between neuroimmune factors and mental illness, the primary aim of the present study was to examine the effects of chronic NS use on manic-like behavior in rats, as well as analyze levels of brain inflammatory mediators following NS intake. Using male and female rats, baseline tests were performed; thereafter, rats were fed either regular food (control) or NS-containing food (treatment) for four weeks. Following intervention, behavioral tests were induced (an open field test, sucrose consumption test, three-chamber sociality test, and amphetamine-induced hyperactivity test). Subsequently, brain samples were extracted, and inflammatory mediators were evaluated, including interleukin-6, leukotriene B4, prostaglandin E2, tumor necrosis factor-α, and nuclear phosphorylated-p65. Our findings show NS to result in a marked antimanic-like effect, in tandem with a positive modulation of select inflammatory mediators among male and female rats. The findings reinforce the proposed therapeutic advantages relating to NS ingestion.

Cerium oxide nanoparticles impact on sepsis-induced cerebral injury: Deciphering miRNA / NF-κB/TLR signalling pathway.

Sepsis is regarded as an inflammatory syndrome that consists of complex biochemical and pathophysiological dysregulation, brought on by endogenous factors in response to systemic infection. Sepsis can cause short- and long-term cerebral injury. Cerium oxide nanoparticles (CeO2 NPs) have been reported to possess both anti-inflammatory and antioxidative properties. The current study investigated the potential role of cerium oxide nanoparticles in the management of sepsis-induced brain injury. To achieve this target, forty male albino rats were divided into 4 groups, ten rats each. Group (i) set as a shame group. Group (ii) set as shame group administrated CeO2 NPs. Group (iii) septic group treated with saline and Group (iv) septic group treated with CeO2 NPs. The sepsis model in rats was induced by cecal ligation and puncture (CLP). Results showed CeO2 NPs administration resulted in significant improvement in the survival rate of rats, suppression in serum sepsis biomarkers (CRP, ESM-1, PCT and D- dimer), amelioration of brain inflammatory mediators (TNF-α- IL-6, NF-kB and LTB4) as well as apoptotic markers (Cas-3 and BAX). Furthermore, immunomodulation of miRNAs expression (155,124 and 146a). These findings demonstrate a promising pivotal role of CeO2 NPs treatment in alleviating the deleterious effects induced by sepsis in the brain.

Microglia contribute to mammary tumor-induced neuroinflammation in a female mouse model.

Following diagnosis but before treatment, up to 30% of breast cancer patients report behavioral side effects (e.g., anxiety, depression, memory impairment). Our rodent mammary tumor model recapitulates aspects of these behavioral sequelae, as well as elevated circulating and brain inflammatory mediators. Neuroinflammation is a proposed mechanism underlying the etiology of mood disorders and cognitive deficits, and therefore may be contributing to tumor-associated behavioral side effects. The cellular mechanisms by which tumor-induced neuroinflammation occurs remain unknown, making targeted treatment approaches inaccessible. Here, we tested the hypotheses that microglia are the primary cells driving tumor-induced neuroinflammation and behavioral side effects. Young adult female BALB/c mice were induced with a 67NR mammary tumor; tumor-free controls underwent a sham surgery. Mammary tumors increased IBA1+ and GFAP+ staining in the amygdala and hippocampus relative to tumor-free controls. However, tumors did not alter gene expression of Percoll-enriched microglia isolated from the whole brain. While cognitive, social, and anhedonia-like behaviors were not altered in tumor-bearing mice, tumors increased central tendency in the open-field test; microglia depletion did not reverse this effect. Brain region RT-qPCR data indicated that microglia depletion attenuated tumor-induced elevations of neuroinflammatory gene expression in a region- and mediator-specific manner. These results indicate a causal role of microglia in tumor-induced neuroinflammation. This research advances our understanding of the cellular mechanisms underlying tumor-induced neuroinflammation in order to understand how brain responses (e.g., behavior) may be altered with subsequent cancer-related immune challenges.

