Juan C Leza

Instituto de Salud Carlos III, Madrid, Madrid, Spain

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Publications (140)546.16 Total impact

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    ABSTRACT: Stress-exposure produces excitoxicity and neuroinflammation, contributing to the cellular damage observed in stress-related neuropathologies. The endocannabinoid system is present in stress-responsive neural circuits and it is emerging as a homeostatic system. The aim of this study was to elucidate the possible regulatory role of cannabinoid-2 receptor in stress-induced excitotoxicity and neuroinflammation. Different genetic and pharmacological approaches were used: 1) Wild type (WT), transgenic over-expressing CB2 receptor (CB2xP) and CB2 receptor knockout (CB2-KO) mice were exposed to immobilization/acoustic stress (2h/day for 4 days), and 2) the CB2 receptor agonist JWH-133 was administered daily (2 mg kg(-1) , i.p.) to WT and CB2 receptor-KO animals. Stress-induced HPA axis activation was not modified by CB2 receptor manipulations. JWH-133 treatment or overexpression of CB2 resulted in an increase of control levels of glutamate uptake, which is then reduced by stress exposure back to control levels. JWH-133 prevented the stress-induced increase in the cytokines TNF-α and MCP-1, the nuclear factor kappa B, the enzymes inducible nitric oxide synthase 2 and cyclooxygenase-2 and the cellular oxidative/nitrosative damage (lipid peroxidation) in brain frontal cortex. CB2xP mice displayed anti-inflammatory/neuroprotective actions similar to those observed in JWH-133 pre-treated animals. Conversely, CB2-KO mice experiments indicated that the lack of CB2 receptor exacerbated stress-induced neuroinflammatory responses and validated the CB2 receptor-dependent effects of JWH-133. These results suggest that pharmacological manipulation of CB2 receptor is a potential therapeutic strategy for the treatment of stress-related pathologies with a neuroinflammatory component, such as depression.
    British Journal of Pharmacology 01/2014; · 5.07 Impact Factor
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    ABSTRACT: The innate immune response is the first line of defence against invading microorganisms and it is also activated in different neurologic/neurodegenerative pathological scenarios. As a result, the family of the innate immune toll-like receptors (TLRs) and, in particular, the genetic/pharmacological manipulation of the TLR-4 signalling pathway emerges as a potential therapeutic strategy. Growing evidence relates stress exposure with altered immune responses, but the precise role of TLR-4 remains partly unknown. The present study aimed to elucidate whether the elements of the TLR-4 signalling pathway are activated after acute stress exposure in rat brain frontal cortex and its role in the regulation of the stress-induced neuroinflammatory response, by means of its pharmacological modulation with the intravenous administration of the TLR-4 specific inhibitor TAK-242. Considering that TLR-4 responds predominantly to lipopolysaccharide from gram-negative bacteria, we checked whether increased intestinal permeability and a resultant bacterial translocation is a potential regulatory mechanism of stress-induced TLR-4 activation. Acute restraint stress exposure upregulates TLR-4 expression both at the mRNA and protein level. Stress-induced TLR-4 upregulation is prevented by the protocol of antibiotic intestinal decontamination made to reduce indigenous gastrointestinal microflora, suggesting a role for bacterial translocation on TLR-4 signalling pathway activation. TAK-242 pre-stress administration prevents the accumulation of potentially deleterious inflammatory and oxidative/nitrosative mediators in the brain frontal cortex of rats. The use of TAK-242 or other TLR-4 signalling pathway inhibitory compounds could be considered as a potential therapeutic adjuvant strategy to constrain the inflammatory process taking place after stress exposure and in stress-related neuropsychiatric diseases.
    Journal of Neuroinflammation 01/2014; 11(1):8. · 4.35 Impact Factor
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    ABSTRACT: Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.
