Publications by authors named "Juan C Leza"

89 Publications

Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology.

J Neuroinflammation 2021 Sep 12;18(1):198. Epub 2021 Sep 12.

Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain.

Background: The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA).

Methods: This work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by high-performance liquid chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored.

Results: In the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzyme expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolite content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC.

Conclusions: Thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.
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http://dx.doi.org/10.1186/s12974-021-02260-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436477PMC
September 2021

Inflammatory dysregulation in women with an eating disorder: Relationships with altered emotional reactivity.

Int J Eat Disord 2021 Aug 21. Epub 2021 Aug 21.

Department of Legal Medicine, Psychiatry, and Pathology, Universidad Complutense de Madrid (UCM), Madrid, Spain.

Background: Some studies suggest that inflammatory signaling dysregulation may contribute to eating disorder (ED) pathophysiology. However, little is known about the influence of inflammatory response on altered processes seen among patients with ED, such as emotional processing and reactivity.

Objectives: The objectives were: (a) to investigate the systemic inflammatory response in ED women; and (b) to analyze the role of inflammatory markers in emotional reactivity.

Method: Concentrations of several intercellular and intracellular inflammatory mediators (cytokines, prostaglandin by-products and enzymes, TBARS, and MAPK proteins) were quantified in plasma and PBMCs from 68 women with an ED (m = 22.01 years, SD = 9.15) and 35 healthy controls (m = 18.54 years, SD = 4.21). Moreover, emotional reactivity to affective pictures (those without either food or thinness content) was studied using the adult (>18 years old) sample (n = 41).

Results: Between-group differences were revealed for most markers (TNF-α, PGE , COX2, and ratio of activated MAPK proteins), pointing to increased inflammatory response in patients (p < .01). Women with ED showed heightened emotional reactivity, regardless of picture valence. Principal components derived from inflammatory markers showed an explanatory loading on patient's emotional reaction, in terms of valence and arousal.

Conclusion: This study corroborates the altered systemic inflammatory response in patients with ED. The inflammatory dysregulation may contribute to ED phenotype, as seen by its relationship with heightened emotional reactivity, even though the inflammatory markers were not evaluated throughout the emotional reactivity protocol.
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http://dx.doi.org/10.1002/eat.23598DOI Listing
August 2021

Neuroplasticity and inflammatory alterations in the nucleus accumbens are corrected after risperidone treatment in a schizophrenia-related developmental model in rats.

Schizophr Res 2021 Sep 20;235:17-28. Epub 2021 Jul 20.

Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla 72570, Mexico. Electronic address:

Increased dopaminergic activity in the striatum underlies the neurobiology of psychotic symptoms in schizophrenia (SZ). Beyond the impaired connectivity among the limbic system, the excess of dopamine could lead to inflammation and oxidative/nitrosative stress. It has been suggested that atypical antipsychotic drugs attenuate psychosis not only due to their modulatory activity on the dopaminergic/serotonergic neurotransmission but also due to their anti-inflammatory/antioxidant effects. In such a manner, we assessed the effects of the atypical antipsychotic risperidone (RISP) on the structural neuroplasticity and biochemistry of the striatum in adult rats with neonatal ventral hippocampus lesion (NVHL), which is a developmental SZ-related model. RISP administration (0.25 mg/kg, i.p.) ameliorated the neuronal atrophy and the impairments in the morphology of the dendritic spines in the spiny projection neurons (SPNs) of the ventral striatum (nucleus accumbens: NAcc) in the NVHL rats. Also, RISP treatment normalized the pro-inflammatory pathways and induced the antioxidant activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this model. Our results point to the neurotrophic, anti-inflammatory, and antioxidant effects of RISP, together with its canonical antipsychotic mechanism, to enhance striatum function in animals with NVHL.
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http://dx.doi.org/10.1016/j.schres.2021.07.014DOI Listing
September 2021

A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders.

Int J Neuropsychopharmacol 2021 Sep;24(9):734-748

Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.

Background: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model.

Methods: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue.

Results: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen).

Conclusions: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.
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http://dx.doi.org/10.1093/ijnp/pyab036DOI Listing
September 2021

Paliperidone Reversion of Maternal Immune Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways.

Front Pharmacol 2021 13;12:682602. Epub 2021 May 13.

Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Bizkaia, Madrid, Spain.

Emerging evidence indicates that early-life exposure to environmental factors may increase the risk for schizophrenia via inflammatory mechanisms. Inflammation can alter the metabolism of tryptophan through the oxidative kynurenine pathway to compounds with neurotoxic and neuroprotective activity and compromise serotonin (5-HT) synthesis. Here we investigate the role of serotonergic and kynurenine pathways in the maternal immune activation (MIA) animal model of schizophrenia. The potential reversion exerted by long-term antipsychotic treatment was also evaluated. MIA was induced by prenatal administration of polyinosinic:polycytidylic acid (poly (I:C)) in mice. Expression of different proteins and the content of different metabolites involved in the function of serotonergic and kynurenine pathways was assessed by RT-PCR, immunoblot and ELISA analyses in frontal cortex of the offspring after puberty. MIA decreased tissue 5-HT content and promoted changes in the expression of serotonin transporter, 5-HT and 5-HT receptors. Expression of indoleamine 2,3-dioxygenase 2 (IDO2) and kynurenine 3-monooxygenase (KMO) was increased by poly (I:C) whereas kynurenine aminotransferase II and its metabolite kynurenic acid were not altered. Long-term paliperidone was able to counteract MIA-induced changes in 5-HT and KMO, and to increase tryptophan availability and tryptophan hydroxylase-2 expression in poly (I:C) mice but not in controls. MIA-induced increase of the cytotoxic risk ratio of kynurenine metabolites (quinolinic/kynurenic acid) was also reversed by paliperidone. MIA induces specific long-term brain effects on serotonergic activity. Such effects seem to be related with alternative activation of the kynurenine metabolic pathway towards a cytotoxic status. Atypical antipsychotic paliperodine partially remediates abnormalities observed after MIA.
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http://dx.doi.org/10.3389/fphar.2021.682602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156415PMC
May 2021

Omega-3 fatty acids during adolescence prevent schizophrenia-related behavioural deficits: Neurophysiological evidences from the prenatal viral infection with PolyI:C.