Montelukast induces beneficial behavioral outcomes and reduces inflammation in male and female rats.

BackgroundAccumulative data links inflammation and immune dysregulation to the pathophysiology of mental disorders; little is known regarding leukotrienes’ (LTs) involvement in this process. Circumstantial evidence suggests that treatment with leukotriene modifying agents (LTMAs) such as montelukast (MTK) may induce adverse neuropsychiatric events. Further methodic evaluation is warranted.ObjectiveThis study aims to examine behavioral effects, as well as inflammatory mediator levels of chronic MTK treatment in male and female rats.MethodsDepression-like phenotypes were induced by exposing male and female rats to a chronic unpredictable mild stress (CUMS) protocol for four weeks. Thereafter, rats were treated (intraperitoneally) once daily, for two weeks, with either vehicle (dimethyl sulfoxide 0.2 ml/rat) or 20 mg/kg MTK. Following treatment protocols, behavioral tests were conducted and brain regions were evaluated for inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and prostaglandin (PG) E2.ResultsOverall, MTK did not invoke negative behavioral phenotypes (except for an aggression-inducing effect in males). Numerous positive behavioral outcomes were observed, including reduction in aggressive behavior in females and reduced manic/hyperactive-like behavior and increased sucrose consumption (suggestive of antidepressant-like effect) in males. Furthermore, in control males, MTK increased IL-6 levels in the hypothalamus and TNF-α in the frontal cortex, while in control females it generated a robust anti-inflammatory effect. In females that were subjected to CUMS, MTK caused a prominent reduction in TNF-α and IL-6 in brain regions, whereas in CUMS-subjected males its effects were inconsistent.ConclusionContrary to prior postulations, MTK may be associated with select beneficial behavioral outcomes. Additionally, MTK differentially affects male vs. female rats in respect to brain inflammatory mediators, plausibly explaining the dissimilar behavioral phenotypes of sexes under MTK treatment.

Neuroinflammation as a mechanism linking hypertension with the increased risk of Alzheimer’s disease

Alzheimer’s disease, the most common type of dementia among older adults, currently cannot be prevented or effectively treated. Only a very small percentage of Alzheimer’s disease cases have an established genetic cause. The majority of Alzheimer’s disease cases lack a clear causative event, but several modifiable factors have been associated with an increased risk of this disease. Persistent midlife hypertension is one such risk factor, which can be effectively controlled through changes in diet, lifestyle, and antihypertensive drugs. Identifying molecular mechanisms linking modifiable risk factors with the increased risk of Alzheimer’s disease could enhance our understanding of this disease and lead to identification of novel targets and therapeutic approaches for effective treatments. Glial cell-driven neuroinflammation is one of the key pathological features of Alzheimer’s disease. In this review, we illustrate that neuroinflammation could also be one of the possible mechanisms linking hypertension and Alzheimer’s disease. Animal studies have demonstrated that chronically elevated blood pressure leads to adverse glial activation and increased brain inflammatory mediators. We highlight damage to cerebral microvasculature and locally activated renin-angiotensin system as the key pathogenetic mechanisms linking hypertension to neuroinflammation and the accompanying neurodegeneration. The role of tumor necrosis factor-α and interleukin-1β as pro-inflammatory signaling molecules providing this link is discussed. We also summarize the available experimental data indicating that neuroinflammatory changes and glial activation can be reversed by several different classes of antihypertensive medicines. These studies suggest antihypertensives could be beneficial in Alzheimer’s disease not only due to their ability to control the blood pressure, but also due to their anti-neuroinflammatory effects. Confirmation of these observations in human subjects is required and recent advances in the brain imaging techniques allowing visualization of both microglia and astrocyte activation will be essential for this research.