    PLoS ONE 01/2014; 9(8):e103639. · 3.73 Impact Factor
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    ABSTRACT: The objective of the study is to examine the association of baseline total antioxidant status (TAS) and glutathione (GSH) levels with short- and long-term cognitive functioning in patients with early onset first-episode psychosis, comparing affective and non-affective psychoses. We analysed 105 patients with an early onset-first episode psychosis (age 9–17 years) and 97 healthy controls. Blood samples were taken at admission for measurement of TAS and GSH, and cognitive performance was assessed at baseline and at 2 years of follow-up. Regression analysis was used to assess the relationship between TAS/GSH levels at baseline and cognitive performance at both time points, controlling for confounders. Baseline TAS and GSH levels were significantly lower in patients than healthy controls. In patients, baseline TAS was positively associated with the global cognition score at baseline (p = 0.048) and two years later (p = 0.005), while TAS was not associated with cognitive functioning in healthy controls. Further, baseline TAS in patients was specifically associated with the memory domain at baseline and with the memory and attention domains two years later. Stratifying by affective and non-affective psychoses, significant associations were only found between TAS and cognition in the non-affective psychosis group. Baseline GSH levels were not associated with cognitive functioning at either time point in either group. The antioxidant defence capacity in early onset first-episode psychotic patients is directly correlated with global cognition at baseline and at 2 years of follow-up, especially in non-affective psychosis.
    Schizophrenia Research 01/2014; · 4.59 Impact Factor
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    ABSTRACT: Noradrenaline (NA) is known to limit neuroinflammation. However, the previously described induction by NA of a chemokine involved in the progression of immune/inflammatory processes, such as chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein-1 (MCP-1), apparently contradicts NA anti-inflammatory actions. In the current study we analyzed NA regulation of astroglial chemokine (C-X3-C motif) ligand 1 (CX3CL1), also known as fractalkine, another chemokine to which both neuroprotective and neurodegenerative actions have been attributed. In addition, NA effects on other chemokines and pro-inflammatory mediators were also analyzed. Primary astrocyte-enriched cultures were obtained from neonatal Wistar rats. These cells were incubated for different time durations with combinations of NA and lipopolysaccharide (LPS). The expression and synthesis of different proteins was measured by RT-PCR and enzyme-linked immunosorbent assay (ELISA) or enzyme immunoassays. Data were analyzed by one-way analysis of variance (ANOVA), followed by Newman-Keuls multiple comparison tests. The data presented here show that in control conditions, NA induces the production of CX3CL1 in rat cultured astrocytes, but in the presence of an inflammatory stimulus, such as LPS, NA has the opposite effect inhibiting CX3CL1 production. This inversion of NA effect was also observed for MCP-1. Based on the observation of this dual action, NA regulation of different chemokines and pro-inflammatory cytokines was also analyzed, observing that in most cases NA exerts an inhibitory effect in the presence of LPS. One characteristic exception was the induction of cyclooxygenase-2 (COX-2), where a summative effect was detected for both LPS and NA. These data suggest that NA effects on astrocytes can adapt to the presence of an inflammatory agent reducing the production of certain cytokines, while in basal conditions NA may have the opposite effect and help to maintain moderate levels of these cytokines.
    Journal of Neuroinflammation 07/2013; 10(1):81. · 4.35 Impact Factor
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    ABSTRACT: Several hypotheses involving alterations of the immune system have been proposed among etiological explanations for psychotic disorders. The endocannabinoid system (ECS) plays a homeostatic role as an endogenous neuroprotective and anti-inflammatory system. Alterations of this system have been associated with psychosis. Cannabis use is a robust risk factor for these disorders that could alter the ECS signalling. In this study, 95 patients with a first episode of psychosis (FEP) and 90 healthy controls were recruited. Protein expression of cannabinoid receptor 2 (CB2), the protein levels of the main endocannabinoid synthesizing enzymes N-acyl phosphatidylethanolamine phospholipase (NAPE) and Diacylglycerol lipase (DAGL) and of degradation enzymes Fatty acid amide hydrolase (FAAH) and Monoacylglycerol lipase (MAGL) were determined by Western-Blot in peripheral blood mononuclear cells (PBMC). Patients with a FEP showed a decreased expression of CB2 and of both endocannabinoids synthesizing enzymes (NAPE and DAGL) in comparison to healthy controls. After controlling for age, gender, body mass index and cannabis use, NAPE and DAGL expression remained significantly decreased, while FAAH and MAGL expression were increased. On the other hand, FEP subjects with history of severe cannabis use showed a larger ECS dysregulation compared to healthy controls. These results indicate an ECS dysregulation in PBMC of FEP patients. The alteration of the ECS presented at the initial phases of psychosis could be contributing to the pathophysiology of the disease and constitutes a possible biomarker of psychotic disorders and an interesting pharmacological target to take into account for therapeutic purposes.Neuropsychopharmacology accepted article preview online, 4 July 2013. doi:10.1038/npp.2013.165.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2013; · 8.68 Impact Factor
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    ABSTRACT: Dysfunctional serotoninergic regulation and hypothalamic-pituitary-adrenal (HPA) axis overreactivity have been consistently reported in research studies with eating disorders (ED). In addition, the links between stress response, serotonin function, HPA axis and inflammatory mechanisms in ED have also been suggested in a number of studies. In our study, inflammatory parameters in white blood cells were investigated in 26 female patients with ED and 25 healthy control subjects matched for sex, age and ethnicity. Patients were free of medication for at least two weeks at the time of the study. Results showed a significant increase in plasma levels of the proinflammatory cytokine IL1β and the protein expression of cyclooxygenase 2 (COX2) in peripheral mononuclear blood cells (PMBC) in ED patients compared with controls. As well as a significant increase of the oxidative-nitrosative marker TBARS (Thiobarbituric Acid Reactive Substances) in plasma. These findings were associated with increased expression of the alpha7 subunit of the nicotinic receptor (α7nAChR) in PMBC in ED patients independent of plasma cotinine levels. These results suggest that a pro-inflammatory and oxidant phenotype might be present in ED patients. Further research on cellular inflammatory and anti-inflammatory pathways might be oriented to investigate differences between ED subtypes and to search for new potential targets for pharmacological treatment.
