Bacterial lipopolysaccharide forms aggregates with apolipoproteins in male and female rat brains after ethanol binges.

Alcohol binge drinking allows the translocation of bacterial lipopolysaccharide (LPS) from the gut to the blood, which activates the peripheral immune system with consequences in neuroinflammation. A possible access/direct signaling of LPS to/in the brain has not yet been described under alcohol abuse conditions. Apolipoproteins are compounds altered by alcohol with high affinity to LPS which may be involved in its transport to the brain or in its elimination. Here, we explored the expression of small components of LPS, in its free form or bound to apolipoproteins, in the brain of female and male rats exposed to alcohol binges. Animals received ethanol oral gavages (3 g/kg every 8 h) for 4 days. LPS or its components (Lipid A and core), LPS-binding protein, corticosterone, lipoproteins (HDL, LDL), apolipoproteins (ApoAI, ApoB, and ApoE), and their receptors were measured in plasma and/or in nonperfused prefrontal cortex (PFC) and cerebellum. Brain LipidA-apolipoprotein aggregates were determined by Western blotting and confirmed by co-immunoprecipitation. In animals exposed to alcohol binges: 1) plasma LPS-binding protein was elevated in both sexes; 2) females showed elevations in plasma ApoAI and corticosterone levels; 3) Lipid A formed aggregates with ApoAI in the female PFC and with ApoB in males, the latter showing Toll-like receptor 4 upregulation in PFC but not females. These results suggest that small bacterial components are present within the brain, forming aggregates with different apolipoproteins, depending on the sex, after alcohol binge intoxications. Results may have implications for the crosstalk between alcohol, LPS, and neuroinflammation.

Differences in the regulation of inflammatory pathways in adolescent- and adult-onset first-episode psychosis.

A precise description of the inflammatory response in first-episode psychosis (FEP) by age of onset does not exist. We explored baseline and 6-month follow-up differences in the pro/anti-inflammatory balance in plasma and peripheral blood mononuclear cells in adolescent-onset FEP (≤ 18 y.o., N = 27) and adult-onset FEP (≥ 25 y.o., N = 43) using non-parametric 1-category ANCOVA, with age group as an independent variable and values of pro- and anti-inflammatory markers at baseline and at follow-up as dependent variables. We used a non-parametric repeated-measures mixed-effects model to explore the baseline/6-month change in pro- and anti-inflammatory markers within adolescent- and adult-onset groups, exploring differential trajectories of change by means of the interaction of time by age-of-onset group. Levels of the nuclear transcription factor (NFκB), a master regulator of the inflammatory and oxido/nitrosative status of cells, were higher in adolescent-onset FEP both at baseline and after 6 months. During follow-up, we found further increases in levels of soluble inflammatory markers (PGE2 and NO2-) only in adolescent-onset FEP. In contrast, in adult-onset FEP, the expression of inducible NO synthase (iNOS), which is also pro-inflammatory, tended to decrease, with no further increase in other pro-inflammatory markers. Significant differences in the direction of change by age-of-onset cohort exist only for NFκB (F = 4.165, df = 2, 70.95, p = 0.019). Our results support the existence of changes in the pro/anti-inflammatory balance in FEP depending on the neurodevelopmental stage at illness onset. These results also suggest that inflammation may be a potential therapeutic target in adolescent-onset FEP.

Cognition and psychopathology in first-episode psychosis: are they related to inflammation?

BACKGROUND: Cognitive deficits are present from the onset of psychosis and are considered a core feature of the disorder. Increasing evidence suggests that cognitive function is associated with inflammatory processes. This study evaluated the association between cognition and inflammatory biomarkers in first-episode psychosis (FEP), in order to identify cognitive phenotypes from inflammatory expression profiles. METHOD: A case-control study of 92 FEP patients and 80 matched controls was used. Neurocognitive assessment, including verbal ability, sustained attention, verbal memory, working memory and executive function, was performed. The expression of pro- and anti-inflammatory mediators of the main intracellular inflammatory pathway was measured in peripheral blood mononuclear cells and plasma. RESULTS: FEP patients performed worse in all cognitive domains compared to controls and had higher expression of pro-inflammatory mediators and lower expression of anti-inflammatory mediators. In the FEP group, cognition and psychopathology were associated with inflammation. Hierarchical regression analysis showed that association between the anti-inflammatory prostaglandin 15d-PGJ2 and sustained attention on one hand, and COX-2 expression and executive function on the other, were statistically significant. CONCLUSIONS: Our study provides evidence for an association between anti-inflammatory biomarkers and cognition in FEP. The identification of a subgroup of patients based on these measures could be useful to guide treatment programmes by providing tools to select a personalized treatment approach, but longitudinal studies are needed before. In the future, establishment of biomarkers linked to cognition would be useful to monitor the course of cognitive impairment, but substantially more data will be required. Determination of IκBα, the inhibitory protein of the pro-inflammatory transcription factor NFκB, could be useful in early phases to assess clinical severity.