Oxidative Stress and Neuronal Injury After Cannabis and Ketamine Administration

Cannabis sativa and ketamine are common substances of abuse causing psychotic events and neurodegeneration. In this study, the effect of pretreatment with Cannabis sativa extract on oxidative stress, inflammatory mediators and brain damage induced by ketamine was investigated. Rats were treated with subcutaneous injections of cannabis extract (10, 20, 30 or 40 mg/kg; expressed as Δ9-THC content) daily for three weeks and then in combination with ketamine (15 mg/kg, intraperitoneally) for another 5 days. Rats were tested for biochemical markers of oxidative stress including malondialdehyde (MDA) reduced glutathione (GSH), and nitric oxide (NO) concentrations in brain. Paraoxonase-1 (PON-1) activity, and levels of the proinflammatory cytokines, interleukin-1β (IL-1β), and tumour necrosis factor-α (TNF-α) in brain were also determined at the end of treatment period. Results indicated that compared with the saline control group, ketamine induced significant elevation in brain MDA and NO, which was accompanied by depletion of GSH and inhibition of PON-1 activity. Ketamine also significantly increased brain IL-1β and TNF-α and induced neuronal necrosis, apoptosis and vacuolation. Cannabis sativa (20-40 mg/kg) pretreated rats showed lower levels of oxidative stress and inflammation and doses of 30 or 40 mg/kg slightly reduced neuronal apoptosis and necrosis. These findings suggest that cannabis constituents do not enhance the neurotoxic effects of ketamine and might partly counteract the effects of ketamine-induced NMDA antagonism by reducing the release of free radicals and inflammatory mediators in brain

Curcumin-laden dual-targeting fucoidan/chitosan nanocarriers for inhibiting brain inflammation via intranasal delivery

Curcumin can reduce the production of brain inflammatory mediators and symptoms of brain diseases. However, a large amount of free curcumin needs to be administered to achieve an effective level in the brain because of its poor water-solubility. Fucoidan and chitosan were reported to respectively target P-selectin and acidic microenvironment expressed by pathologically inflammatory cells/tissues. Herein, the self-assembly of chitosan and fucoidan which could encapsulate curcumin was developed to form the multi-stimuli-responsive nanocarriers, and their pathological pH- and P-selectin-responsive aspects were characterized. Through intranasal delivery to the brain, these curcumin-containing chitosan/fucoidan nanocarriers with dual pH-/P-selectin-targeting properties to the brain lesions improved drug delivery, distribution, and accumulation in the inflammatory brain lesions as evidenced by an augmented inhibitory effect against brain inflammation. This promising multifunctional nanocarrier with a novel drug-delivery route should allow potential clinical biomedical uses by neurosurgeon in the future.

Neuroinflammation, Pain and Depression: An Overview of the Main Findings.

Chronic pain is a serious public health problem with a strong affective-motivational component that makes it difficult to treat. Most patients with chronic pain suffer from severe depression; hence, both conditions coexist and exacerbate one another. Brain inflammatory mediators are critical for maintaining depression-pain syndrome and could be substrates for it. The goal of our paper was to review clinical and preclinical findings to identify the neuroinflammatory profile associated with the cooccurrence of pain and depression. In addition, we aimed to explore the regulatory effect of neuronal reorganization on the inflammatory response in pain and depression. We conducted a quantitative review supplemented by manual screening. Our results revealed inflammatory signatures in different preclinical models and clinical articles regarding depression-pain syndrome. We also identified that improvements in depressive symptoms and amelioration of pain can be modulated through direct targeting of inflammatory mediators, such as cytokines and molecular inhibitors of the inflammatory cascade. Additionally, therapeutic targets that improve and regulate the synaptic environment and its neurotransmitters may act as anti-inflammatory compounds, reducing local damage-associated molecular patterns and inhibiting the activation of immune and glial cells. Taken together, our data will help to better elucidate the neuroinflammatory profile in pain and depression and may help to identify pharmacological targets for effective management of depression-pain syndrome.

