Publications by authors named "Karina S MacDowell"

25 Publications

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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 Jun 24. Epub 2021 Jun 24.

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 were injected to pregnant Wistar rats. 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 (PPI). 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 PPI 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
June 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 interplay between functioning problems and symptoms in first episode of psychosis: An approach from network analysis.

J Psychiatr Res 2021 04 15;136:265-273. Epub 2021 Feb 15.

Department of Psychiatry, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, IIS Princesa, CIBERSAM, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address:

The relationship between psychotic symptoms and global measures of functioning has been widely studied. No previous study has assessed so far the interplay between specific clinical symptoms and particular areas of functioning in first-episode psychosis (FEP) using network analysis methods. A total of 191 patients with FEP (age 24.45 ± 6.28 years, 64.9% male) participating in an observational and longitudinal study (AGES-CM) comprised the study sample. Functioning problems were assessed with the WHO Disability Assessment Schedule (WHODAS), whereas the Positive and Negative Syndrome Scale (PANSS) was used to assess symptom severity. Network analysis were conducted with the aim of analysing the patterns of relationships between the different dimensions of functioning and PANSS symptoms and factors at baseline. According to our results, the most important nodes were "conceptual disorganization", "emotional withdrawal", "lack of spontaneity and flow of conversation", "delusions", "unusual thought content", "dealing with strangers" and "poor rapport". Our findings suggest that these symptoms and functioning dimensions should be prioritized in the clinical assessment and management of patients with FEP. These areas may also become targets of future early intervention strategies, so as to improve quality of life in this population.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.024DOI Listing
April 2021

Periodontal diseases and depression: A pre-clinical in vivo study.

J Clin Periodontol 2021 04 9;48(4):503-527. Epub 2021 Feb 9.

ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group (UCM), Madrid, Spain.

Aim: To analyse, through a pre-clinical in vivo model, the possible mechanisms linking depression and periodontitis at behavioural, microbiological and molecular levels.

Materials And Methods: Periodontitis (P) was induced in Wistar:Han rats (oral gavages with Porphyromonas gingivalis and Fusobacterium nucleatum) during 12 weeks, followed by a 3-week period of Chronic Mild Stress (CMS) induction. Four groups (n = 12 rats/group) were obtained: periodontitis and CMS (P+CMS+); periodontitis without CMS; CMS without periodontitis; and control. Periodontal clinical variables, alveolar bone levels (ABL), depressive-like behaviour, microbial counts and expression of inflammatory mediators in plasma and brain frontal cortex (FC), were measured. ANOVA tests were applied.

Results: The highest values for ABL occurred in the P+CMS+ group, which also presented the highest expression of pro-inflammatory mediators (TNF-α, IL-1β and NF-kB) in frontal cortex, related to the lipoprotein APOA1-mediated transport of bacterial lipopolysaccharide to the brain and the detection of F. nucleatum in the brain parenchyma. A dysregulation of the hypothalamic-pituitary-adrenal stress axis, reflected by the increase in plasma corticosterone and glucocorticoid receptor levels in FC, was also found in this group.

Conclusions: Neuroinflammation induced by F. nucleatum (through a leaky mouth) might act as the linking mechanism between periodontal diseases and depression.
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http://dx.doi.org/10.1111/jcpe.13420DOI Listing
April 2021

Paliperidone attenuates chronic stress-induced changes in the expression of inflammasomes-related protein in the frontal cortex of male rats.

Int Immunopharmacol 2021 Jan 4;90:107217. Epub 2020 Dec 4.