Paliperidone prevents brain toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress.

BACKGROUND: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. METHODS: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress-induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. RESULTS: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. CONCLUSIONS: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies.

Late onset eating disorders in Spain: clinical characteristics and therapeutic implications.

OBJECTIVE: The literature on later age of onset (LAO) in women with eating disorders is scarce. We compared the severity of eating disorders, eating disorder subtype, and personality profiles in a clinical sample of consecutively assessed women with eating disorders with later age of onset (LAO, > = 25 years) to women with typical age of onset (TAO, <25 years). METHOD: All eating disorder patients met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria and were admitted to the Eating Disorder Unit of the University Hospital of Bellvitge in Barcelona, Spain. Ninety-six patients were classified as LAO and 759 as TAO. ASSESSMENT: Measures included the Eating Attitude Test-40 (EAT-40), Eating Disorders Inventory-2 (EDI-2), Bulimic Investigatory Test Edinburgh (BITE), Symptom Checklist Revised (SCL-90-R), and the Temperament and Character Inventory-Revised (TCI-R), as well as other clinical and psychopathological indices. RESULTS: LAO individuals reported significantly fewer weekly vomiting episodes, fewer self-harming behaviours, less drug abuse, and lower scores on the BITE symptoms, the EDI-2 drive for thinness, and the TCI-R harm avoidance scales than TAO individuals. Conversely, the LAO group reported more current and premorbid obesity than the TAO group. CONCLUSION: LAO eating disorder patients in this sample presented with milder symptomatology and less extreme personality traits. Premorbid obesity may be more relevant to LAO than TAO eating disorders and should be routinely assessed and considered when planning treatment.

Evaluation of endometrial and subendometrial vascularization and endometrial volume by 3-D power Doppler ultrasound and its relationship with age and pregnancy in intrauterine insemination cycles.

AIMS: To measure endometrial volume and endometrial-subendometrial vascularization by 3-D power Doppler ultrasound in patients undergoing cycles of artificial insemination with ovarian stimulation, to evaluate their relationship with patients' age and pregnancy development. METHODS: We included patients with primary and secondary infertility of one year of evolution. We measured vascular indexes and endometrial volume by 3-D power Doppler ultrasound. RESULTS: Seventy-nine consecutive cycles were studied. Endometrial volume average was 4.7 ± 2.66 ml. We did not find any difference between the endometrial volumes in women who did versus did not become pregnant (9 vs. 70 women, respectively). The endometrial vascular index was significantly higher in patients aged between 31 and 33 years old. In patients between the ages of 31 and 33, both the endometrial flow index (FI; p = 0.017) and the endometrial vascular FI (p = 0.013) were higher. At the subendometrial area, the vascular FI was lower in women older than 33 years old (p = 0.024), while the FI was higher in patients that achieved pregnancy (p = 0.047). CONCLUSIONS: Endometrial volumes were independent of pregnancy development. Endometrial and subendometrial vascularization FIs were significantly higher in younger women. The subendometrial FI was significantly higher in patients who achieved pregnancy.

Memory and strategic processing in first-degree relatives of obsessive compulsive patients.