Eur Neuropsychopharmacol 2021 May 15;46:14-27. Epub 2021 Mar 15.

Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; CIBER de Salud Mental (CIBERSAM), Madrid, Spain. Electronic address:

The likely involvement of inflammation and oxidative stress (IOS) in mental disease has led to advocate anti-oxidant and anti-inflammatory drugs as therapeutic strategies in the treatment of schizophrenia. Since omega-3 fatty acids (ω-3) show anti-inflammatory/neuroprotective properties, we aim to evaluate whether ω-3 treatment during adolescence in the maternal immune stimulation (MIS) animal model of schizophrenia could prevent the brain and behavioural deficits described in adulthood. At gestational day 15, PolyI:C (4 mg/kg) or saline (VH) were injected to pregnant Wistar rats. Male offspring received ω-3 (800 mg/kg) or saline (Sal) daily from postnatal day (PND) 35-49, defining 4 groups: MIS-ω-3; MIS-Sal; VH-ω-3 and VH-Sal. At PND70, rats were submitted to prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed in adulthood and analyzed by means of SPM12. IOS markers were measured in selected brain areas. MIS-offspring showed a PPI deficit compared with VH-offspring and ω-3 treatment prevented this deficit. Also, ω-3 reduced the brain metabolism in the deep mesencephalic area and prevented the volumetric abnormalities in the hippocampus but not in the ventricles in MIS-offspring. Besides, ω-3 reduced the expression of iNOS and Keap1 and increased the activity/concentration of HO1, NQO1 and GPX. Our study demonstrates that administration of ω-3 during adolescence prevents PPI behavioural deficits and hippocampal volumetric abnormalities, and partially counteracts IOS deficits via iNOS and Nrf2-ARE pathways in the MIS model. This study highlights the need for novel strategies based on anti-inflammatory/anti-oxidant compounds to alter the disease course in high-risk populations at early stages.
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http://dx.doi.org/10.1016/j.euroneuro.2021.02.001DOI Listing
May 2021

The prefrontal cortex as a target for atypical antipsychotics in schizophrenia, lessons of neurodevelopmental animal models.

Prog Neurobiol 2021 04 30;199:101967. Epub 2020 Nov 30.

Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico. Electronic address:

Prefrontal cortex (PFC) inflammatory imbalance, oxidative/nitrosative stress (O/NS) and impaired neuroplasticity in schizophrenia are thought to have neurodevelopmental origins. Animal models are not only useful to test this hypothesis, they are also effective to establish a relationship among brain disturbances and behavior with the atypical antipsychotics (AAPs) effects. Here we review data of PFC post-mortem and in vivo neuroimaging, human induced pluripotent stem cells (hiPSC), and peripheral blood studies of inflammatory, O/NS, and neuroplasticity alterations in the disease as well as about their modulation by AAPs. Moreover, we reviewed the PFC alterations and the AAP mechanisms beyond their canonical antipsychotic action in four neurodevelopmental animal models relevant to the study of schizophrenia with a distinct approach in the generation of schizophrenia-like phenotypes, but all converge in O/NS and altered neuroplasticity in the PFC. These animal models not only reinforce the neurodevelopmental risk factor model of schizophrenia but also arouse some novel potential therapeutic targets for the disease including the reestablishment of the antioxidant response by the perineuronal nets (PNNs) and the nuclear factor erythroid 2-related factor (Nrf2) pathway, as well as the dendritic spine dynamics in the PFC pyramidal cells.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101967DOI Listing
April 2021

Functionality and Neurocognition in Patients With Bipolar Disorder After a Physical-Exercise Program (FINEXT-BD Study): Protocol of a Randomized Interventionist Program.

Front Psychiatry 2020 29;11:568455. Epub 2020 Oct 29.

Severe Mental Illness Research Group, Bioaraba Health Research Institute, Vitoria-Gasteiz, Spain.

Recent studies have shown that symptoms of psychiatric illness, functionality, and cognitive function improve with exercise. The aim of this study will be to investigate whether the implementation of an individualized exercise program will improve the functional status of patients with bipolar disorder (BD). This longitudinal, interventional, randomized, controlled, simple-blind clinical trial will include 80 patients aged 18-65 years, all of them with BD diagnosis. Patients will be randomly assigned to a physical exercise intervention + Treatment-As-Usual (TAU) group and a non-intervention + TAU group. Patients will be assessed by an extensive battery of clinical tests, physical parameters (e.g., brain structure changes measured by optical coherence tomography, cardiorespiratory fitness) and biological parameters (inflammation, oxidative stress and neurotrophic factors) at baseline, after a 4-month intervention period, and 6-month follow-up. This is an innovative study aimed at gaining a deeper understanding of the physiopathology of BD and determining whether the prognosis and evolution of the disease can be improved through modifiable areas of the patient's lifestyle. NCT04400630. NCT clinicaltrials.gov. Date of registration in primary registry 22 May 2020. clinicaltrials.gov.
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http://dx.doi.org/10.3389/fpsyt.2020.568455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670851PMC
October 2020

Acute effects of a session of electroconvulsive therapy on brain-derived neurotrophic factor plasma levels.

Rev Psiquiatr Salud Ment (Engl Ed) 2020 Jul 13. Epub 2020 Jul 13.