Short-term exposure to dietary cholesterol is associated with downregulation of interleukin-15, reduced thigmotaxis and memory impairment in mice

Alzheimer’s disease (AD) is a neurodegenerative condition associated with loss of memory function, depression and anxiety. The etiology of AD is poorly understood, but both cholesterol dyshomeostasis and dysregulation of the immune system are contributing factors. Current evidence is consistent with a detrimental effect of excess cholesterol on neuroinflammation, both in mouse models of memory loss and in dementia in humans. However, whether the impact of cholesterol on neuroinflammation occurs early and contributes to pathogenesis of the disease or simply reflects a pleiotropic impact at advanced stages of disease is unclear. To explore this question, we measured, in 9–13 week-old mice, cognitive status and changes in brain inflammatory mediators in response to a short-term high-cholesterol diet. We hypothesized that short-term exposure to excess dietary cholesterol would alter the early inflammatory responses associated with cognitive and/or behavioral impairment. We report that short-term exposure to a high-cholesterol diet led to decreased thigmotaxis and short-term spatial memory impairment without affecting long-term recognition memory. Furthermore, cognitive and behavioral phenotypes in these mice were associated with a reduction in interleukin-15 levels in the absence of changes in other inflammatory mediators. Our findings indicate that interleukin-15 may play a role in early stages of cognitive impairment secondary to hypercholesterolemia. Consequently, optimization of interleukin-15 signaling may be a viable effective cognitive therapy in the population susceptible to developing dementia due to risk factors associated with cholesterol dysregulation.

Neuroinflammation impact in epileptogenesis and new treatment strategy.

Epilepsy is considered a major serious chronic neurological disorder, characterized by recurrent seizures. It is usually associated with a history of a lesion in the nervous system. Irregular activation of inflammatory molecules in the injured tissue is an important factor in the development of epilepsy. It is unclear how the imbalanced regulation of inflammatory mediators contributes to epilepsy. A recent research goal is to identify interconnected inflammation pathways which may be involved in the development of epilepsy. The clinical use of available antiepileptic drugs is often restricted by their limitations, incidence of several side effects, and drug interactions. So development of new drugs, which modulate epilepsy through novel mechanisms, is necessary. Alternative therapies and diet have recently reported positive treatment outcomes in epilepsy. Vitamin D (Vit D) has shown prophylactic and therapeutic potential in different neurological disorders. So, the aim of current study was to review the associations between different brain inflammatory mediators and epileptogenesis, to strengthen the idea that targeting inflammatory pathway may be an effective therapeutic strategy to prevent or treat epilepsy. In addition, neuroprotective effects and mechanisms of Vit D in clinical and preclinical studies of epilepsy were reviewed.

Gentiopicroside abrogates lipopolysaccharide-induced depressive-like behavior in mice through tryptophan-degrading pathway.

Targeting neuroinflammatory disturbances has been acknowledged as a potential strategy for treatment of depressive disorder in humans. Over-activation of tryptophan-degrading pathway by pro-inflammatory cytokines resulted in N-methyl-d-aspartate (NMDA)-mediated excitotoxicity, which is implicated in pathophysiology of depression. Gentiopicroside (Gent) has powerful anti-inflammatory property and exhibits promising antidepressant effect in an animal model of pain/depression dyad by down-regulating GluN2B-containing NMDA receptors. Therefore, the present study aimed to investigate the ability of Gent to abolish depressive-like behavior induced by lipopolysaccharide (LPS) in mice. Acute administration of LPS (0.5mg/kg, i.p.) increased immobility time in both forced swimming test (FST) and tail suspension test (TST) without affecting spontaneous locomotor activity, indicative of depressive-like behavior. Gent (50mg/kg, i.p.) administered once a day for three consecutive days prevented the development of depressive-like behavior induced by LPS. The antidepressant-like effect was paralleled with restoration of LPS-induced alterations in brain inflammatory mediators (i.e. IL-1β and TNF-α). In addition, Gent prevented over-activation of indoleamine 2,3-double oxygen enzyme (IDO) and recovered GluN2B subunit expression in the PFC challenged by LPS. In conclusion, our results suggested that Gent pretreatment provided protection against LPS-induced depressive-like behavior and the effect appeared to be demonstrated, at least partially, by blocking various steps of tryptophan-degrading pathway.