    Brain Behavior and Immunity 04/2013; · 5.61 Impact Factor
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    ABSTRACT: Background:Schizophrenia is a chronic syndrome of unknown etiology, predominantly defined by signs of psychosis. The onset of the disorder occurs typically in late adolescence or early adulthood. Efforts to study pathophysiological mechanisms in early stages of the disease are crucial in order to prompt intervention.Methods:Case-control study of first-episode psychotic (FEP) patients and matched controls. We recruited 117 patients during the first year after their FEP according to the DSM-IV criteria and recruited 106 gender-, race-, and age-matched controls between September 2010 and June 2011.Results:Biochemical studies carried out in peripheral mononuclear blood cells (PMBC) and plasma evidence a significant increase in intracellular components of a main proinflammatory pathway, along with a significant decrease in the anti-inflammatory ones. Multivariate logistic regression analyses identified the expression of inducible isoforms of nitric oxide synthase and cyclooxygenase in PMBC and homocysteine plasma levels as the most reliable potential risk factors and the inhibitor of the inflammatory transcription factor NFκB, IκBα, and the anti-inflammatory prostaglandin 15d-PGJ2 as potential protection factors.Discussion:Taken as a whole, the results of this study indicate robust phenotypical differences at the cellular machinery level in PMBC of patients with FEP. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways including the activity of nuclear receptors has interesting potential as biological markers and potential risk/protective factors for FEP. Due to its soluble nature, a notable finding in this study is that the anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis.
    Schizophrenia Bulletin 03/2013; · 8.80 Impact Factor
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    ABSTRACT: 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.
    Translational psychiatry. 01/2013; 3:e221.
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    ABSTRACT: BACKGROUND: Our objective was to determine antioxidant defence activity in healthy controls (HC) and healthy unaffected second-degree relatives of patients with early onset psychosis (HC-FHP), and to assess its relationship with familiar environment measured using the Family Environment Scale (FES). METHODS: We included 82 HC and 14 HC-FHP aged between 9 and 17 years. Total antioxidant status, lipid peroxidation, antioxidant enzyme activities and glutathione levels were determined in blood samples. RESULTS: There was a significant decrease in the total antioxidant level in the HC-FHP group compared with the HC group (OR = 2.94; p = 0.009), but no between-group differences in the Global Assessment of Functioning (GAF) scale scores. For the FES, the HC-FHP group had significantly higher scores in the cohesion (p = 0.007) and intellectual-cultural dimensions (p=0.025). After adjusting for these two FES dimensions, total antioxidant status remained significantly different between groups (OR = 10.86, p = 0.009). CONCLUSIONS: Although causal relationships cannot be assumed, we can state that family environment is not playing a role in inducing oxidative stress in these healthy subjects. It could be hypothesized that families with affected relatives protect themselves from psychosis with positive environmental factors such as cohesion and intellectual-cultural activities.
