Person: Leza Cerro, Juan Carlos
Loading...
First Name
Juan Carlos
Last Name
Leza Cerro
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Farmacología y Toxicología
Area
Farmacología
Identifiers
5 results
Search Results
Now showing 1 - 5 of 5
Item Paliperidone Prevents Brain Toll-Like Receptor 4 Pathway Activation and Neuroinflammation in Rat Models of Acute and Chronic Restraint Stress(International Journal of Neuropsychopharmacology, 2015) Mac-Dowell Mata, Karina Soledad; Caso Fernández, Javier Rubén; Martín Hernández, D.; Muñoz Madrigal, José Luis; Leza Cerro, Juan Carlos; García Bueno, BorjaBackground: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. Methods: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress-induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. Results: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. Conclusions: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies.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 Periodontal diseases and depression: A pre‐clinical in vivo study(Journal of Clinical Periodontology, 2021) Martínez, María; Martín‐Hernández, David; Virto Ruiz, Leire; Mac-Dowell Mata, Karina Soledad; Leza Cerro, Juan Carlos; García Bueno, Borja; Figuero Ruiz, Elena; Ambrosio Elejalde, Nagore; Herrera González, David; Montero Solís, Eduardo; González Bris, Álvaro; Marín Cuenda, María José; Sanz Martín, MarianoAim: 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.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) Mac-Dowell Mata, Karina Soledad; Pinacho, Raquel; Costa, Joan; Ramos, Belén; 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 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.