Person: Leza Cerro, Juan Carlos
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First Name
Juan Carlos
Last Name
Leza Cerro
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Farmacología y Toxicología
Area
Farmacología
Identifiers
8 results
Search Results
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Item Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology(Journal of Neuroinflammation, 2021) Ben Afia, Amira; Vila, Èlia; Ormazabal, Aida; Haro, Josep M.; Artuch, Rafael; Ramos, Belén; Mac-Dowell Mata, Karina Soledad; Leza Cerro, Juan Carlos; García Bueno, BorjaBackground: 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.Item The interplay between functioning problems and symptoms in first episode of psychosis: An approach from network analysis(Journal of Psychiatric Research, 2021) Ana Izquierdo; María Cabello; Itziar Leal; Blanca Mellor-Marsá; Miriam Ayora; María-Fe Bravo-Ortiz; Ángela Ibáñez; Karina S. MacDowell; Norberto Malpica; Enrique Baca-García; Natalia E. Fares-Otero; Helena Melero; Pilar López-García; Covadonga M. Díaz-Caneja; Jose Luis Ayuso-Mateos; Manuel Durán-Cutilla; Jessica Merchán-Naranjo; Roberto Mediavilla-Torres; Ainoa Muñoz-Sanjosé; Luis Sanchez-Pastor; Monica Dompablo; Patricia Fernández-Martín; Pablo Puras-Rico; Lucía Albarracin-García; Melero Carrasco, Helena; Rodríguez Jiménez, Roberto; Díaz Marsa, Marina Francisca; Arango López, Celso; García-Albea Martín, Julia Isabel; Leza Cerro, Juan Carlos; Leticia León QuismondoThe 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.Item Gut microbiota, innate immune pathways, and inflammatory control mechanisms in patients with major depressive disorder(Translational Psychiatry, 2021) González-Pinto, Ana; García, Saínza; Diego-Adeliño, Javier de; Carceller-Sindreu, Mar; Sarramea, Fernando; Caballero-Villarraso, Javier; Gracia-García, Patricia; De la Cámara, Concepción; Rodríguez, Juan M.; Caso Fernández, Javier Rubén; Mac-Dowell Mata, Karina Soledad; Leza Cerro, Juan Carlos; Gómez-Lus Centelles, María Luisa; Agüera Ortiz, Luis Fernando; Alba Rubio, ClaudioAlthough alterations in the gut microbiota have been linked to the pathophysiology of major depressive disorder (MDD), including through effects on the immune response, our understanding is deficient about the straight connection patterns among microbiota and MDD in patients. Male and female MDD patients were recruited: 46 patients with a current active MDD (a-MDD) and 22 in remission or with only mild symptoms (r-MDD). Forty-five healthy controls (HC) were also recruited. Psychopathological states were assessed, and fecal and blood samples were collected. Results indicated that the inducible nitric oxide synthase expression was higher in MDD patients compared with HC and the oxidative stress levels were greater in the a-MDD group. Furthermore, the lipopolysaccharide (an indirect marker of bacterial translocation) was higher in a-MDD patients compared with the other groups. Fecal samples did not cluster according to the presence or the absence of MDD. There were bacterial genera whose relative abundance was altered in MDD:Bilophila(2-fold) andAlistipes(1.5-fold) were higher, whileAnaerostipes(1.5-fold) andDialister(15-fold) were lower in MDD patients compared with HC. Patients with a-MDD presented higher relative abundance ofAlistipesandAnaerostipes(1.5-fold) and a complete depletion ofDialistercompared with HC. Patients with r-MDD presented higher abundance ofBilophila(2.5-fold) compared with HC. Thus, the abundance of bacterial genera and some immune pathways, both with potential implications in the pathophysiology of depression, appear to be altered in MDD, with the most noticeable changes occurring in patients with the worse clinical condition, the a-MDD group.Item Peripheral Endocannabinoid System Dysregulation in First-Episode Psychosis(Neuropsychopharmacology, 2013) Bioque, Miquel; García Bueno, Borja; Mac-Dowell Mata, Karina Soledad; Meseguer, Ana; Saiz, Pilar ; Parellada Redondo, María José; Gonzalez-Pinto, Ana; Rodríguez Jiménez, Roberto; Lobo, Antonio; Leza Cerro, Juan Carlos; Bernardo, MiguelSeveral 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.Item Pro-/Anti-inflammatory Dysregulation in Patients With First Episode of Psychosis: Toward an Integrative Inflammatory Hypothesis of Schizophrenia(Schizophrenia Bulletin, 2014) García