    BMC Psychiatry 11/2012; 12(1):200. · 2.23 Impact Factor
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    ABSTRACT: A case-control study including patients (n = 20) with Borderline Personality Disorder (BPD) and healthy controls (n = 33) was carried out. To avoid interferences of other clinical conditions on biological findings, patients were free of current major depressive episodes or substance dependence disorders, and had no life history of schizophrenia, bipolar or neuropsychiatric disorders. Patients were free of medication for at least two weeks at the time of the study. Studies carried out in peripheral mononuclear blood cells and plasma evidence a systemic inflammatory condition in unstable-impulsive BPD patients. Specifically, a significant increase in some intracellular components of two main pro-inflammatory pathways such as iNOS and COX-2, as well as an increase in the plasma levels of the inflammatory cytokine IL1β. Interestingly, patients have an increase in the protein expression of the anti-inflammatory subtype of nicotinic receptor α7nAChR. This finding may reflect a possible mechanism trying to maintain intracellular inflammation pathways under control. All together, these results describe an imbalanced, pro-inflammatory and oxidant phenotype in BPD patients independent of plasma cotinine levels. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways have interesting potential as biological markers for BPD and other generalized impulsive syndromes, specially data obtained with α7nAChR and its lack of correlation with plasma levels of nicotine metabolites. Their pharmacological modulation with receptor modulators can be a promising therapeutic target to take into account in mental health conditions associated with inflammatory or oxido/nitrosative consequences. Also, identifying at-risk individuals would be of importance for early detection and intervention in adolescent subjects before they present severe behavioural problems.
    Journal of Psychiatric Research 10/2012; · 4.09 Impact Factor
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    ABSTRACT: BACKGROUND: Stressful challenges are associated with variations in immune parameters, including increased innate immunity/inflammation. Among possible mechanisms through which brain monitors peripheral immune responses, toll-like receptors (TLRs) recently emerged as the first line of defense against invading microorganisms. Their expression is modulated in response to pathogens and other environmental stresses. METHODS: Taking into account this background, the present study aimed to elucidate whether the toll-like receptor-4 (TLR-4) signaling pathway is activated after repeated restraint/acoustic stress exposure in mice prefrontal cortex (PFC), the potential regulatory mechanism implicated (i.e., bacterial translocation), and its role in conditions of stress-induced neuroinflammation, using a genetic strategy: C3H/HeJ mice with a defective response to lipopolysaccharide stimulation of TLR-4. RESULTS: Stress exposure upregulates TLR-4 pathway in mice PFC. Stress-induced inflammatory nuclear factor κB activation, upregulation of the proinflammatory enzymes nitric oxide synthase and cyclooxygenase type 2, and cellular oxidative/nitrosative damage are reduced when the TLR-4 pathway is defective. Conversely, TLR-4 deficient mice presented higher levels of the anti-inflammatory nuclear factor peroxisome proliferator activated receptor-gamma after stress exposure than control mice. The series of experiments using antibiotic intestinal decontamination also suggest a role for bacterial translocation on TLR-4 activation in PFC after stress exposure. CONCLUSIONS: Taken together, all the data presented here suggest a bifunctional role of TLR-4 signaling pathway after stress exposure by triggering neuroinflammation at PFC level and regulating gut barrier function/permeability. Furthermore, our data suggest a possible protective role of antibiotic decontamination in stress-related pathologies presenting increased intestinal permeability (leaky gut) such as depression, showing a potential therapeutic target that deserves further consideration.
    Biological psychiatry 08/2012; · 8.93 Impact Factor
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    ABSTRACT: Chronic pain and depression are two complex states with sensory/somatic and emotional components, and they may mutually exacerbate one another in conditions of comorbidity, leading to a poorer prognosis. The authors have evaluated the sensory and emotional components in a rat model combining chronic constriction injury (CCI, a model of chronic neuropathic pain) with unpredictable chronic mild stress (CMS, an experimental model of depression). In addition, the phosphorylation/activation of the extracellular signal-regulated kinases 1 and 2 and neuronal density was also evaluated in the anterior cingulate cortex. Four groups were tested: sham-control, sham-CMS, CCI-control, and CCI-CMS. CMS selectively heightens aversion to painful experiences in animals subjected to CCI, as measured in the place escape/avoidance test at 20, 25, and 30 min (CCI-CMS (mean±SEM): 75.68±3.32, 66.75±4.70, 77.54±3.60 vs. CCI-control: 44.66±6.07, 43.17±6.92, 52.83±5.92, respectively), in conjunction with an increase in the accumulation of phosphorylation/activation of the extracellular signal-regulated kinases (CCI-CMS: 4.17±0.52 vs. sham-control: 0.96±0.05) and a decrease in neuronal density in the anterior cingulate cortex. In contrast, chronic pain did not exacerbate the characteristic profile of depression (anhedonia and behavioral despair) in rats subjected to CMS. Furthermore, depression enhances the perception of some specific modalities of sensorial pain such as cold allodynia but has no influence on mechanical threshold. These findings support the theory that depression leads to emotional dysfunction in the interpretation of pain in patients suffering chronic pain. In addition, combined animal models of pain-depression may provide a valuable tool to study the comorbidity of pain and depression.