Barcelona Clínic Schizophrenia Unit, Neuroscience Institute, Hospital Clínic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en red en salud Mental (CIBERSAM), Departament de Medicina, Universitat de Barcelona, Spain.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are neurotrophins that play critical roles in brain neuronal function. Previous studies have established the association between BDNF and NGF signaling and severe mental disorders, but changes in BDNF plasma levels and electroconvulsive therapy (ECT) response are controversial. The aim of his study was to explore the acute effects of a single session of ECT on these neurotrophins signaling. Plasma levels of BDNF and NGF and their tyrosine kinase-type receptors expression in peripheral blood mononuclear cells (PBMCs) were determined before and two hours after a single ECT session in 30 subjects with a severe mental disorder. Two hours after an ECT session we found a statistically significant decrease of BDNF plasma levels (p=0.007). We did not find significant acute effects on NGF plasma levels or receptors expression in PBMCs. We found a significant inverse correlation between the time of convulsion and BDNF plasma levels decrease (r=-0.041, p=0.024). We have identified a decrease in BDNF plasma levels after 2h of a single ECT session. These results indicate the interest for future research in the role of neurotrophins in the response and safety of ECT.
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http://dx.doi.org/10.1016/j.rpsm.2020.05.011DOI Listing
July 2020

Microglial CX3CR1 production increases in Alzheimer's disease and is regulated by noradrenaline.

Glia 2021 01 14;69(1):73-90. Epub 2020 Jul 14.

Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain.

The loss of noradrenergic neurons and subsequent reduction of brain noradrenaline (NA) levels are associated with the progression of Alzheimer's disease (AD). This seems to be due mainly to the ability of NA to reduce the activation of microglial cells. We previously observed that NA induces the production of the chemokine Fractalkine/CX3CL1 in neurons. The activation of microglial CX3CR1, sole receptor for CX3CL1, reduces the activation of microglia, which is known to largely contribute to the neuronal damage characteristic of AD. Therefore, alterations of CX3CR1 production in microglia could translate into the enhancement or inhibition of CX3CL1 anti-inflammatory effects. In order to determine if microglial CX3CR1 production is altered in AD and if NA can control it, CX3CR1 expression and synthesis were analyzed in 5xFAD mice and human AD brain samples. In addition, the effects of NA and its reuptake inhibitor reboxetine were analyzed in microglial cultures and mice respectively. Our results indicate that in AD CX3CR1 production is increased in the brain cortex and that reboxetine administration further increases it and enhances microglial reactivity toward amyloid beta plaques. However, direct administration of NA to primary rat microglia or human HMC3 cells inhibits CX3CR1 production, suggesting that microglia responses to NA may be altered in the absence of CX3CL1-producing neurons or other nonmicroglial external factors.
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http://dx.doi.org/10.1002/glia.23885DOI Listing
January 2021

Childhood trauma determines different clinical and biological manifestations in patients with eating disorders.

Eat Weight Disord 2021 Apr 18;26(3):847-857. Epub 2020 May 18.

Department of Psychiatry and Psychology, Medical School, Complutense University, Av. Séneca, 2, 28040, Madrid, Spain.

Purpose: There is a significant relationship between childhood trauma and the development of an eating disorder in adolescence or adulthood, possibly influenced by circulating levels of inflammatory parameters. The main objective is to identify and describe a subgroup of patients with eating disorders and a history of trauma in childhood or adolescence with differential clinical features.

Methods: An observational study on a sample of 55 patients who met the diagnostic criteria for any DSM-5 eating disorder was carried out. Inflammatory parameters in white blood cells were examined. Patients underwent different assessments, including clinical and personality scales.

Results: Patients with a history of trauma had higher scores in the delirious and narcissistic items of the Millon Clinical Multiaxial Inventory (MCMI-II) (p < 0.05) and a higher score in the paranoid item of the SCID-5 Personality Disorders Version (SCID-5-PD) (p < 0.05). Patients with distinguishing personality features were grouped according to the Childhood Trauma Questionnaire sexual subscale. Tumor necrosis alpha (TNF-α) showed a significant association with childhood trauma history.

Conclusions: There is a profile of patients with eating disorders who have increased activity in the inflammatory pathways that, if identified precociously, can benefit from specifically aimed interventions.

Level Of Evidence: Level V, observational study.
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http://dx.doi.org/10.1007/s40519-020-00922-7DOI Listing
April 2021

Depletion of brain perivascular macrophages regulates acute restraint stress-induced neuroinflammation and oxidative/nitrosative stress in rat frontal cortex.

Eur Neuropsychopharmacol 2020 05 31;34:50-64. Epub 2020 Mar 31.

Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, Madrid 28040, Spain. Electronic address:

The central nervous system can respond to peripheral immune stimuli through the activation of the neurovascular unit. One of the cellular types implicated are perivascular macrophages (PVMs), hematopoietic-derived brain-resident cells located in the perivascular space. PVMs have been implicated in the immune surveillance and in the regulation of the accumulation/trafficking of macromolecules in brain-blood interfaces. Recent studies suggested that the role of PVMs could vary depending on the nature and duration of the immune challenge applied. Here, we investigate the role of PVMs in stress-induced neuroinflammation and oxidative/nitrosative consequences. The basal phagocytic activity of PVMs was exploited to selectively deplete them by ICV injection of liposomes encapsulating the pro-apoptotic drug clodronate. Acute restraint stress-induced neuroinflammation and oxidative/nitrosative stress in rat brain frontal cortex samples were assessed by western blot and RT-PCR analyses. The depletion of PVMs: (1) decreased tumor necrosis-α levels (2) prevented the Janus kinase/signal transducers and activators of transcription pathway and increased interleukin-6 receptor protein-expression in stress conditions; (3) prevented the stress-induced Toll-like receptor 4/Myeloid differentiation primary response 88 protein signaling pathway; (4) down-regulated the pro-inflammatory nuclear factor κB/cyclooxygenase-2 pathway; (5) prevented stress-induced lipid peroxidation and the concomitant increase of the endogenous antioxidant mediators nuclear factor (erythroid-derived 2)-like 2, glutathione reductase 1 and Parkinsonism-associated deglycase mRNA expression. Our results point to PVMs as regulators of stress-induced neuroinflammation and oxidative/nitrosative stress. Much more scientific effort is still needed to evaluate whether their selective manipulation is promising as a therapeutic strategy for the treatment of stress-related neuropsychopathologies.
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http://dx.doi.org/10.1016/j.euroneuro.2020.03.004DOI Listing
May 2020

Inflammatory and antioxidant pathway dysfunction in borderline personality disorder.

Psychiatry Res 2020 02 11;284:112782. Epub 2020 Jan 11.