Bueno, Borja; Mac-Dowell Mata, Karina Soledad; Rodríguez Jiménez, Roberto; Rubio Valladolid, Gabriel; Leza Cerro, Juan CarlosBackground: Schizophrenia is a chronic syndrome of unknown etiology, predominantly defined by signs of psychosis. The onset of the disorder occurs typically in late adolescence or early adulthood. Efforts to study pathophysiological mechanisms in early stages of the disease are crucial in order to prompt intervention. Methods: Case-control study of first-episode psychotic (FEP) patients and matched controls. We recruited 117 patients during the first year after their FEP according to the DSM-IV criteria and recruited 106 gender-, race-, and age-matched controls between September 2010 and June 2011. Results: Biochemical studies carried out in peripheral mononuclear blood cells (PMBC) and plasma evidence a significant increase in intracellular components of a main proinflammatory pathway, along with a significant decrease in the anti-inflammatory ones. Multivariate logistic regression analyses identified the expression of inducible isoforms of nitric oxide synthase and cyclooxygenase in PMBC and homocysteine plasma levels as the most reliable potential risk factors and the inhibitor of the inflammatory transcription factor NFκB, IκBα, and the anti-inflammatory prostaglandin 15d-PGJ2 as potential protection factors. Discussion: Taken as a whole, the results of this study indicate robust phenotypical differences at the cellular machinery level in PMBC of patients with FEP. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways including the activity of nuclear receptors has interesting potential as biological markers and potential risk/protective factors for FEP. Due to its soluble nature, a notable finding in this study is that the anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis.Item Differential regulation of the TLR4 signalling pathway in post-mortem prefrontal cortex and cerebellum in chronic schizophrenia: Relationship with SP transcription factors(Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2017) MacDowell, Karina S.; Pinacho, Raquel; Costa, Joan; Ramos, Belén; Mac-Dowell Mata, Karina Soledad; Leza Cerro, Juan Carlos; García Bueno, BorjaAlterations 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.Item Inflammatory activation and cholinergic anti-inflammatory system in eating disorders(Brain, Behavior, and Immunity, 2013) Güemes, Itziar; Rodríguez, Alberto; Mac-Dowell Mata, Karina Soledad; Díaz Marsa, Marina Francisca; Leza Cerro, Juan Carlos; Carrasco Perera, José LuisDysfunctional 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.Item Decreased oxytocin plasma levels and oxytocin receptor expression in borderline personality disorder(Acta Psychiatrica Scandinavica, 2020) Buenache, E.; De la Vega, I.; López‐Villatoro, J. M.; Moreno Moreno, Beatriz; Carrasco Perera, José Luis; Mac-Dowell Mata, Karina Soledad; Díaz Marsa, Marina Francisca; Leza Cerro, Juan CarlosIntroduction: Borderline personality disorder (BPD) is characterized by intense affective reactions with underlying social and interpersonal cognitive deficits. Oxytocin has largely been associated with both stress regulation and social cognition in psychiatric patients and in non-clinical populations in previous studies. Finally, abnormal oxytocin levels have been preliminary reported in BPD patients. Methods: 53 patients with moderate-severe BPD and 31 healthy control subjects were investigated for plasma levels of oxytocin and protein expression of oxytocin receptor in blood mononuclear cells. Clinical assessments were made for severity, functionality, and comorbidity with axis I and II conditions. Results: Oxytocin plasma levels were significantly lower in BPD patients compared with controls. In addition, protein expression of oxytocin receptor was significantly reduced in the BPD group. A positive correlation was found between plasma oxytocin levels and the activity index score of the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ). Oxytocin receptor protein expression, on the contrary, had a negative correlation with the ZKPQ sociability index score. Conclusions: Results support the evidence of a dysfunction of the oxytocin system in borderline personality disorder, which could be involved in emotional dysregulation and interpersonal disturbances in these patients.