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 (IUINQ), Avda. Complutense s/n, 28040 Madrid, Spain. Electronic address:

Several stress-related neuropsychiatric diseases are related to inflammatory phenomena. Thus, a better understanding of stress-induced immune responses could lead to enhanced treatment alternatives. Little is known about the possible involvement of inflammasomes in the stress-induced proinflammatory response. Antipsychotics have anti-inflammatory effects, but the possible antipsychotic treatment actions on inflammasomes remain unexplored. Our aim was to study whether inflammasomes are involved in the neuroinflammation induced by a paradigmatic model of chronic stress and whether the monoamine receptor antagonist paliperidone can modulate the possible stress-induced inflammasomes activation in the frontal cortex (FC). Thus, the effects of paliperidone (1 mg/Kg, oral gavage) administered during a chronic restraint stress protocol (6 h/day for 21 days) on the possible stress-related inflammasomes protein induction were evaluated through Western blot in the FC of male Wistar rats. Stress increased protein expression levels of the inflammasome complexes NALP1, NLRP3 and AIM2 and augmented caspase-1 and mature interleukin (IL)-1β protein levels. Paliperidone pre-treatment normalized the protein expression of the inflammasome pathway. In conclusion, our data indicate an induction of inflammasome complexes by chronic restraint stress in the FC of rats. The antipsychotic paliperidone has an inhibitory action on some of the stress-induced inflammasomes stimulation trying to normalize the neuroinflammatory scenario caused by stress. Considering the emerging role of inflammation in neuropsychiatric diseases, the development of new drugs targeting inflammasome pathways is a promising approach for future therapeutic interventions.
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http://dx.doi.org/10.1016/j.intimp.2020.107217DOI Listing
January 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

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

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

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

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

Association Between Medication Adherence and Oxidative Stress in Patients With First-Episode Mania.

Front Psychiatry 2019 26;10:162. Epub 2019 Mar 26.

Department of Psychiatry, University Hospital of Alava-Santiago, Vitoria, Spain.

Poor adherence is a major problem in patients with manic episodes that impairs functionality and has unknown effects on oxidative stress. The objective of this study was to analyze the relationship between adherence to medication, severity of symptoms and oxidative stress in a sample of patients with a first episode of mania. A longitudinal, 6-month study was performed in 60 patients, who were classified as adherent and non-adherent to medication (mainly antipsychotics). Blood levels of oxidative stress parameters and expression of the antioxidant nuclear transcription factor NRF2 in mononuclear cells of peripheral blood were assessed at baseline and at the end of follow-up. In addition, clinical symptoms and functioning were evaluated. Linear multivariate regression was used to determine the relationship between adherence, oxidative stress, and clinical symptoms. Finally, 44 patients completed follow-up. The results of this study showed that at 6-month follow-up, adherence was significantly associated with better functioning and reduced clinical symptoms. Additionally, more severe symptoms were associated with increased levels of oxidative stress and antioxidant parameters. At study completion, non-adherents exhibited greater levels of antioxidants than adherent patients. In conclusion, poor adherence to medication is associated with a poorer prognosis in the medium term and causes increased antioxidant response.
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http://dx.doi.org/10.3389/fpsyt.2019.00162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445053PMC
March 2019

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

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

Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex.

World J Biol Psychiatry 2017 09 18;18(6):457-470. Epub 2016 Mar 18.

a Department of Pharmacology, Faculty of Medicine , University Complutense (UCM), Centro de Investigación Biomédica en Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre and Instituto Universitario de Investigación en Neuroquímica UCM , 28040 Madrid , Spain.

Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.
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http://dx.doi.org/10.3109/15622975.2016.1151075DOI Listing
September 2017

Bacterial translocation affects intracellular neuroinflammatory pathways in a depression-like model in rats.

Neuropharmacology 2016 Apr 11;103:122-33. Epub 2015 Dec 11.

Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain. Electronic address:

Recent studies have suggested that depression is accompanied by an increased intestinal permeability which would be related to the inflammatory pathophysiology of the disease. This study aimed to evaluate whether experimental depression presents with bacterial translocation that in turn can lead to the TLR-4 in the brain affecting the mitogen-activated protein kinases (MAPK) and antioxidant pathways. Male Wistar rats were exposed to chronic mild stress (CMS) and the intestinal integrity, presence of bacteria in tissues and plasma lipopolysaccharide levels were analyzed. We also studied the expression in the prefrontal cortex of activated forms of MAPK and some of their activation controllers and the effects of CMS on the antioxidant Nrf2 pathway. Our results indicate that after exposure to a CMS protocol there is increased intestinal permeability and bacterial translocation. CMS also increases the expression of the activated form of the MAPK p38 while decreasing the expression of the antioxidant transcription factor Nrf2. The actions of antibiotic administration to prevent bacterial translocation on elements of the MAPK and Nrf2 pathways indicate that the translocated bacteria are playing a role in these effects. In effect, our results propose a role of the translocated bacteria in the pathophysiology of depression through the p38 MAPK pathway which could aggravate the neuroinflammation and the oxidative/nitrosative damage present in this pathology. Moreover, our results reveal that the antioxidant factor Nrf2 and its activators may be involved in the consequences of the CMS on the brain.
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http://dx.doi.org/10.1016/j.neuropharm.2015.12.003DOI Listing
April 2016

Modulation of the antioxidant nuclear factor (erythroid 2-derived)-like 2 pathway by antidepressants in rats.

Neuropharmacology 2016 Apr 12;103:79-91. Epub 2015 Dec 12.

Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain; Department of Psychiatry, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain. Electronic address:

Patients with major depression who are otherwise medically healthy have activated inflammatory pathways in their organism. It has been described that depression is not only escorted by inflammation but also by induction of multiple oxidative/nitrosative stress pathways. Nevertheless, there are finely regulated mechanisms involved in preserving cells from damage, such as the antioxidant nuclear transcription factor Nrf2. We aim to explore in a depression-like model the Nrf2 pathway in the prefrontal cortex (PFC) and the hippocampus of rats and to analyze whether antidepressants affect the antioxidant activity of the Nrf2 pathway. Male Wistar rats were exposed to chronic mild stress (CMS) and some of them were treated with desipramine, escitalopram or duloxetine. We studied the expression of upstream and downstream elements of the Nrf2 pathway and the oxidative damage induced by the CMS. After CMS, there is an inhibition of upstream and downstream elements of the Nrf2 pathway in the PFC (e.g. PI3K/Akt, GPx…). Moreover, antidepressant treatments, particularly desipramine and duloxetine, are able to recover some of these elements and to reduce the oxidative damage induced by the CMS. However, in the hippocampus, Nrf2 pathways are not that affected and antidepressants do not have many actions. In conclusion, Nrf2 pathway is differentially regulated by antidepressants in the PFC and hippocampus. The Nrf2 pathway is involved in the oxidative/nitrosative damage detected in the PFC and antidepressants have a therapeutic action through this pathway. However, it seems that Nrf2 is not involved in the effects caused by CMS in the hippocampus.
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http://dx.doi.org/10.1016/j.neuropharm.2015.11.029DOI Listing
April 2016

Pro-/antiinflammatory dysregulation in early psychosis: results from a 1-year follow-up study.

Int J Neuropsychopharmacol 2014 Oct 31;18(2). Epub 2014 Oct 31.

Department of Pharmacology, Faculty of Medicine, Complutense University, Instituto de Investigación Sanitaria -IIS- Hospital 12 de Octubre (i+12), Madrid, Spain (Drs García-Bueno, MacDowell, and Leza); Unitat d'Esquizofrènia Clínic, Hospital Clínic, University of Barcelona, IDIBAPS, Barcelona, Spain (Drs Bioque and Bernardo); Department of Preventive Medicine and Public Health, University of Zaragoza, Zaragoza, Spain (Dr Santabárbara); Hospital Universitario, Alava, EHU/UPV and National Distance Education University, Vitoria, Spain (Drs Martínez-Cengotitabengoa and González-Pinto); Child and Adolescent Psychiatry Department IIS Gregorio Marañón (IISGM), Hospital General Universitario Gregorio Marañón, Madrid, Spain (Drs Moreno and Parellada); Department of Psychiatry, Faculty of Medicine, University of Oviedo, Oviedo, Spain (Drs Sáiz and Bobes); Department of Pharmacology, Faculty of Medicine, University of Cádiz, Cádiz, Spain (Drs Berrocoso and Micó); Department of Pharmacology, Faculty of Medicine, University of Barcelona, Barcelona, Spain (Dr Gassó); Hospital Clínico Universitario, Zaragoza, Spain (Dr Fe Barcones).

