Transdiagnostic inflammatory and oxidative biomarkers with predictive capacity of self-injurious behavior in impulsive and unstable disorders.

INTRODUCTION: Alterations in inflammatory processes have previously been reported in impulsive and unstable disorders, as well as in other psychiatric conditions. In order to investigate transdiagnostic biomarkers associated with various phenotypic features of these disorders, this study is designed to identify biomarkers of inflammatory and oxidative endophenotypes related to autolytic behavior. METHODS: Peripheral blood mononuclear cells were collected from 35 patients with borderline personality disorder (BPD), 29 patients with restrictive eating disorder (rED), 21 patients with purging eating disorder (pED) and 23 control subjects. Plasma levels of different inflammatory and oxidative factors were measured by ELISA and the expression of selected proteins was by Western Blot. Principal component analysis (PCA) was performed to categorize the different inflammatory factors. Additionally, Ancova was performed to observe the differences in the principal components among the different groups and logistic regression analysis was conducted to assess the predictive capacity of these components for autolytic behaviors. RESULTS: We found two inflammatory/oxidative components were associated with BPD, characterized by high levels of JNK and ERK and low levels of GPx, SOD and Keap1; and two other inflammatory/oxidative components were linked to pED, associated with more JNK, TBARS and TNF-α and less GPx and SOD. Two components, with more JNK and ERK and less GPx, SOD and Keap1, predicted non-suicidal self-injury and three components, with higher JNK, TBARS and TNF-α levels and lower GPx, SOD and iNOS levels, predicted suicide attempts. CONCLUSIONS: These results strongly support the endophenotypic characterization of impulsivity and the identification of transdiagnostic inflammatory/oxidative biomarkers relevant to autolytic behavior in impulsive and unstable disorders. These dates lay the groundwork for developing of screening tests for these biomarker components to rapidly detect biological risk factors for specific impulse control disorders and future self-injurious behaviors.

Decreased oxytocin plasma levels and oxytocin receptor expression associated with aggressive behavior in aggressive-impulsive disorders.

INTRODUCTION: This study aims to enhance the understanding of the association between the phenotypic and endophenotypic characteristics of impulsive-aggressive disorders, through the study of plasma oxytocin (OXT) and oxytocin receptor (OXTR) levels in patients with borderline personality disorder (BPD) and patients with eating disorders (ED), as well as to examine the relationship of OXT system with aggressive behavior in these disorders. METHODS: 68 patients with BPD, 67 patients with ED and 57 healthy control subjects were examined for plasma oxytocin levels and protein expression of OXTR in blood mononuclear cells. Aggressive behavior was assessed using the State-Trait Anger Expression Inventory (STAXI-2). Other self and hetero-aggressive behaviors were also evaluated through interviews. RESULTS: BPD and ED patients exhibited significantly lower plasma oxytocin levels than control subjects. Furthermore, BPD patients demonstrated significantly reduced expression of OXTR compared to controls. Plasma oxytocin levels negatively correlated with verbal aggression, while OXTR expression was inversely associated with the STAXI trait subscale. CONCLUSIONS: The findings validate the existence of oxytocin system dysfunction in impulsive-aggressive disorders. They also support the link between low OXT levels in plasma and OXTR expression and the impulsive-aggressive behavior that characterizes these patients in both state and trait situations.

Inflammatory and oxidative endophenotypes in borderline personality disorder: A biomarker cluster analysis.

OBJECTIVES: This study is designed to search for aggrupation of inflammatory/oxidative biomarker alterations in borderline personality disorder (BPD) and their association with phenotypic features. METHODOLOGY: Inflammatory/nitrosative proteins were measures in plasma and peripheral blood mononuclear cells obtained from BPD patients. Patients were assessed on different clinical dimensions of BPD. Oxidative damage was tested by measuring TBARS, nitrites, catalase, GPx and SOD. Protein expression of IκBα, NFκB, iNOS, COX-2, PPARγ, Keap1, NQO1, Nrf2 and α7nAChR was also determined. Western blot and ELISA were used for measurements and a cluster analysis of inflammatory/oxidative biomarkers alterations was performed to investigate subgroups of patients with similar alterations and its relationship with clinical features of BPD. RESULTS: 69 patients were included in the study. Two inflammatory/nitrosative clusters of patients were found: Cluster 1 patients showed significantly higher levels of GPx, IκBα, keap1, NQO1, PPARγ, α7nAChR and Nrf2 than cluster 2 patients. These patients had significantly longer duration of illness, milder anxiety symptoms and lower prescription of antipsychotic drugs than cluster 2. CONCLUSIONS: Two clusters of BPD patients according to the inflammatory/nitrosative profiles were identified. Cluster 1 had increased antioxidant and anti-inflammatory biomarkers and was characterised by greater chronicity of illness but less acute symptomatic severity.