Biomedical Research Networking Consortium for Mental Health (CIBERSAM), Hospital Gregorio Marañón, Pabellón de Gobierno 1ª Planta C/Dr. Esquerdo 46, 28007 Madrid, Spain; Department of Psychiatry and Medical Psychology, Faculty of Medicine, Universidad Complutense de Madrid (UCM), Ciudad Universitaria s/n, 28040 Madrid, Spain.

Introduction: This study investigates the alteration of the inflammatory/oxidative pathway in patients with borderline personality disorder (BPD) and its relationship with clinical features of the disorder.

Methods: 49 BPD patients and 33 healthy control subjects were studied. Plasma levels of TBARS, nitrites, and the antioxidant enzymes CAT, GPx and SOD were measured. In addition, peripheral blood mononuclear cells were obtained to investigate levels of intracellular components of the inflammatory/oxidative pathway including the IκBα, NFκB, iNOS, COX2, Keap1, NQO1, and HO1. Western Blot and ELISA were used to measure protein expression. Patients were assessed for different clinical dimensions of BPD with scales for depression, anxiety, impulsivity and functioning.

Results: A significant decrease of IκBα levels and a significant increase of inflammatory factors, including NFκB, COX2 and iNOS levels were found in patients. On the other hand, a significant decrease was observed for all antioxidant enzymes in patients with BPD, except for HO1. The inflammatory factor NFκB showed a significant positive correlation with impulsivity scores.

Conclusions: Patients with BPD presented an increased activation of several components of the inflammatory pathways, as well as an inhibition of the antioxidant path. These alterations appear partially correlated with the impulsivity scores in these patients.
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http://dx.doi.org/10.1016/j.psychres.2020.112782DOI Listing
February 2020

Toll-like receptor 4 agonist and antagonist lipopolysaccharides modify innate immune response in rat brain circumventricular organs.

J Neuroinflammation 2020 Jan 6;17(1). Epub 2020 Jan 6.

Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM); Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12); Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain.

Background: The circumventricular organs (CVOs) are blood-brain-barrier missing structures whose activation through lipopolysaccharide (LPS) is a starting point for TLR-driven (Toll-like receptors) neuroinflammation. The aim of this study was to evaluate in the CVO area postrema (AP), subfornical organ (SFO), and median eminence (ME), the inflammatory response to two TLR4 agonists: LPS from Escherichia coli (EC-LPS), the strongest endotoxin molecule described, and LPS from Porphyromonas gingivalis (PG-LPS), a pathogenic bacteria present in the periodontium related to neuroinflammation in neurodegenerative/psychiatric diseases. The response to LPS from the cyanobacteria Rhodobacter sphaeroides (RS-LPS), a TLR4 antagonist with an interesting anti-inflammatory potential, was also assessed.

Methods: LPSs were intraperitoneally administered to Wistar rats and, as indicatives of neuroinflammation in CVOs, the cellular localization of the nuclear factor NF-κB was studied by immunofluorescence, and microglia morphology was quantified by fractal and skeleton analysis.

Results: Data showed that EC-LPS increased NF-κB nuclear translocation in the three CVOs studied and PG-LPS only induced NF-κB nuclear translocation in the ME. RS-LPS showed no difference in NF-κB nuclear translocation compared to control. Microglia in the three CVOs showed an ameboid-shape after EC-LPS exposure, whereas PG-LPS only elicited a mild tendency to induce an ameboid shape. On the other hand, RS-LPS produced a markedly elongated morphology described as "rod" microglia in the three CVOs.

Conclusions: In conclusion, at the doses tested, EC-LPS induces a stronger neuroinflammatory response than PG-LPS in CVOs, which might be related to their different potency as TLR4 agonists. The non-reduction of basal NF-κB activation and induction of rod microglia by RS-LPS, a cell morphology only present in severe brain injury and infections, suggests that this molecule must be carefully studied before being proposed as an anti-inflammatory treatment for neuroinflammation related to neurodegenerative/psychiatric diseases.
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http://dx.doi.org/10.1186/s12974-019-1690-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945636PMC
January 2020

Risperidone Ameliorates Prefrontal Cortex Neural Atrophy and Oxidative/Nitrosative Stress in Brain and Peripheral Blood of Rats with Neonatal Ventral Hippocampus Lesion.

J Neurosci 2019 10 13;39(43):8584-8599. Epub 2019 Sep 13.

Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, 72570, Mexico,

Reduction of the dendritic arbor length and the lack of dendritic spines in the pyramidal cells of the prefrontal cortex (PFC) are prevalent pathological features in schizophrenia (SZ). Neonatal ventral hippocampus lesion (NVHL) in male rats reproduces these neuronal characteristics and here we describe how this is a consequence of BDNF/TrkB pathway disruption. Moreover, COX-2 proinflammatory state, as well as Nrf-2 antioxidant impairment, triggers oxidative/nitrosative stress, which also contributes to dendritic spine impairments in the PFC. Interestingly, oxidative/nitrosative stress was also detected in the periphery of NVHL animals. Furthermore, risperidone treatment had a neurotrophic effect on the PFC and antioxidant effects on the brain and periphery of NVHL animals; these cellular effects were related to behavioral improvement. Our data highlight the link between brain development and immune response, as well as several other factors to understand mechanisms related to the pathophysiology of SZ. Prefrontal cortex dysfunction in schizophrenia can be a consequence of morphological abnormalities and oxidative/nitrosative stress, among others. Here, we detailed how impaired plasticity-related pathways and oxidative/nitrosative stress are part of the dendritic spine pathology and their modulation by atypical antipsychotic risperidone treatment in rats with neonatal ventral hippocampus lesion. Moreover, we found that animals with neonatal ventral hippocampus lesion had oxidative/nitrosative stress in the brain as well as in the peripheral blood, an important issue for the translational approaches of this model. Then, risperidone restored plasticity and reduced oxidative/nitrosative stress of prefrontal cortex pyramidal cells, and ultimately improved the behavior of lesioned animals. Moreover, risperidone had differential effects than the brain on peripheral blood oxidative/nitrosative stress.
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http://dx.doi.org/10.1523/JNEUROSCI.1249-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807277PMC
October 2019

Dysfunction of inflammatory pathways in adolescent female patients with anorexia nervosa.