    Anesthesiology 07/2012; 117(3):613-25. · 5.16 Impact Factor
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    ABSTRACT: This study measures the levels of various markers of oxidative stress and inflammation in blood samples from first-episode psychosis (FEP) patients, and examines the association between these peripheral biomarkers and cognitive performance at 6 months after treatment. Twenty-eight FEP patients and 28 healthy controls (matched by age, sex and educational level) had blood samples taken at admission for assessment of total antioxidant status, superoxide dismutase (SOD), total glutathione (GSH), catalase (CAT), glutathione peroxidase, lipid peroxidation, nitrites and the chemokine monocyte chemoattractant protein-1 (MCP-1). A battery of cognitive tests was also applied to the healthy controls and those FEP patients who were in remission at 6 months after the acute episode. FEP patients had significantly lower levels of total antioxidant status, catalase and glutathione peroxidase, compared with the healthy controls. Regression analyses found that MCP-1 levels were negatively associated with learning and memory (verbal and working), nitrite levels were negatively associated with executive function, and glutathione levels were positively associated with executive function. Our results suggest an association between certain peripheral markers of oxidative stress and inflammation and specific aspects of cognitive functioning in FEP patients. Further studies on the association between MCP-1 and cognition are warranted.
    Schizophrenia Research 03/2012; 137(1-3):66-72. · 4.59 Impact Factor
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    ABSTRACT: Recent evidence suggests that children with autism have impaired detoxification capacity and may suffer from chronic oxidative stress. To our knowledge, there has been no study focusing on oxidative metabolism specifically in Asperger syndrome (a milder form of autism) or comparing this metabolism with other psychiatric disorders. In this study, total antioxidant status (TAOS), non-enzymatic (glutathione and homocysteine) and enzymatic (catalase, superoxide dismutase, and glutathione peroxidase) antioxidants, and lipid peroxidation were measured in plasma or erythrocyte lysates in a group of adolescent patients with Asperger syndrome, a group of adolescents with a first episode of psychosis, and a group of healthy controls at baseline and at 8-12 weeks. TAOS was also analyzed at 1 year. TAOS was reduced in Asperger individuals compared with healthy controls and psychosis patients, after covarying by age and antipsychotic treatment. This reduced antioxidant capacity did not depend on any of the individual antioxidant variables measured. Psychosis patients had increased homocysteine levels in plasma and decreased copper and ceruloplasmin at baseline. In conclusion, Asperger patients seem to have chronic low detoxifying capacity. No impaired detoxifying capacity was found in the first-episode psychosis group in the first year of illness.
    Journal of Psychiatric Research 03/2012; 46(3):394-401. · 4.09 Impact Factor
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    ABSTRACT: Progressive loss of cortical gray matter (GM), as measured by magnetic resonance imaging, has been described early in the course of first-episode psychosis. This study aims to assess the relationship between oxidative balance and progression of cortical GM changes in a multicenter sample of first-episode early-onset psychosis (EOP) patients from baseline to two-year follow-up. A total of 48 patients (13 females, mean age 15.9±1.5 years) and 56 age- and gender-matched healthy controls (19 females, 15.3±1.5 years) were assessed. Magnetic resonance imaging (MRI) scans performed both at the time of the first psychotic episode and 2 years later were used for volumetric measurements of left and right gray matter regions (frontal, parietal, and temporal lobes) and total sulcal cerebrospinal fluid (CSF). Total glutathione (GSH) blood levels were determined at baseline. In patients, after controlling for possible confounding variables, lower baseline GSH levels were significantly associated with greater volume decrease in left frontal (B=0.034, 95% confidence interval (CI): 0.011 to 0.056, r=0.620, p=0.006), parietal (B=0.039, 95% CI: 0.020 to 0.059, r=0.739, p=0.001), temporal (B=0.026, 95% CI: 0.016 to 0.036, r=0.779, p<0.001), and total (B=0.022, 95% CI: 0.014 to 0.031, r=0.803, p<0.001) gray matter, and with greater increase in total CSF (B=-0.560, 95% CI: -0.270 to -0.850, r=-0.722, p=0.001). Controls did not show significant associations between brain volume changes and GSH levels. GSH deficit during the first psychotic episode was related to greater loss of cortical GM two years later in patients with first-episode EOP, suggesting that oxidative damage may contribute to the progressive loss of cortical GM found in patients with first-episode psychosis.