Neuroimaging revealed long-lasting glucose metabolism changes to morphine withdrawal in rats pretreated with the cannabinoid agonist CP-55,940 during periadolescence.

This study evaluates the long-term effects of a six and 14-week morphine withdrawal in rats pretreated with a cannabinoid agonist (CP-55,940, CP) during periadolescence. Wistar rats (33 males; 32 females) were treated with CP or its vehicle (VH) from postnatal day (PND) 28-38. At PND100, rats performed morphine self-administration (MSA, 15d/12 h/session). Eight groups were defined according to pretreatment (CP), treatment (morphine), and sex. Three [18F]FDG-PET brain images were acquired: after MSA, and after six and 14 weeks of withdrawal. PET data were analyzed with SPM12. Endocannabinoid (EC) markers were evaluated in frozen brain tissue at endpoint. Females showed a higher mean number of self-injections than males. A main Sex effect on global brain metabolism was found. FDG uptake in males was discrete, whereas females showed greater brain metabolism changes mainly in areas of the limbic system after morphine treatment. Moreover, the morphine-induced metabolic pattern in females was exacerbated when CP was previously present. In addition, the CP-Saline male group showed reduced CB1R, MAGL expression, and NAPE/FAAH ratio compared to the control group, and morphine was able to reverse CB1R and MAGL expression almost to control levels. In conclusion, females showed greater and longer-lasting metabolic changes after morphine withdrawal than males, indicating a higher vulnerability and a different sensitivity to morphine in subjects pre-exposed to CP. In contrast, males primarily showed changes in EC markers. Together, our results suggest that CP pre-exposure contributes to the modulation of brain metabolism and EC systems in a sex-dependent manner.

Decreased oxytocin plasma levels and oxytocin receptor expression in borderline personality disorder.

INTRODUCTION: Borderline personality disorder (BPD) is characterized by intense affective reactions with underlying social and interpersonal cognitive deficits. Oxytocin has largely been associated with both stress regulation and social cognition in psychiatric patients and in non-clinical populations in previous studies. Finally, abnormal oxytocin levels have been preliminary reported in BPD patients. METHODS: 53 patients with moderate-severe BPD and 31 healthy control subjects were investigated for plasma levels of oxytocin and protein expression of oxytocin receptor in blood mononuclear cells. Clinical assessments were made for severity, functionality, and comorbidity with axis I and II conditions. RESULTS: Oxytocin plasma levels were significantly lower in BPD patients compared with controls. In addition, protein expression of oxytocin receptor was significantly reduced in the BPD group. A positive correlation was found between plasma oxytocin levels and the activity index score of the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ). Oxytocin receptor protein expression, on the contrary, had a negative correlation with the ZKPQ sociability index score. CONCLUSIONS: Results support the evidence of a dysfunction of the oxytocin system in borderline personality disorder, which could be involved in emotional dysregulation and interpersonal disturbances in these patients.

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.

Early versus late stage schizophrenia. What markers make the difference?

OBJECTIVES: To identify the psychopathological, cognitive, functional, physical health and inflammatory markers that differentiate between early-stage schizophrenia (ESSCH) and late-stage schizophrenia (LSSCH). METHODS: Cross-sectional, naturalistic study of 104 patients with SCH. The sample was divided in two groups: 35 ESSCH (≤7 years' duration of illness) and 69 LSSCH (>10 years' duration of illness). STATISTICAL ANALYSIS: chi-square test and Student's t-test and ANCOVA (or Quade test) controlling for age, sex, BMI and number of cigarettes/day. Finally, a binomial logistic regression was made. RESULTS: ESSCH show greater negative symptom severity (t = 2.465, p = 0.015), lower levels of IκBα (F = 7.644, p = 0.007), were more frequently classified as normal weight (40% vs 18.8%, p = 0.032) compared with LSSCH. The binomial logistic regression model included age (B = 0.127, p = 0.001) and IκBα (B = 0.025, p = 0.002) and accounted for 38.9% of the variance (model df =7, chi-square =41.841, p < 0.0001). CONCLUSIONS: Age and IκBα are the unique markers that differentiate between ESSCH patients whose duration of illness is less than 7 years and LSSCH patients. These results support the hypothesis of toxicity of episodes and highlight the importance of preventing new episodes.

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.