Prog Neuropsychopharmacol Biol Psychiatry 2020 01 6;96:109727. Epub 2019 Aug 6.

Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Dept. of Psychiatry, Legal Medicine & Pathology, Faculty of Medicine, (UCM), IIS Hospital Clínico San Carlos, Madrid, Spain. Electronic address:

Background: The pathogenesis of Eating Disorders is still unknown. However, a growing body of evidence shows that there are changes in cytokine levels and an alteration in the stress response in patients with anorexia nervosa (AN). For this reason, we decided to test whether there are differences in immune parameters involved in the regulation of the inflammatory response between female adolescents with AN and healthy adolescents.

Methods: The sample 27 drug-naïve AN patients the study sample included 27 AN patients at a very early stage of the disease and 23 healthy controls. Plasma and peripheral blood mononuclear cells (PBMCs) were obtained for biochemical study.

Results: Plasma levels of the pro-inflammatory cytokines TNF-α and IL-1β were significantly increased in patients with AN, while the levels of prostaglandins PGE (proinflammatory) and 15d-PGJ, (anti-inflammatory) were lower compared with controls. Protein expression in PBMCs of cyclooxygenase-2 (COX-2) and the activated forms of the mitogen-activated protein kinases p38 and ERK were also increased in the AN group. Expression levels of the anti-inflammatory factor peroxisome proliferator-activated receptor gamma (PPARγ) were significantly decreased in patients. Plasma levels of lipid peroxidation markers -TBARS- were not increased in patients with AN. Components of the biochemical inflammatory response (COX-2, PGE, TBARS, 15d-PGJ, ERK, p65 NFκB) and glucocorticoid receptor -GR- expression and the scores on the impulsivity measures in the BARRATT, EDI and BITE questionnaires showed a significant correlation within the AN patients group.

Conclusions: The results for female adolescent patients with AN indicate that there is a dysfunction of intra- and intercellular inflammatory pathways characterized by higher levels of pro-inflammatory parameters in plasma and a decrease in one of the controlling cytoplasmic-nuclear pathways implicated in their modulation (i.e. PPARγ) with, at this very early stage of the disease, no effect on oxidative stress markers plasma levels. Most notably, higher severity of illness (restrictive and purging behaviour) correlated with higher levels of inflammatory markers.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109727DOI Listing
January 2020

Reboxetine Treatment Reduces Neuroinflammation and Neurodegeneration in the 5xFAD Mouse Model of Alzheimer's Disease: Role of CCL2.

Mol Neurobiol 2019 Dec 11;56(12):8628-8642. Epub 2019 Jul 11.

Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid (UCM), Av. Complutense s/n, 28040, Madrid, Spain.

The reduction of brain noradrenaline levels is associated to the initiation of Alzheimer's disease and contributes to its progression. This seems to be due mainly to the anti-neuroinflammatory actions of noradrenaline. The analysis of noradrenaline effects on brain cells demonstrates that it also regulates the production of the chemokine CCL2. In the present study, we analyzed the effect of the selective noradrenaline reuptake inhibitor, reboxetine, on the inflammatory and neurodegenerative alterations present in 5xFAD mice, and how the genetic removal of CCL2 affects reboxetine actions. We observed that the removal of CCL2 reduced the memory impairments in 5xFAD mice as well as the neuroinflammatory response, the accumulation of amyloid beta plaques, and the degeneration of neurons in the brain cortex. The administration of reboxetine with osmotic pumps for 28 days also resulted in anti-inflammatory and neuroprotective changes in 5xFAD mice, even in the absence of CCL2. Yet, 6-month-old CCL2KO mice presented a significant degree of neuroinflammation and neuronal damage. These findings indicate that reboxetine treatment prevents the brain alterations caused by prolonged overproduction of amyloid beta, being these effects independent of CCL2, which is a mediator of the damage caused by amyloid beta in the brain cortex, but necessary for the prevention of the development of neurodegeneration in normal healthy conditions.
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http://dx.doi.org/10.1007/s12035-019-01695-6DOI Listing
December 2019

Effects of electroconvulsive therapy in the systemic inflammatory balance of patients with severe mental disorder.

Psychiatry Clin Neurosci 2019 Oct 15;73(10):628-635. Epub 2019 Jul 15.

Barcelona Clínic Schizophrenia Unit, Neuroscience Institute, Hospital Clínic de Barcelona, Barcelona, Spain.

Aim: There is a great interest in the role of the immune system and the inflammatory balance as key mechanisms involved in the pathophysiology of severe mental disorders. Previous studies have indicated that electroconvulsive therapy (ECT) produces changes in certain inflammatory mediators or in the immune system response. This study aimed to explore the effects of ECT on the nuclear transcription factor κB (NFκB) pathway, a main regulatory pathway of the inflammatory/immune response.

Methods: Thirty subjects with a severe mental disorder receiving treatment with ECT in our center were included. Thirteen systemic biomarkers related to the NFκB pathway were analyzed right before and 2 h after a single ECT session.

Results: An ECT session significantly decreased the expression of NFκB (P = 0.035) and of the inducible nitric oxide synthase (P = 0.012), and the plasma levels of nitrites (P = 0.027), prostaglandin E (P = 0.049), and 15-deoxy-PGJ (P < 0.001). Decrease in plasmatic levels of nitrites was greater in females than in males (P = 0.021). A positive correlation between the ECT stimulus load and changes in the expression of NFkB was found (P = 0.036). Thiobarbituric acid reactive substance levels were decreased in treatment responders and increased in non-responders (P = 0.047).

Conclusion: Our study shows the effects that a single session of ECT produces on a canonical regulatory pathway of the inflammatory/innate immune system and the inflammatory balance. These biomarkers could be useful as treatment response targets and could help to clarify the biological basis of ECT action. These findings warrant greater attention in future investigations and in the translational significance of these data.
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http://dx.doi.org/10.1111/pcn.12906DOI Listing
October 2019

Risperidone administered during adolescence induced metabolic, anatomical and inflammatory/oxidative changes in adult brain: A PET and MRI study in the maternal immune stimulation animal model.

