RESUMO
BACKGROUND: The clinical debut of schizophrenia is frequently a first episode of psychosis (FEP). As such, there is considerable interest in identifying associations between biological markers and clinical or cognitive characteristics that help predict the progression and outcome of FEP patients. Previous studies showed that high prolactin, low oxytocin, and high homocysteine are factors associated with FEP 6 months after diagnosis, at which point plasma levels were correlated with some clinical and cognitive characteristics. METHODS: We reexamined 75 patients at 12 months after diagnosis to measure the evolution of these molecules and assess their association with clinical features. RESULTS: At follow-up, FEP patients had lower prolactin levels than at baseline, and patients treated with risperidone or paliperidone had higher prolactin levels than patients who received other antipsychotic agents. By contrast, no changes in oxytocin and homocysteine plasma levels were observed between the baseline and follow-up. In terms of clinical features, we found that plasma prolactin and homocysteine levels were correlated with the severity of the psychotic symptoms in male FEP patients, suggesting that they might be factors associated with psychotic symptomatology but only in men. Together with oxytocin, these molecules may also be related to sustained attention, verbal ability, and working memory cognitive domains in FEP patients. CONCLUSION: This study suggests that focusing on prolactin, oxytocin, and homocysteine at a FEP may help select adequate pharmacological treatments and develop new tools to improve the outcome of these patients, where sex should also be borne in mind.
Assuntos
Homocisteína , Ocitocina , Prolactina , Transtornos Psicóticos , Humanos , Masculino , Cognição , Seguimentos , Ocitocina/sangue , Prolactina/sangue , Transtornos Psicóticos/sangue , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Homocisteína/sangueRESUMO
BACKGROUND: Approximately 3% of the population suffers a first episode of psychosis (FEP), and a high percentage of these patients subsequently relapse. Because the clinical course following a FEP is hard to predict, it is of interest to identify cognitive and biological markers that will help improve the diagnosis, treatment, and outcome of such events and to define new therapeutic targets. Here we analyzed the plasma oxytocin and prolactin levels during an FEP, assessing their correlation with clinical and cognitive features. METHODS: The oxytocin and prolactin in plasma was measured in 120 FEP patients and 106 healthy controls, all of whom were subjected to a clinical and neuropsychological assessment. Most patients were under antipsychotics. Statistical analyses aimed to identify factors associated with the FEP and to search for associations between the variables. This study is preliminary and exploratory because the P-values were not corrected for multiple comparisons. RESULTS: FEP patients had less oxytocin, more prolactin, and a poor premorbid IQ, and they performed worse in sustained attention. Male patients with higher prolactin levels experienced more severe psychotic symptoms and required higher doses of antipsychotics. Low oxytocin was associated with poor sustained attention in women, whereas low oxytocin and high prolactin in men correlated with better performance in sustained attention. CONCLUSION: Low oxytocin, high prolactin, and poor premorbid IQ and sustained attention are factors associated with an FEP, representing potential therapeutic targets in these patients. These biological factors and cognitive domains might play an important role during a FEP, which could help us to develop new strategies that improve the outcomes of this disorder and that should perhaps be gender specific.
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Antipsicóticos , Transtornos Psicóticos , Antipsicóticos/uso terapêutico , Cognição , Feminino , Humanos , Masculino , Ocitocina , Prolactina , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/psicologia , Caracteres SexuaisRESUMO
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.
Assuntos
Cinurenina , Esquizofrenia , Cerebelo/metabolismo , Humanos , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismoRESUMO
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.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Encefalopatias Metabólicas/tratamento farmacológico , Minociclina/farmacologia , Malformações do Sistema Nervoso/patologia , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Inibição Pré-Pulso/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Encefalopatias Metabólicas/etiologia , Modelos Animais de Doenças , Feminino , Imageamento por Ressonância Magnética , Masculino , Minociclina/administração & dosagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/etiologia , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/imunologia , Tomografia por Emissão de Pósitrons , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente , Esquizofrenia/imunologiaRESUMO
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-1ß 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.