Background: Previous studies indicated a systemic deregulation of the pro-/antiinflammatory balance in subjects after 6 months of a first psychotic episode. This disruption was reexamined 12 months after diagnosis to identify potential risk/protective factors and associations with symptom severity.

Methods: Eighty-five subjects were followed during 12 months and the determination of the same pro-/antiinflammatory mediators was carried out in plasma and peripheral blood mononuclear cells. Multivariate logistic regression analyses were used to identify risk/protective factors. Multiple linear regression models were performed to detect the change of each biological marker during follow-up in relation to clinical characteristics and confounding factors.

Results: This study suggests a more severe systemic pro-/antiinflammatory deregulation than in earlier pathological stages in first psychotic episode, because not only were intracellular components of the inflammatory response increased but also the majority of soluble elements. Nitrite plasma levels and cyclooxygenase-2 expression in peripheral blood mononuclear cells are reliable potential risk factors and 15d-prostaglandin-J2 plasma levels a protection biomarker. An interesting relationship exists between antipsychotic dose and the levels of prostaglandin-E2 (inverse) and 15d-prostaglandin-J2 (direct). An inverse relationship between the Global Assessment of Functioning scale and lipid peroxidation is also present.

Conclusions: Summing up, pro-/antiinflammatory mediators can be used as risk/protection biomarkers. The inverse association between oxidative/nitrosative damage and the Global Assessment of Functioning scale, and the possibility that one of the targets of antipsychotics could be the restoration of the pro-/antiinflammatory balance support the use of antiinflammatory drugs as coadjuvant to antipsychotics.
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http://dx.doi.org/10.1093/ijnp/pyu037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368893PMC
October 2014

Peripheral endocannabinoid system dysregulation in first-episode psychosis.

Neuropsychopharmacology 2013 Dec 4;38(13):2568-77. Epub 2013 Jul 4.

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

Several hypotheses involving alterations of the immune system have been proposed among etiological explanations for psychotic disorders. The endocannabinoid system (ECS) has 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 analysis in peripheral blood mononuclear cells (PBMCs). 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, whereas FAAH and MAGL expression were increased. On the other hand, FEP subjects with history of severe cannabis use showed a larger ECS dysregulation compared with 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.
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http://dx.doi.org/10.1038/npp.2013.165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828529PMC
December 2013

Inflammatory activation and cholinergic anti-inflammatory system in eating disorders.

Brain Behav Immun 2013 Aug 25;32:33-9. Epub 2013 Apr 25.

Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.

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 (PMBCs) 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.
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http://dx.doi.org/10.1016/j.bbi.2013.04.006DOI Listing
August 2013

Activation of the cholinergic anti-inflammatory system in peripheral blood mononuclear cells from patients with borderline personality disorder.

J Psychiatr Res 2012 Dec 17;46(12):1610-7. Epub 2012 Oct 17.

Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.

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.
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http://dx.doi.org/10.1016/j.jpsychires.2012.09.009DOI Listing
December 2012

Risperidone normalizes increased inflammatory parameters and restores anti-inflammatory pathways in a model of neuroinflammation.

Int J Neuropsychopharmacol 2013 Feb 16;16(1):121-35. Epub 2011 Dec 16.

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

Unlabelled: 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.
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http://dx.doi.org/10.1017/S1461145711001775DOI Listing
February 2013