Eur Neuropsychopharmacol 2019 07 20;29(7):880-896. Epub 2019 Jun 20.

Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; CIBER de Salud Mental (CIBERSAM), Madrid, Spain.

Inflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.
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http://dx.doi.org/10.1016/j.euroneuro.2019.05.002DOI Listing
July 2019

Modulation of Monoaminergic Systems by Antidepressants in the Frontal Cortex of Rats After Chronic Mild Stress Exposure.

Mol Neurobiol 2019 Nov 3;56(11):7522-7533. Epub 2019 May 3.

Departamento de Farmacología y Toxicología, Facultad de Medicina; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM); Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12); Instituto Universitario de Investigación en Neuroquímica UCM, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain.

The standard pharmacological treatment of the major depressive disorder (MDD) is still grounded in a monoaminergic approach. Consequently, antidepressant treatments pursue to heighten serotonergic and noradrenergic neurotransmissions. Thus, the aim of this study was to assess the impact of exposure to a well-characterized animal model, the chronic mild stress (CMS) on serotonin (5-HT) and noradrenaline (NE) levels, and reuptake transporters and receptors in the frontal cortex (FC) of CMS-exposed rats. Moreover, considering the diverse pharmacological profiles of existing antidepressants and the large number of patients not responding to treatments, we have investigated whether generally utilized antidepressants can modulate their expression. Male Wistar rats were exposed to CMS and some of them treated with desipramine, escitalopram, or duloxetine. Possible changes in the described monoaminergic neurotransmission elements were evaluated. CMS induced differences in the expression of reuptake transporters and receptors involved in the monoaminergic neurotransmission pointing towards the weakening of their signaling. CMS antidepressant-treated rats showed an improvement of the monoaminergic tone, being desipramine and duloxetine more influential than escitalopram over noradrenergic elements and having the three antidepressant-tested effects on serotonergic transmission. In summary, there are molecular alterations on the monoaminergic neurotransmission in FC induced by CMS exposure. Besides, antidepressant treatments modulate the elements of these neurotransmission systems differentially.
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http://dx.doi.org/10.1007/s12035-019-1619-xDOI Listing
November 2019

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants.

J Neuroinflammation 2018 Sep 4;15(1):251. Epub 2018 Sep 4.

Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III (ISCIII), C/ Monforte de Lemos 3-5, 28029, Madrid, Spain.

Background: Studies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). However, evidence of this participation in the brain of patients with MDD has been elusive.

Methods: This work explores whether the protein expression by immunodetection assays (Western blot) of elements of TLR-4 pathways controlling inflammation and the oxidative/nitrosative stress are altered in postmortem dorsolateral prefrontal cortex of subjects with MDD. The potential modulation induced by the antidepressant treatment on these parameters was also assessed. Thirty MDD subjects (15 antidepressant-free and 15 under antidepressant treatment) were matched for gender and age to 30 controls in a paired design.

Results: No significant changes in TLR-4 expression were detected. An increased expression of the TLR-4 endogenous ligand Hsp70 (+ 33%), but not of Hsp60, and the activated forms of mitogen-activated protein kinases (MAPKs) p38 (+ 47%) and JNK (+ 56%) was observed in MDD. Concomitantly, MDD subjects present a 45% decreased expression of DUSP2 (a regulator of MAPKs) and reduced (- 21%) expression of the antioxidant nuclear factor Nrf2. Antidepressant treatment did not modify the changes detected in the group with MDD and actually increased (+ 25%) the expression of p11, a protein linked with the transport of neurotransmitters and depression.

Conclusion: Data indicate an altered TLR-4 immune response in the brain of subjects with MDD. Additional research focused on the mechanisms contributing to the antidepressant-induced TLR-4 pathway modulation is warranted and could help to develop new treatment strategies for MDD.
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http://dx.doi.org/10.1186/s12974-018-1294-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122627PMC
September 2018

Oxidative Stress and Inflammation in First-Episode Psychosis: A Systematic Review and Meta-analysis.

Schizophr Bull 2019 06;45(4):742-751

Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain.

Despite mixed findings, increasing evidence suggests that people with first-episode psychosis (FEP) show increased pro-inflammatory and pro-oxidative status. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to conduct a systematic literature search of cross-sectional studies comparing in vivo inflammatory and oxidative blood markers between FEP patients and healthy controls. We analyzed 61 independent samples from 59 publications, including 3002 patients with FEP (ie, patients with FEP, early psychosis, first-episode schizophrenia or early schizophrenia) and 2806 controls. After controlling for multiple comparisons, our meta-analysis showed that total antioxidant status and docosahexaenoic acid levels were significantly lower in FEP patients than in controls, whereas levels of homocysteine, interleukin-6 and tumor necrosis factor alpha were significantly higher in FEP patients than in controls. This suggests that FEP patients had reduced antioxidant status and a pro-inflammatory imbalance, and that these biological processes may be targets for managing FEP.
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http://dx.doi.org/10.1093/schbul/sby125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581144PMC
June 2019

Alternative Method to Detect Neuronal Degeneration and Amyloid β Accumulation in Free-Floating Brain Sections With Fluoro-Jade.

ASN Neuro 2018 Jan-Dec;10:1759091418784357

1 Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid (UCM), Spain.

Fluoro-Jade is a fluorescein-derived fluorochrome which specifically binds to damaged neurons. Due to this characteristic, it is commonly used for the histochemical detection and quantification of neurodegeneration in mounted brain sections. Here, we describe an alternative and simpler histochemistry protocol based on the use of free-floating brain sections. For this purpose, we have used brain slices from wild-type and 5xFAD mice as well as from mice that received an intracerebral injection of oligomeric amyloid beta peptides. We observed that our histochemistry staining procedure allows for a well-defined labeling of degenerating neurons providing a better signal-to-noise ratio staining than the commonly used one. In addition, our modified protocol demonstrates the ability of Fluoro-Jade C to also fluorescently label amyloid beta plaques.
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http://dx.doi.org/10.1177/1759091418784357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043921PMC
July 2019

Chronic Mild Stress Alters Kynurenine Pathways Changing the Glutamate Neurotransmission in Frontal Cortex of Rats.