Memory enhancement and protective effects of crocin against D-galactose aging model in the hippocampus of Wistar rats.

Objective(s):The neurodegeneration and loss of memory function are common consequences of aging. Medicinal plants have potent protective effects against chronic neurodegenerative diseases. The aim of this study was to investigate the beneficial effects and molecular mechanisms of crocin on brain function in D-galactose (D-gal)-induced aging model in rats.Materials and Methods:Male Wistar rats weighing 220 ± 20 g were randomly divided into six groups: control, D-gal (400 mg/kg, SC), D-gal (400 mg/kg) plus crocin (7.5, 15, 30 mg/kg, IP) and crocin alone at dose of 30 mg/kg for 8 weeks. The neuroprotective effects of crocin were evaluated by Morris water maze, determination of malondialdehyde (MDA) levels and Western blot analysis.Results:Crocin significantly inhibited the neurotoxic effects of D-gal through improvement of spatial learning and memory functions as well as the reduction of MDA levels. It was also found that administration of crocin up-regulated pAkt/Akt and pErk/Erk ratio which were decreased by chronic D-gal treatment. In addition, the elevated level of carboxymethyl lysine (CML), as an advance glycation product (AGE), NF-κB p65, TNFα and IL1β significantly decreased in crocin treated rats compared to D-gal group.Conclusion:These findings suggest that crocin is able to enhance memory function in D-gal aging model through anti-glycative and anti-oxidative properties which finally can suppress brain inflammatory mediators (IL-1, TNF and NF-κB) formations and increase PI3K/Akt and Erk/MAPK pathways activity. Therefore, crocin can be considered as healthcare product to prevent age-related brain diseases such as Alzheimer.

Neuroprotective Effect of Hydroxytyrosol in Experimental Diabetes Mellitus.

The aim of the study was to analyze the possible neuroprotective effect of hydroxytyrosol (HT) in diabetic animals in a model of hypoxia-reoxygenation. Rats (10 animals/group) were distributed in five groups: nondiabetic rats, control diabetic rats (DR), and DR rats treated for 2 months with 1, 5, or 10 mg/kg/day po HT. At the end of follow-up, an experimental model of hypoxia-reoxygenation in brain slices was tested. The DR group showed increased cell death, oxidative and nitrosative stress, and an increase in brain inflammatory mediators. These alterations were significantly greater in DR than in normoglycemic animals. HT significantly reduced oxidative (38.5-52.4% lipid peroxidation) and nitrosative stress (48.0-51.0% nitric oxide and 43.9-75.2% peroxynitrite concentration) and brain inflammatory mediators (18.6-40.6% prostaglandin E2 and 17.0-65.0% interleukin 1β concentration). Cell death was reduced by 25.9, 37.5, and 41.0% after the administration of 1, 5, or 10 mg/kg/day. The administration of HT in rats with experimental diabetes thus had a neuroprotective effect.

Novel environment influences the effect of paradoxical sleep deprivation upon brain and peripheral cytokine gene expression

Sleep loss increases inflammatory mediators in brain and peripheral tissues, but the mechanisms underlying this association are not fully understood. Male C57BL/6j mice were exposed to paradoxical sleep deprivation (PSD) for 24h using the modified multiple platform (MMP) technique (platforms over water) or two different controls: home cage or a dry platform cage, which constituted a novel environment. PSD mice exhibited increased IL-1β and TNF-α pro-inflammatory gene expression in brain (hypothalamus, hippocampus, pre-frontal cortex), as well as in peripheral tissues (liver, spleen), when compared with home-cage controls. In addition, among PSD mice, TGFβ1, an anti-inflammatory cytokine, was increased in pre-frontal cortex, liver, and spleen in conjunction with elevated serum corticosterone concentration relative to home-cage controls. However, these differences were nearly abolished when PSD mice were compared with control mice subjected to a dry MMP cage, suggesting that simply exposing mice to a novel environment can induce an acute inflammatory response.