BACKGROUND: The same executive dysfunctions and alterations in neuroimaging tests (both functional and structural) have been found in obsessive-compulsive patients and their first-degree relatives. These neurobiological findings are considered to be intermediate markers of the disease. The aim of our study was to assess verbal and non-verbal memory in unaffected first-degree relatives, in order to determine whether these neuropsychological functions constitute a new cognitive marker for obsessive-compulsive disorder (OCD). METHOD: Recall and use of organizational strategies in verbal and non-verbal memory tasks were measured in 25 obsessive-compulsive patients, 25 unaffected first-degree relatives and 25 healthy volunteers. RESULTS: First-degree relatives and healthy volunteers did not show differences on most measures of verbal memory. However, during the recall and processing of non-verbal information, deficits were found in first-degree relatives and patients compared with healthy volunteers. CONCLUSIONS: The presence of the same deficits in the execution of non-verbal memory tasks in OCD patients and unaffected first-degree relatives suggests the influence of certain genetic and/or familial factors on this cognitive function in OCD and supports the hypothesis that deficits in non-verbal memory tasks could be considered as cognitive markers of the disorder.

Reliability, validity, and classification accuracy of a Spanish translation of a measure of DSM-IV diagnostic criteria for pathological gambling.

The aim of this study was to measure the reliability, validity, and classification accuracy of a Spanish translation of a measure of DSM-IV diagnostic criteria for Pathological Gambling (PG). Participants were 263 male and 23 female patients seeking treatment for PG and a matched non-psychiatric control sample of 259 men and 24 women. A Spanish translation of a 19-item measure of DSM-IV diagnostic criteria for PG (Stinchfield 2003) was administered along with other validity measures. The DSM-IV diagnostic criteria were found to be internally consistent with a coefficient alpha of .95 in the combined sample. Evidence of satisfactory convergent validity included moderate to high correlations with other measures of problem gambling. Using the standard DSM-IV cut-score of five, the ten criteria were found to yield satisfactory classification accuracy results with a high hit rate (.95), high sensitivity (.92), high specificity (.99), low false positive (.01), and low false negative rate (.08). Lowering the cut score to four resulted in modest improvements in classification accuracy and reduced the false negative rate from .08 to .05. The Spanish translation of a measure of DSM-IV diagnostic criteria for PG demonstrated satisfactory psychometric properties and a cut score of four improved diagnostic precision.

Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide.

BACKGROUND AND PURPOSE: Chronic alcohol consumption alters the gut-brain axis, but little is known about alcohol binge episodes on the functioning of the intestinal barrier. We investigated the influence of ethanol binges on bacterial translocation, gut inflammation and immunity, and tight junction (TJ) structure and the ability of the biolipid oleoylethanolamide (OEA) to prevent ethanol binge-induced intestinal barrier dysfunction. EXPERIMENTAL APPROACH: OEA was injected i.p. before repeated ethanol administration by oral gavage. Plasma, spleen, liver and mesenteric lymph nodes (MLN) were collected in sterile conditions for determination of bacterial load. Immune/inflammatory parameters, TJ proteins and apoptotic markers were determined in colonic tissue by RT-PCR and Western blotting. TJ ultrastructure was examined by transmission electron microscopy. KEY RESULTS: Ethanol binges induced bacterial translocation to the MLN (mainly) and spleen. Colonic tissues showed signs of inflammation, and activation of innate (Toll-like receptor-4) and adaptive (IgA) immune systems and TJ proteins (occludin and claudin-3) were decreased after ethanol binges. Pretreatment with OEA reduced intestinal inflammation and immune activation and partially preserved the TJ structure affected by alcohol binges but had no effect on alcohol-induced apoptosis. Ultrastructural analyses of colonic TJs revealed dilated TJs in all ethanol groups, with less electron-dense material in non-pretreated rats. The protective effects of i.p. OEA did not reduce bacterial translocation to the MLN. However, intragastric OEA administration significantly reduced plasma LPS levels and bacterial translocation to the MLN. CONCLUSION AND IMPLICATIONS: OEA-based pharmacotherapies could potentially be useful to treat disorders characterized by intestinal barrier dysfunction, including alcohol abuse.

Corticosterone as a marker of susceptibility to oxidative/nitrosative cerebral damage after stress exposure in rats.