Mol Neurobiol 2019 Jan 3;56(1):490-501. Epub 2018 May 3.

Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain.

Immune stimulation might be involved in the pathophysiology of major depressive disorder (MDD). This stimulation induces indoleamine 2,3-dioxygenase (IDO), an enzyme that reduces the tryptophan bioavailability to synthesize serotonin. IDO products, kynurenine metabolites, exert neurotoxic/neuroprotective actions through glutamate receptors. Thus, we study elements of these pathways linked to kynurenine metabolite activity examining whether antidepressants (ADs) can modulate them. Male Wistar rats were exposed to chronic mild stress (CMS), and some of them were treated with ADs. The expression of elements of the IDO pathway, including kynurenine metabolites, and their possible modulation by ADs was studied in the frontal cortex (FC). CMS increased IDO expression in FC compared to control group, and ADs restored the IDO expression levels to control values. CMS-induced IDO expression led to increased levels of the excitotoxic quinolinic acid (QUINA) compared to control, and ADs prevented the rise in such levels. Neither CMS nor ADs changed significantly the antiexcitotoxic kynurenic acid (KYNA) levels. The QUINA/KYNA ratio, calculated as excitotoxicity risk indicator, increased after CMS and ADs prevented this increase. CMS lowered excitatory amino acid transporter (EAAT)-1 and EAAT-4 expression, and some ADs restored their expression levels. Furthermore, CMS decreased N-methyl-D-aspartate receptor (NMDAR)-2A and 2B protein expression, and ADs mitigated this decrease. Our research examines the link between CMS-induced pro-inflammatory cytokines and the kynurenine pathway; it shows that CMS alters the kynurenine pathway in rat FC. Importantly, it also reveals the ability of classic ADs to prevent potentially harmful situations related to the brain scenario caused by CMS.
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http://dx.doi.org/10.1007/s12035-018-1096-7DOI Listing
January 2019

Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions.

Sci Rep 2017 10 13;7(1):13113. Epub 2017 Oct 13.

Department of Pharmacology, Faculty of Medicine, Hospital 12 de Octubre Imas12, IUINQ, University Complutense, Madrid, 28040, Spain.

Physiologically, lipopolysaccharide (LPS) is present in the bloodstream and can be bound to several proteins for its transport (i.e.) LPS binding protein (LBP) and plasma lipoproteins). LPS receptors CD14 and TLR-4 are constitutively expressed in the Central Nervous System (CNS). To our knowledge, LPS infiltration in CNS has not been clearly demonstrated. A naturalistic experiment with healthy rats was performed to investigate whether LPS is present with its receptors in brain. Immunofluorescences showed that lipid A and core LPS were present in circumventricular organs, choroid plexus, meningeal cells, astrocytes, tanycytes and endothelial cells. Co-localization of LPS regions with CD14/TLR-4 was found. The role of lipoprotein receptors (SR-BI, ApoER2 and LDLr) in the brain as targets for a LPS transport mechanism by plasma apolipoproteins (i.e. ApoAI) was studied. Co-localization of LPS regions with these lipoproteins markers was observed. Our results suggest that LPS infiltrates in the brain in physiological conditions, possibly, through a lipoprotein transport mechanism, and it is bound to its receptors in blood-brain interfaces.
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http://dx.doi.org/10.1038/s41598-017-13302-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640642PMC
October 2017

Differential regulation of the TLR4 signalling pathway in post-mortem prefrontal cortex and cerebellum in chronic schizophrenia: Relationship with SP transcription factors.

Prog Neuropsychopharmacol Biol Psychiatry 2017 10 10;79(Pt B):481-492. Epub 2017 Aug 10.

Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; Dept. of Pharmacology, Faculty of Medicine, Hospital 12 de Octubre Imas12, IUINQ, University Complutense, 28040 Madrid, Spain. Electronic address:

Alterations in innate immunity may underlie the pathophysiology of schizophrenia (SZ). Toll-like receptor-4 (TLR4) is a master element of innate immunity. The specificity proteins (SPs), transcription factors recently implicated in SZ, are putative regulatory agents of this. This work was aimed at describing alterations in the TLR4 signalling pathway in postmortem brain prefrontal cortex (PFC) and cerebellum (CB) of 16 chronic SZ patients and 14 controls. The possible association of TLR4 pathway with SP1 and SP4 and SZ negative symptomatology is explored. In PFC, TLR4/myeloid differentiation factor 88 (MyD88)/inhibitory subunit of nuclear factor kappa B alpha (IκBα) protein levels were lower in SZ patients, while nuclear transcription factor-κB (NFκB) activity, cyclooxygenase-2 (COX-2) expression and the lipid peroxidation index malondialdehyde (MDA) appeared increased. The pattern of changes in CB is opposite, except for COX-2 expression that remained augmented and MDA levels unaltered. Network interaction analysis showed that TLR4/MyD88/IκBα/NFκB/COX-2 pathway was coupled in PFC and uncoupled in CB. SP4 co-expressed with TLR4 and NFκB in PFC and both SP1 and SP4 co-expressed with NFκB in CB. In PFC, correlation analysis found an inverse relationship between NFκB and negative symptoms. In summary, we found brain region-specific alterations in the TLR4 signalling pathway in chronic SZ, in which SP transcription factors could participate at different levels. Further studies are required to elucidate the regulatory mechanisms of innate immunity in SZ and its relationship with symptoms.
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http://dx.doi.org/10.1016/j.pnpbp.2017.08.005DOI Listing
October 2017

Paliperidone reverts Toll-like receptor 3 signaling pathway activation and cognitive deficits in a maternal immune activation mouse model of schizophrenia.

Neuropharmacology 2017 04 28;116:196-207. Epub 2016 Dec 28.