Effects of Acute Lithium Treatment on Brain Levels of Inflammatory Mediators in Poststroke Rats.

Stroke is a leading cause of mortality and morbidity worldwide. Few therapeutic options with proven efficacy are available for the treatment of this disabling disease. Lithium is the gold standard treatment for bipolar disorder. Moreover, lithium has been shown to exhibit neuroprotective effects and therapeutic efficacy as a treatment of other neurological disorders. This study was undertaken to examine the effects of lithium on brain inflammatory mediators levels, fever, and mortality in postischemic stroke rats. Ischemic stroke was induced by occlusion of the mid cerebral artery (MCAO). Pretreatment with a single dose of lithium at 2 hours before MCAO induction significantly reduced the elevation in interleukin- (IL-) 6 and prostaglandin E2 levels in brain of post-MCAO rats, as compared to vehicle-treated animals. On the other hand, lithium did not affect the elevation in IL-1α, IL-10, IL-12, and tumor necrosis factor-α levels in brain of post-MCAO rats. Moreover, pretreatment with lithium did not alter post-MCAO fever and mortality. These results suggest that acute pretreatment with a single dose of lithium did not markedly affect post-MCAO morbidity and mortality in rats.

Indomethacin in Combination with Exercise Leads to Muscle and Brain Inflammation in Mice

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used by athletes to reduce exercise-induced inflammation and pain. However, NSAID use has been linked to side effects, including mucosal damage in the gastrointestinal tract resulting in endotoxemia and inflammation. Incidentally, when NSAID use is combined with exercise there is some evidence that this effect may be exacerbated; however, this hypothesis has not been directly tested in a controlled experiment. We examined the combined effect of indomethacin (IND) and exercise on muscle and brain inflammation in mice. Male C57BL/6 mice were randomly assigned to: Exercise 0 mg/Kg IND (Ex-0), Sedentary 0 mg/Kg IND (Sed-0), Exercise 2.5 mg/Kg IND (Ex-2.5), or Sedentary 2.5 mg/Kg IND (Sed-2.5) (n=8-11/group). Mice were given IND (gavage) 1 h before exercise (treadmill run at 25 m/min, 8% grade for 90 min) or rest for 5 consecutive days. Run times and body weight were recorded daily. Muscle and brain were examined for gene expression of inflammatory mediators after 5 days of treatment. While IND and exercise alone had little effect on inflammation, the combination treatment produced substantial increases in the muscle (IL-1β, MCP-1 & TNF-α) and brain (IL-1β & MCP-1) (P<0.05). Hematocrit and hemoglobin were decreased along with body weight (days 3-5), and run time to fatigue (days 3-5) (P<0.05) and in general, these were correlated with the increased expression of muscle and brain inflammatory mediators. The combination of IND and exercise can lead to inflammation in both the muscle and brain that is associated with serious side effects and impaired performance in mice.

Brain Inflammatory Mediators induced by high fat diet are significantly blunted with the deletion of MCP‐1

Consumption of a high fat diet (HFD) can lead to central nervous system (CNS) inflammation. Monocyte chemoattractant protein (MCP‐1) is fundamental in the release of inflammatory mediators, but its role in HFD induced CNS inflammation has not yet been determined. The purpose of this study was to determine the role of MCP‐1 on brain inflammation following 15 weeks of HFD feedings. C57BL/6 wildtype mice (n=20) and MCP‐1 −/− mice (n=32), 4 weeks of age were randomly assigned to one of four groups: normal diet wildtype (ND‐WT), HFD wildtype (HFD‐WT), normal diet MCP‐1−/− (ND‐MCP‐1−/−) or HFD MCP‐1 −/− (HFD‐MCP‐1−/−). The mice were fed the HFD (41% of total caloric intake from fat) or normal diet (11.5% of total caloric intake from fat) for 15 weeks. Mice were sacrificed at 19 weeks of age and the brainstem was dissected and analyzed for mRNA gene expression of TLR4, F4/80, CD11c and TNF‐α using real time RT‐PCR. Gene expression of TLR4, CD11c and TNF‐α was increased in the brainstem of HFD‐WT relative to ND‐WT (p&lt;0.05), whereas HFD‐MCP‐1−/− was not different from ND‐WT. A similar effect was observed for F4/80, but this did not reach statistical significance. No differences were found among the other groups. These data support a necessary role of MCP‐1 on the brain inflammatory response following HFD feedings. MCP‐1 may be an important therapeutic target in HFD‐induced brain inflammation.