Regulation of inflammatory pathways in schizophrenia: A comparative study with bipolar disorder and healthy controls.

BACKGROUND: Immune-inflammatory processes have been implicated in schizophrenia (SCH), but their specificity is not clear. MAIN AIM: To identify potential differential intra-/intercellular biochemical pathways controlling immune-inflammatory response and their oxidative-nitrosative impact on SCH patients, compared with bipolar disorder (BD) patients and healthy controls (HC). METHODS: Cross-sectional, naturalistic study of a cohort of SCH patients (n=123) and their controls [BD (n=102) and HC (n=80)]. STATISTICAL ANALYSIS: ANCOVA (or Quade test) controlling for age and gender when comparing the three groups, and controlling for age, gender, length of illness, cigarettes per day, and body mass index (BMI) when comparing SCH and BD. RESULTS: Pro-inflammatory biomarkers: Expression of COX-1 was statistically higher in SCH and BD than HC (P<0.0001; P<0.0001); NFκB and PGE2 were statistically higher in SCH compared with BD (P=0.001; P<0.0001) and HC (P=0.003; P<0.0001); NLRP3 was higher in BD than HC (P=0.005); and CPR showed a gradient among the three groups. Anti-inflammatory biomarkers: BD patients had lower PPARγ and higher 15d-PGJ2 levels than SCH (P=0.005; P=0.008) and HC (P=0.001; P=0.001). Differences between SCH and BD: previous markers of SCH (NFκB and PGE2) and BD (PPARγ and 15d-PGJ2) remained statistically significant and, interestingly, iNOS and COX-2 (pro-inflammatory biomarkers) levels were statistically higher in SCH than BD (P=0.019; P=0.040). CONCLUSIONS: This study suggests a specific immune-inflammatory biomarker pattern for established SCH (NFκB, PGE2, iNOS, and COX-2) that differentiates it from BD and HC. In future, their pharmacological modulation may constitute a promising therapeutic target.

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.

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.

Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration.

Major depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs, mostly inhibiting the serotonin transporter (SERT). As a result, ~80% of patients show recurrent or chronic depression, resulting in a poor quality of life and increased suicide risk. RNA interference (RNAi) strategies have been preliminarily used to evoke antidepressant-like responses in experimental animals. However, the main limitation for the medical use of RNAi is the extreme difficulty to deliver oligonucleotides to selected neurons/systems in the mammalian brain. Here we show that the intranasal administration of a sertraline-conjugated small interfering RNA (C-SERT-siRNA) silenced SERT expression/function and evoked fast antidepressant-like responses in mice. After crossing the permeable olfactory epithelium, the sertraline-conjugated-siRNA was internalized and transported to serotonin cell bodies by deep Rab-7-associated endomembrane vesicles. Seven-day C-SERT-siRNA evoked similar or more marked responses than 28-day fluoxetine treatment. Hence, C-SERT-siRNA (i) downregulated 5-HT1A-autoreceptors and facilitated forebrain serotonin neurotransmission, (ii) accelerated the proliferation of neuronal precursors and (iii) increased hippocampal complexity and plasticity. Further, short-term C-SERT-siRNA reversed depressive-like behaviors in corticosterone-treated mice. The present results show the feasibility of evoking antidepressant-like responses by selectively targeting neuronal populations with appropriate siRNA strategies, opening a way for further translational studies.

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.

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.

Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs.

Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.

Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia.

Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D(1) receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder.

Stress-induced neuroinflammation: mechanisms and new pharmacological targets

Stress is triggered by numerous unexpected environmental, social or pathological stimuli occurring during the life of animals, including humans, which determine changes in all of their systems. Although acute stress is essential for survival, chronic, long-lasting stress can be detrimental. In this review, we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO) and an excess of pro-oxidants in various brain areas as responsible for both neuronal functional impairment and structural damage. Similarly, cyclooxygenase-2 (COX-2), another known source of oxidants, may account for stress-induced brain damage. Interestingly, some of the COX-2-derived mediators, such as the prostaglandin 15d-PGJ2 and its peroxisome proliferator-activated nuclear receptor PPARγ, are activated in the brain in response to stress, constituting a possible endogenous anti-inflammatory mechanism of defense against excessive inflammation. The stress-induced activation of both biochemical pathways depends on the activation of the N-methyl-D-aspartate (NMDA) glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFκB). In the case of inducible NO synthase (iNOS), release of the cytokine TNF-α also accounts for its expression. Different pharmacological strategies directed towards different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNF-α activation and release, inhibitors of NFκB, specific inhibitors of iNOS and COX-2 activities and PPARγ agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.