Department of Pharmacology, Faculty of Medicine, University Complutense, Madrid, Spain; Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre & IUINQ, Madrid, Spain. Electronic address:

The pathophysiology of psychotic disorders is multifactorial, including alterations in the immune system caused by exogenous or endogenous factors. Epidemiological and experimental studies indicate that infections during the gestational period represent a risk factor to develop schizophrenia (SZ) along lifetime. Here, we tested the hypothesis that the antipsychotic paliperidone regulates immune-related brain effects in an experimental model of SZ. A well described prenatal immune activation model of SZ in mice by maternal injection of the viral mimetic poly(I:C) during pregnancy was used. Young-adult offspring animals (60PND) received paliperidone ip (0.05 mg/kg) for 21 consecutive days. One day after last injection, animals were submitted to a cognitive test and brain frontal cortex (FC) samples were obtained for biochemical determinations. The adults showed an activated innate immune receptor TLR-3 signaling pathway, oxidative/nitrosative stress and accumulation of pro-inflammatory mediators such as nuclear transcription factors (i.e., NFκB) and inducible enzymes (i.e., iNOS) in FC. Chronic paliperidone blocked this neuroinflammatory response possibly by the synergic activation and preservation of endogenous antioxidant/anti-inflammatory mechanisms such as NRF2 and PPARγ pathways, respectively. Paliperidone administration also stimulated the alternative polarization of microglia to the M2 anti-inflammatory profile. In addition, paliperidone treatment improved spatial working memory deficits of this SZ-like animal model. In conclusion, chronic administration of paliperidone to young-adult mice prenatally exposed to maternal immune (MIA) challenge elicits a general preventive anti-inflammatory/antioxidant effect at both intracellular and cellular polarization (M1/M2) level in FC, as well as ameliorates specific cognitive deficits.
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http://dx.doi.org/10.1016/j.neuropharm.2016.12.025DOI Listing
April 2017

Noradrenaline induces CX3CL1 production and release by neurons.

Neuropharmacology 2017 03 5;114:146-155. Epub 2016 Dec 5.

Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Av. Complutense s/n, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Neuroquímica and Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain. Electronic address:

CX3CL1 is a chemokine for which neurons constitute its primary source within the brain. Besides acting as a chemokine, CX3CL1 regulates multiple processes and is known to inhibit microglial activation. Because of this, CX3CL1 is considered as a messenger used by neurons to communicate with microglia. Similarly, the neurotransmitter noradrenaline reduces microglial activation and production of neurotoxic agents. Based on this, the regulation of neuronal CX3CXL1 by noradrenaline was analyzed. In primary cortical neurons, noradrenaline induced the accumulation of CX3CL1 protein and mRNA. Noradrenaline also increased CX3CL1 in its soluble form despite the inhibition of the activity and synthesis of ADAM10 and ADAM17, the main proteases known to cleave CX3CL1 from the neuronal membrane. Noradrenaline-treated neurons displayed a higher degree of dendritic arborization and a characteristic accumulation of CX3CL1 in the dendritic bifurcation zones. The soluble CX3CL1 produced by neurons after noradrenaline treatment, reduced the accumulation of nitrites in microglia. These findings indicate that NA anti-inflammatory actions are mediated by neuronal CX3CL1. In addition, CX3CL1 seems to be involved in the development of neuronal processes stimulated by noradrenaline.
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http://dx.doi.org/10.1016/j.neuropharm.2016.12.001DOI Listing
March 2017

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress.

Neurotherapeutics 2016 10;13(4):833-843

Department of Pharmacology, Faculty of Medicine, University Complutense, 28040, Madrid, Spain.

Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stress-induced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-β and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future.
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http://dx.doi.org/10.1007/s13311-016-0438-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081131PMC
October 2016

Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia.

J Psychiatry Neurosci 2016 04;41(3):E46-55

From the CIBERSAM. ISCIII, Spain (García-Bueno, MacDowell, Callado, Mas, Bernardo, Lafuente, Meana, Leza); the Department of Pharmacology, School of Medicine, Complutense University & Instituto de Investigación Hospital 12 de Octobre (Imas12). Madrid (García-Bueno, MacDowell, Leza); the Department of Anatomic Pathology, Pharmacology and Microbiology. School of Medicine, University of Barcelona, Barcelona (Gassó, Mas, Lafuente); the Department of Pharmacology, University of Basque Country UPV/EHU and BioCruces Institute, Bizkaia (Callado, Meana); the IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona (Gassó, Mas, Bernardo, Lafuente); and the Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona. Department of Psychiatry and Clinical Psychobiology, University of Barcelona (Bernardo).

Background: Alterations in the innate immune/inflammatory system may underlie the pathophysiology of schizophrenia, but we do not understand the mechanisms involved. The main agents of innate immunity are the Toll-like receptors (TLRs), which detect molecular patterns associated with damage and pathogens. The TLR first reported was TLR4, and it is still the most studied one.

Methods: We aimed to describe putative modifications to the TLR4 proinflammatory pathway using 2 different strategies in 2 cohorts of patients with schizophrenia and matched controls: 1) quantification of protein and mRNA expression in postmortem prefrontal cortex samples from 30 patients with schizophrenia and 30 controls, and 2) identification of single nucleotide polymorphisms associated with the risk of schizophrenia using whole blood samples from 214 patients with schizophrenia and 216 controls.

Results: We found evidence of alterations in the expression of the initial elements of the TLR4 signalling pathway (TLR4, Myeloid differentiation primary response gene 88 [MyD88] and nuclear factor-κ B [NF-κB]) in the PFC of patients with schizophrenia. These alterations seem to depend on the presence/absence of antipsychotic treatment at death. Moreover, a polymorphism within the MyD88 gene was significantly associated with schizophrenia risk.

Limitations: The use of 2 different approaches in 2 different cohorts, the lack of a complementary neuropsychiatric group, the possible confounding effects of antipsychotic treatment and suicide are the main limitations of our study.

Conclusion: The evidence from this dual approach suggests there is an altered innate immune response in patients with chronic schizophrenia in which the TLR4 proinflammatory pathway could be affected. Improved understanding of the stimuli and mechanisms responsible for this response could lead to improved schizophrenia treatment and better control of the side effects of current antipsychotics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853215PMC
http://dx.doi.org/10.1503/jpn.150195DOI Listing
April 2016
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