Role of brain inflammatory mediators in the restraint stress-induced elevation of plasma catecholamines

Role of brain inflammatory mediators in the restraint stress-induced elevation of plasma catecholamines

Ethanol intake enhances inflammatory mediators in brain: role of glial cells and TLR4/IL-1RI receptors

The brain is one of the major target organs of ethanol actions, and its chronic and acute intoxication results in significant alterations in brain structure and function, and in some cases to neurodegeneration. Glial cells and Toll-like receptors (TLRs) are vital players in CNS immune response; dysregulation of this response plays an important role in brain damage and neurodegeneration. Ethanol has immunomodulatory effects and induces specific alterations in the TLRs response in many tissues. These actions depend on the cell type, ethanol dose and treatment duration, as well as the concomitant presence of pathogens and their characteristics. Recent findings indicate that low concentrations of ethanol (10 mM) promote inflammatory processes in brain and in glial cells by up-regulating cytokines and inflammatory mediators (iNOS, NO, COX-2), and by activating signaling pathways (IKK, MAPKs) and transcriptional factors (NF-kappaB, AP-1) implicated in inflammatory injury. TLR4/IL-1RI receptors may be involved in ethanol-mediated inflammatory signaling, since blocking these receptors abolishes the production of ethanol-induced inflammatory mediators and cell death. We propose that at low physiologically relevant concentrations, ethanol facilitates TLR4/IL-1RI recruitment into lipid rafts microdomains, leading to the activation and signaling of these receptors. In summary, current results suggest that TLR4/ IL-1RI are important targets of ethanol-induced inflammatory brain damage.

Cyclooxygenase-2 is Involved in HIV-1 Tat-Induced Inflammatory Responses in the Brain

Cyclooxygenase (COX)-2, a rate-limiting enzyme for prostanoid synthesis, can be involved in inflammatory-mediated cytotoxicity. Although the contribution of COX-2 to peripheral inflammation is well understood, its role in brain inflammation is not fully recognized. In particular, COX-2 involvement in inflammatory responses induced by HIV proteins in the central nervous system is not known. Therefore, the present study focused on COX-2 expression and its role in modulating the expression of brain inflammatory-related genes following exposure to the HIV-1 transactivating protein Tat. Intrahippocampal injections of Tat induced dose-dependent upregulation of COX-2 mRNA and protein levels in C57BL/6 mice. COX-2 immunoreactivity was primarily localized in microglial cells and astrocytes. Tat-induced COX-2 expression was partially prevented by pyrrolidine dithiocarbamate, a potent antioxidant and an inhibitor of the transcription factor, nuclear factor kappaB. Most importantly, administration of the COX-2 inhibitor NS-398 attenuated Tat-mediated upregulation of mRNA and protein expression of inflammatory mediators, such as monocyte chemoattractant protein-1, interleukin-1beta, tumor necrosis factor-alpha, and inducible nitric oxide synthase. Moreover, treatment with NS-398 significantly attenuated Tat-induced activation of microglial cells. These results provide evidence that COX-2 overexpression can modulate induction of brain inflammatory mediators in response to HIV-1 Tat protein. Such alterations may play an important role in the development of brain inflammatory reactions in HIV-infected patients and contribute to the development of neurological complications in the course of HIV-1 infection.