Mecanismos inflamatorios/antiinflamatorios en el cerebro tras la exposición a estrés / Inflammatory/anti-inflammatory mechanisms in the brain following exposure to stress

La mayoría de los sistemas biológicos que conforman un organismo se ven afectados por el estrés. Elsistema nervioso central no sólo tiene un papel esencial en la regulación de la respuesta general al estrés, sino que es una de las principales dianas. Las consecuencias pueden ser positivas (por ejemplo, estado de alerta) o negativas (patologías neuropsiquiátricas).Específicamente, la exposición a ciertos estímulos estresantes puede desencadenar un proceso neuroinflamatorio. Desarrollo. Se ha descrito que una respuesta neuroinflamatoria excesiva contribuye decisivamente al daño funcional y estructuralobservado en numerosas enfermedades neurológicas y neuropsiquiátricas relacionadas con el estrés, como el síndrome de estrés postraumático, la depresión y la esquizofrenia. El proceso inflamatorio generado por la exposición a estrés se caracteriza por una compleja liberación en cadena de diferentes mediadores celulares, tales como citocinas, factores de transcripción, prostaglandinas, radicales libres, etc. Paralelamente, se ha demostrado que la vía antiinflamatoria de las deoxiprostaglandinas se activa después de estrés en el sistema nervioso central, activación que podría constituir un mecanismo endógeno reguladordel propio proceso inflamatorio. Conclusiones. En el futuro, el mayor conocimiento y estudio de esta vía endógena podría convertirla en una nueva e interesante estrategia preventiva o neuroprotectora frente a las numerosas patologías que poseen un claro componente inflamatorio perjudicial, tales como la isquemia cerebral, enfermedades de Alzheimer y Parkinson, así comolas citadas anteriormente entre las relacionadas con la exposición a estrés

Most of the biological systems that go to make up an organism can be affected by stress. The centralnervous system not only plays an essential role in regulating the general response to stress, but it is also one of its main targets. The consequences may be positive (for example, a state of alertness) or negative (neuropsychiatric pathologies). More specifically, exposure to certain stressing stimuli can trigger a neuroinflammatory process. Development. Reports haveappeared describing how an excessive neuroinflammatory response makes a decisive contribution to the functional and structural damage that is often observed in stress-related neurological and neuropsychiatric diseases, such as post-traumatic stress syndrome, depression and schizophrenia. The inflammatory process generated by exposure to stress is characterised bya complex release of a chain of different cell mediators, such as cytosines, transcription factors, prostaglandins, free radicals, and so forth. In parallel to this, it has been proved that the anti-inflammatory pathway of deoxyprostaglandins is activatedafter stress in the central nervous system, and this activation could constitute an endogenous mechanism that regulates the inflammatory process itself. Conclusions. In the future, further studies and a deeper understanding of this endogenouspathway could make it into a new, interesting preventive or neuroprotective strategy for use in a number of pathologies that have a clear harmful inflammatory component, such as cerebral ischaemia, Alzheimer’s and Parkinson’s diseases, as well asthose mentioned earlier as being related to exposure to stress

[Inflammatory/anti-inflammatory mechanisms in the brain following exposure to stress]. / Mecanismos inflamatorios/antiinflamatorios en el cerebro tras la exposición a estrés.

INTRODUCTION: Most of the biological systems that go to make up an organism can be affected by stress. The central nervous system not only plays an essential role in regulating the general response to stress, but it is also one of its main targets. The consequences may be positive (for example, a state of alertness) or negative (neuropsychiatric pathologies). More specifically, exposure to certain stressing stimuli can trigger a neuroinflammatory process. DEVELOPMENT: Reports have appeared describing how an excessive neuroinflammatory response makes a decisive contribution to the functional and structural damage that is often observed in stress-related neurological and neuropsychiatric diseases, such as post-traumatic stress syndrome, depression and schizophrenia. The inflammatory process generated by exposure to stress is characterised by a complex release of a chain of different cell mediators, such as cytosines, transcription factors, prostaglandins, free radicals, and so forth. In parallel to this, it has been proved that the anti-inflammatory pathway of deoxyprostaglandins is activated after stress in the central nervous system, and this activation could constitute an endogenous mechanism that regulates the inflammatory process itself. CONCLUSIONS: In the future, further studies and a deeper understanding of this endogenous pathway could make it into a new, interesting preventive or neuroprotective strategy for use in a number of pathologies that have a clear harmful inflammatory component, such as cerebral ischaemia, Alzheimer's and Parkinson's diseases, as well as those mentioned earlier as being related to exposure to stress.