There are important individual differences in susceptibility to stress-induced diseases, most of them associated to the hypothalamic-pituitary and sympatho-medullo-adrenal axis functioning. Characterization of individual differences in animals may help to find the origin of this susceptibility. In order to study differences in oxidative and neuroinflammatory consequences in brain after stress exposure, we used an adult, male, outbred (Wistar:Hannover) population of 60 rats. Animals were subjected to 6h of immobilisation stress. Basal (1 week before stress) and post-stress (immediately after stress) plasma corticosterone (CC) was measured for each animal from the tail vein (basal: 239.74+/-19.44 ng/ml at 1500 h). Group H was assigned to animals with 33% higher levels of CC (>279.53 ng/ml) and group L to animals with 33% lower levels of CC (<199.09 ng/ml). After stress, animals with higher plasma CC levels in basal conditions showed higher adrenal response (higher post-stress CC levels) than rats with lower levels of basal CC. Furthermore, rats from H group are more vulnerable to accumulation of oxidative/nitrosative mediators in brain (higher calcium-independent nitric oxide activity and higher lipid peroxidation, by malondialdehyde determination, MDA) and also to the accumulation of proinflammatory mediators (higher PGE(2) levels) whereas showing less antiinflammatory protection (less 15-deoxy-PGJ(2) levels). Statistical analysis, by using ROC curves revealed cut-off values of basal plasma CC predicting animals with higher post-stress MDA and PGE(2) and lower PGJ(2) levels in brain. These data indicate that plasma basal levels of CC are an easily detectable and reproducible parameter for predicting the response of the individuals after an acute stress, providing further support for studies on individual differences.

The labor induction: integrated clinical and sonographic variables that predict the outcome.

OBJECTIVE: To analyze the clinical and sonographic variables that predicts the success of labor induction. STUDY DESIGN: We studied the Bishop score, cervical length and parity in 196 pregnant women in the prediction of successful vaginal delivery within 24 h of induction. Logistic regression and segmentation analysis were performed. RESULTS: Cervical length (odds ratio (OR) 1.089, P<0.001), Bishop score (OR 0.751, P=0.001) and parity (OR 4.7, P<0.001) predict the success of labor induction. In a global analysis of the variables studied, the best statistic sequence that predicts the labor induction was found when we introduced parity in the first place. The success of labor induction in nulliparous was 50.8 and 83.3% in multiparous women (P=0.0001). CONCLUSIONS: Cervical length, Bishop score and parity, integrated in a flow chart, provide independent prediction of vaginal delivery within 24 h of induction.

Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases.

The innate immunity is a stereotyped first line of defense against pathogens and unspecified damage signals. One of main actors of innate immunity are the Toll-like receptors (TLRs), and one of the better characterized members of this family is TLR-4, that it is mainly activated by Gram-negative bacteria lipopolysaccharide. In brain, TLR-4 organizes innate immune responses against infections or cellular damage, but also possesses other physiological functions. In the last years, some evidences suggest a role of TLR-4 in stress and stress-related neuropsychiatric diseases. Peripheral and brain TLR-4 activation triggers sickness behavior, and its expression is a risk factor of depression. Some elements of the TLR-4 signaling pathway are up-regulated in peripheral samples and brain post-mortem tissue from depressed and suicidal patients. The "leaky gut" hypothesis of neuropsychiatric diseases is based on the existence of an increase of the intestinal permeability which results in bacterial translocation able to activate TLR-4. Enhanced peripheral TLR-4 expression/activity has been described in subjects diagnosed with schizophrenia, bipolar disorder and in autistic children. A role for TLR-4 in drugs abuse has been also proposed. The therapeutic potential of pharmacological/genetic modulation of TLRs signaling pathways in neuropsychiatry is promising, but a great preclinical/clinical scientific effort is still needed.

BDNF and NGF Signalling in Early Phases of Psychosis: Relationship With Inflammation and Response to Antipsychotics After 1 Year.