    Schizophrenia Research 02/2012; 137(1-3):58-65. · 4.59 Impact Factor
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    ABSTRACT: Ibuprofen arginate is a highly soluble salt formed by combining racemic ibuprofen with the amino acid l-arginine. This formulation is absorbed faster, and it is safe and effective in treating many forms of mild to moderate pain. We compared the analgesic effect of ibuprofen arginate and conventional ibuprofen in rat models of pain. Mechanical and cold allodynia were assessed in the chronic constriction injury (CCI) model of neuropathic pain, and mechanical allodynia was also examined in capsaicin-injected rats (a model of central sensitization). Inflammatory hypersensitivity was assessed with the formalin test. Ibuprofen-l-arginine, ibuprofen, l-arginine or saline was administered orally on a daily basis after CCI or capsaicin injection, and the von Frey and cold plate tests were performed on days 1, 3 and 7 after CCI or capsaicin administration. In the formalin-induced inflammatory pain test, the drugs were administered 30 min before formalin injection. Ibuprofen only exerts an antinociceptive effect in the formalin model whereas ibuprofen-l-arginine exerts antinociceptive effects on both mechanical and cold allodynia induced by CCI, mechanical allodynia induced by capsaicin injection, and in phase 2 of the formalin test, exhibiting superior antinociceptive activity to ibuprofen in all these tests. l-Arginine only exerted antinociceptive effects on cold allodynia in CCI. These results demonstrate that ibuprofen arginate has stronger antinociceptive effects than ibuprofen in all the models used, suggesting it might improve the therapeutic management of neuropathic and inflammatory pain.
    Life sciences 01/2012; 90(1-2):13-20. · 2.56 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE The aim of this study was to explore the effects of CB2 receptor agonist and antagonist in the regulation of anxiety‐like behaviours.EXPERIMENTAL APPROACHES Effects of acute and chronic treatment with the CB2 receptor agonist JWH133 and CB2 receptor antagonist AM630 were evaluated in the light‐dark box (LDB) and elevated plus maze (EPM) tests in Swiss ICR mice. CB2 receptor, GABAAα2 and GABAAγ2 gene and protein expression in the cortex and amygdala of mice chronically treated with JWH133 or AM630 were examined by RT‐PCR and Western blot. Effects of chronic AM630 treatment were evaluated in spontaneously anxious DBA/2 mice in LDB.KEY RESULTS Acute JWH133 treatment failed to produce any effect. Acute AM630 treatment increased anxiety and was blocked by pre‐treatment with JWH133. Chronic JWH133 treatment increased anxiety‐like behaviour whereas chronic AM630 treatment was anxiolytic in LDB and EPM tests. Chronic AM630 treatment increased gene and reduced protein expression of CB2 receptors, GABAAα2 and GABAAγ2 in cortex and amygdala. Chronic JWH133 treatment resulted in opposite gene and protein alterations. In addition, chronic AM630 administration decreased the anxiety of DBA/2 mice in the LDB test.CONCLUSIONS AND IMPLICATIONS The opposing behavioural and molecular changes observed after chronic treatment with AM630 or JWH133 support the key role of CB2 receptors in the regulation of anxiety. Indeed, the efficacy of AM630 in reducing the anxiety of the spontaneously anxious DBA/2 strain of mice strengthens the potential of the CB2 receptor as a new target in the treatment of anxiety‐related disorders.
    British Journal of Pharmacology 01/2012; 165(4). · 5.07 Impact Factor
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    ABSTRACT: Inflammation, caused by both external and endogenous factors, has been implicated as a main pathophysiological feature of chronic mental illnesses, including schizophrenia. An increase in pro-inflammatory cytokines has been described both in experimental models and in schizophrenia patients. However, not much is known about the effects that antipsychotic drugs have on intra- and intercellular mechanisms controlling inflammation. The aim of the present study was to investigate the possible anti-inflammatory effect of a standard schizophrenia treatment not only at the level of soluble mediators, but also at intra- and intercellular inflammatory pathways. The present study was conducted in a model of mild neuroinflammation using a lipopolysaccharide (LPS) challenge that was not an endotoxaemic dose (0.5 mg/kg i.p.) in young adult rats. Main results: single doses of risperidone (0.3-3.0 mg/kg i.p.) prevented increased inflammatory parameters induced by LPS in brain cortex [expression of inflammatory cytokines, interleukin (IL)-1β and tumour necrosis factor (TNF)-α, activity of the inducible inflammatory enzymes nitric oxide synthase and cyclooxygenase, p38 mitogen-activated protein kinase (MAPK) and inflammatory nuclear transcription factor κB] and restored anti-inflammatory pathways decreased by LPS challenge (deoxyprostaglandins and peroxisome proliferator activated receptor γ). This is the first study demonstrating that risperidone elicits a preventive effect on the anti-inflammatory arm of the homeostatic mechanism controlling inflammation in a model of mild encephalitis in rats. Our findings suggest a possible protective effect of risperidone on brain cells.
    The International Journal of Neuropsychopharmacology 12/2011; · 5.64 Impact Factor
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    ABSTRACT: The deleterious effects of stress on the gastrointestinal tract seem to be mainly mediated by the induction of intestinal barrier dysfunction and subsequent subtle mucosal inflammation. Cannabinoid 1 receptor (CB1R) is expressed in the mammalian gut under physiological circumstances. The aim of this investigation is to study the possible role of CB1R in the maintenance of mucosal homeostasis after stress exposure. CB1R knockout mice (CB1R(-/-)) and their wild-type (WT) counterparts were exposed to immobilization and acoustic (IA) stress for 2 h per day during 4 consecutive days. Colonic protein expression of the inducible forms of the nitric oxide synthase and cyclooxygenase (NOS2 and COX2), IgA production, permeability to (51)Cr-EDTA, and bacterial translocation to mesenteric lymph nodes were evaluated. Stress exposure induced greater expression of proinflammatory enzymes NOS2 and COX2 in colonic mucosa of CB1R(-/-) mice when compared with WT animals. These changes were related with a greater degree of colonic barrier dysfunction in CB1R(-/-) animals determined by 1) a significantly lower IgA secretion, 2) higher paracellular permeability to (51)Cr-EDTA, and 3) higher bacterial translocation, both under basal conditions and after IA stress exposure. Pharmacological antagonism with rimonabant reproduced stress-induced increase of proinflammatory enzymes in the colon described in CB1R(-/-) mice. In conclusion, CB1R exerts a protective role in the colon in vivo through the regulation of intestinal secretion of IgA and paracellular permeability. Pharmacological modulation of cannabinoid system within the gastrointestinal tract might be therapeutically useful in conditions on which intestinal inflammation and barrier dysfunction takes place after exposure to stress.
    AJP Gastrointestinal and Liver Physiology 12/2011; 302(5):G565-71. · 3.65 Impact Factor

Publication Stats

3k Citations
546.16 Total Impact Points

Institutions

  • 2012–2014
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain
    • Hospital General Universitario Gregorio Marañón
      • Department of Psychiatry
      Madrid, Madrid, Spain
  • 1990–2014
    • Complutense University of Madrid
      • • Department of Pharmacology
      • • Facultad de Medicina
      Madrid, Madrid, Spain
  • 2013
    • Hospital 12 de Octubre
      Madrid, Madrid, Spain
  • 2010–2013
    • Centro de Investigación Biomedica En Red del Área de Salud Mental
      Madrid, Madrid, Spain
  • 2009–2011
    • Universidad Miguel Hernández de Elche
      • Instituto de Neurociencias
      Elx, Valencia, Spain
    • University of São Paulo
      • Departamento de Farmacologia (ICB)
      São Paulo, Estado de Sao Paulo, Brazil
  • 2008
    • Hospital Clínico San Carlos
      Madrid, Madrid, Spain
    • Salk Institute
      • Laboratory of Neuronal Structure and Function
      La Jolla, California, United States
  • 2006
    • University of Illinois at Chicago
      • Department of Anesthesiology (Chicago)
      Chicago, IL, United States
  • 1995
    • Hospital Carlos III - Madrid
      Madrid, Madrid, Spain
    • Facultad de Medicina
      Madrid, Madrid, Spain