Previous studies have indicated systemic deregulation of the proinflammatory or anti-inflammatory balance in individuals with first-episode psychosis (FEP) that persists 12 months later. To identify potential risk/protective factors and associations with symptom severity, we assessed possible changes in plasma levels of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and their receptors in peripheral blood mononuclear cells (PBMCs). Expression of the 2 forms of BDNF receptors (active TrkB-FL and inactiveTrkB-T1) in PBMCs of FEP patients changed over time, TrkB-FL expression increasing by 1 year after diagnosis, while TrkB-T1 expression decreased. The TrkB-FL/TrkB-T1 ratio (hereafter FL/T1 ratio) increased during follow-up in the nonaffective psychosis group only, suggesting different underlying pathophysiological mechanisms in subgroups of FEP patients. Further, the expression of the main NGF receptor, TrkA, generally increased in patients at follow-up. After adjusting for potential confounders, baseline levels of inducible isoforms of nitric oxide synthase, cyclooxygenase, and nuclear transcription factor were significantly associated with the FL/T1 ratio, suggesting that more inflammation is associated with higher values of this ratio. Interestingly, the FL/T1 ratio might have a role as a predictor of functioning, a regression model of functioning at 1 year suggesting that the effect of the FL/T1 ratio at baseline on functioning at 1 year depended on whether patients were treated with antipsychotics. These findings may have translational relevance; specifically, it might be useful to assess the expression of TrkB receptor isoforms before initiating antipsychotic treatment in FEPs.

Obesity favors surgical and infectious complications after renal transplantation.

UNLABELLED: The prevalence of obesity is increasing in the renal transplant population. There are controversial data with respect to posttransplant outcome. We performed a study comparing the incidence of surgical and infectious complications among 40 obese patients (body mass index [BMI] pretransplant > or =30 kg/m2) versus a matched nonobese control group (BMI <30 kg/m2) transplanted at our center between June 1989 and March 2001. RESULTS: There were no differences in patient demographic variables (mean age, gender, cause of renal failure, or percentage of diabetes or hepatitis C virus infection). Donor age, HLA mismatching, sensitization, cold ischemia time, and immunosuppressive regimen were similar in both groups. The mean pretransplant BMI in obese and nonobese patients was 34.1+/-4.0 versus 23.00+/-2.73 kg/m2 (P<.01). The obese group showed a higher incidence of delayed graft function (30% versus 5%, P<.05) and wound infections (12.5%) posttransplant with similar incidences of wound dehiscence, perigraft collections, and graft function at the end of follow up.

Results of kidney transplantation in recipients over 70 years of age: experience at a single center.

We performed 41 kidney transplants in patients >70 years (35 single and 6 dual), with a mean recipient age of 72+/-2 years, from January 1990 to December 2001. Mean age of the donors was 69+/-12 years. Immunosuppression used triple therapy with steroids, mycophenolate mofetil, and cyclosporine or tacrolimus. Cold ischemia time was 23+/-3 hours. The incidence of primary nonfunction was 4.8%, and delayed graft function 58.5%. Acute rejection incidence was 12%. The actuarial patient survival rates at 12, 24, and 36 months were 82.5%, 82.5%, and 75%, respectively. Actuarial survival rates of the grafts censuring for death of the recipient with a functioning graft were 89.5%, 86%, and 68%, respectively. Nine of the 18 graft losses were due to recipient death. Overall, renal transplant recipients >70 years showed good results. The principal cause of graft loss was recipient death.

[Membranoproliferative glomerulonephritis associated with autoimmune thyroiditis]. / Glomerulonefritis membranoproliferativa hipocomplementémica asociada a tiroiditis autoinmune.

Several cases of glomerular disease have been associated to thyroid diseases. The most frequent lesion described is membranous glomerulopathy, presented as a nephrotic syndrome. Here we report a 67-year-old man who developed a nephrotic syndrome accompanied by rapid derangement of renal function shortly after the onset of a primary hypothyroidism due to autoimmune thyroiditis. High titers of circulating anti-thyroglobulin and anti-microsomal thyroid antigen antibodies were detected. Serum levels of C3 and C4 fractions of complement were markedly decreased. Renal biopsy showed a membranoproliferative glomerulonephritis with severe mesangial proliferation, a type of glomerular involvement non-described previously in the literature, in relation with thyroid diseases. Four boluses of intravenous steroids were administered, followed by oral prednisone for three months. A dramatic recovery of renal function, together with normalization of urinary sediment, proteinuria decrease and normalization of serum complement were observed. Three years later, the patient suffered from a similar event, with a positive response to steroids again. One year later, the patient had a new recurrence and was treated with mycophenolate mofetil , improving his clinical situation.

[Immunoallergic interstitial nephritis vs. cholesterol atheroembolism. Differentiating characteristics]. / Nefritis intersticial inmunoalérgica vs ateroembolismo de colesterol. Características diferenciales.

The commonest clinical presentation of both immunoalergic interstitial nephritis (IIN) and atheroembolic renal disease (ATD) is an acute renal failure accompanied by skin lesions and eosinophilia. As a consequence, differential diagnosis between both entities is often very difficult. We have performed a comparative retrospective study of those patients diagnosed as having IIN or ATD in our Hospital in the period 1980-2000. A total of 42 patients have been diagnosed of IIN and 16 of ATD. Demographic data, as well as clinical and laboratory parameters and outcomes of every studied patient were analysed. We found a significantly higher prevalence of male sex (100% vs 57%, p < 0.01), previous history of hypertension (100% vs 55%, p < 0.01), chronic renal insufficiency (56% vs 17%, p < 0.01), ischemic heart disease (56% vs 14%, p < 0.001), peripheral ischemic disease, endovascular procedures (87% vs 7%, p < 0.001) and anticoagulant treatments (25% vs 5%, p < 0.001) among patients with ATD as compared with IIN, respectively. On the contrary, previous infections (45% vs 12%, p < 0.01) and exposure to new drugs (100% vs 40%, p < 0.001) were significantly more frequent among IIN patients in compare with ATD. ATD patients showed skin lesions consisting of livedo reticularis and digital infarcts (63% vs 31%, p < 0.05) accompanied by blood pressure increase (100% vs 24%, p < 0.001), whereas IIN patients showed fever (41% vs 19%, p < 0.05) and cutaneous rash as significant clinical manifestations, respectively. The number of ATD patients with proteinuria > 1 g/24 h was significantly higher, but no differences between both groups in the prevalence of urinary sediment abnormalities were observed. The prevalence of absolute eosinophilia was high in both groups (88% among ATD patients, 64% among IIN patients; pNS). Prognosis of both entities was clearly different: Almost all patients with ATD died (69%) or evolved to end-stage renal failure, whereas most patients with IIN showed a recovery of renal function after withdrawal of responsible drugs and steroid treatment. In summary, the analysis of clinical and laboratory data allows an initial differential diagnosis in patients suspected as having IIN or ATD.

Regulatory role of the cannabinoid CB2 receptor in stress-induced neuroinflammation in mice.

BACKGROUND AND PURPOSE: Stress exposure produces excitotoxicity and neuroinflammation, contributing to the cellular damage observed in stress-related neuropathologies. The endocannabinoids provide a homeostatic system, present in stress-responsive neural circuits. Here, we have assessed the possible regulatory role of cannabinoid CB2 receptors in stress-induced excitotoxicity and neuroinflammation. EXPERIMENTAL APPROACH: We used wild type (WT), transgenic overexpressing CB2 receptors (CB2xP) and CB2 receptor knockout (CB2-KO) mice exposed to immobilization and acoustic stress (2 h·day(-1) for 4 days). The CB2 receptor agonist JWH-133 was administered daily (2 mg·kg(-1), i.p.) to WT and CB2-KO animals. Glutamate uptake was measured in synaptosomes from frontal cortex; Western blots and RT-PCR were used to measure proinflammatory cytokines, enzymes and mediators in homogenates of frontal cortex. KEY RESULTS: Increased plasma corticosterone induced by stress was not modified by manipulating CB2 receptors. JWH-133 treatment or overexpression of CB2 receptors increased control levels of glutamate uptake, which were reduced by stress back to control levels. JWH-133 prevented the stress-induced increase in proinflammatory cytokines (TNF-α and CCL2), in NF-κB, and in NOS-2 and COX-2 and in the consequent cellular oxidative and nitrosative damage (lipid peroxidation). CB2xP mice exhibited anti-inflammatory or neuroprotective actions similar to those in JWH-133 pretreated animals. Conversely, lack of CB2 receptors (CB2-KO mice) exacerbated stress-induced neuroinflammatory responses and confirmed that effects of JWH-133 were mediated through CB2 receptors. CONCLUSIONS AND IMPLICATIONS: Pharmacological manipulation of CB2 receptors is a potential therapeutic strategy for the treatment of stress-related pathologies with a neuroinflammatory component, such as depression.