Assuntos
Depressão , Doenças Periodontais , Animais , Fusobacterium nucleatum , Porphyromonas gingivalis , Ratos , Ratos WistarRESUMO
Despite the growing importance of the cerebellum as a region highly vulnerable to accumulating molecular errors in schizophrenia, limited information is available regarding altered molecular networks with potential therapeutic targets. To identify altered networks, we conducted one-shot liquid chromatography-tandem mass spectrometry in postmortem cerebellar cortex in schizophrenia and healthy individuals followed by bioinformatic analysis (PXD024937 identifier in ProteomeXchange repository). A total of 108 up-regulated proteins were enriched in stress-related proteins, half of which were also enriched in axonal cytoskeletal organization and vesicle-mediated transport. A total of 142 down-regulated proteins showed an enrichment in proteins involved in mitochondrial disease, most of which were also enriched in energy-related biological functions. Network analysis identified a mixed module of mainly axonal-related pathways for up-regulated proteins with a high number of interactions for stress-related proteins. Energy metabolism and neutrophil degranulation modules were found for down-regulated proteins. Further, two double-hit postnatal stress murine models based on maternal deprivation combined with social isolation or chronic restraint stress were used to investigate the most robust candidates of generated networks. CLASP1 from the axonal module in the model of maternal deprivation was combined with social isolation, while YWHAZ was not altered in either model. METTL7A from the degranulation pathway was reduced in both models and was identified as altered also in previous gene expression studies, while NDUFB9 from the energy network was reduced only in the model of maternal deprivation combined with social isolation. This work provides altered stress- and mitochondrial disease-related proteins involved in energy, immune and axonal networks in the cerebellum in schizophrenia as possible novel targets for therapeutic interventions and suggests that METTL7A is a possible relevant altered stress-related protein in this context.
Assuntos
Cerebelo/metabolismo , Vias Neurais , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Regulação para Cima , Proteínas 14-3-3/metabolismo , Animais , Axônios/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Biologia Computacional , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Redes Reguladoras de Genes , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , NADH Desidrogenase/metabolismo , Neutrófilos/metabolismo , Proteômica/métodos , Ratos , Ratos WistarRESUMO
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.
Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos , Adolescente , Adulto , Transtornos da Alimentação e da Ingestão de Alimentos/diagnóstico , Humanos , Personalidade , Transtornos da Personalidade , Inquéritos e QuestionáriosRESUMO
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.SIGNIFICANCE STATEMENT 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.
Assuntos
Antipsicóticos/uso terapêutico , Atrofia/tratamento farmacológico , Hipocampo/patologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Risperidona/uso terapêutico , Animais , Antipsicóticos/farmacologia , Atrofia/metabolismo , Atrofia/patologia , Espinhas Dendríticas/metabolismo , Hipocampo/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Ratos , Risperidona/farmacologiaRESUMO
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.
Assuntos
Fator 88 de Diferenciação Mieloide/genética , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/imunologia , Esquizofrenia/genética , Esquizofrenia/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Idoso , Antipsicóticos/uso terapêutico , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , RNA Mensageiro , Estudos Retrospectivos , Esquizofrenia/tratamento farmacológico , Transdução de SinaisRESUMO
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.
Assuntos
Transtornos Psicóticos/imunologia , Adolescente , Adulto , Biomarcadores/sangue , Criança , Feminino , Seguimentos , Humanos , Leucócitos Mononucleares/imunologia , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Transtornos Psicóticos/sangue , Transtornos Psicóticos/tratamento farmacológico , Fatores de Risco , Adulto JovemRESUMO
Prenatal infections and cannabis use during adolescence are well-recognized risk factors for schizophrenia. As inflammation and oxidative stress (OS) contribute to this disorder, anti-inflammatory drugs have been proposed as potential therapies. This study aimed to evaluate the association between delta-9-tetrahydrocannabinol (THC) and schizophrenia-like abnormalities in a maternal immune activation (MIA) model. Additionally, we assessed the preventive effect of cannabidiol (CBD), a non-psychotropic/anti-inflammatory cannabinoid. THC and/or CBD were administered to Saline- and MIA-offspring during periadolescence. At adulthood, THC-exposed MIA-offspring showed significant improvements in sensorimotor gating deficits. Structural and metabolic brain changes were evaluated by magnetic resonance imaging, revealing cortical shrinkage in Saline- and enlargement in MIA-offspring after THC-exposure. Additionally, MIA-offspring displayed enlarged ventricles and decreased hippocampus, which were partially reverted by both cannabinoids. CBD prevented THC-induced reduction in the corpus callosum, despite affecting white matter structure. Post-mortem studies revealed detrimental effects of THC, including increased inflammation and oxidative stress. CBD partially reverted these pro-inflammatory alterations and modulated THC's effects on the endocannabinoid system. In conclusion, contrary to expectations, THC exhibited greater behavioural and morphometric benefits, despite promoting a pro-inflammatory state that CBD partially reverted. Further research is needed to elucidate the underlying mechanisms involved in the observed benefits of THC.
Assuntos
Canabidiol , Canabinoides , Cannabis , Esquizofrenia , Humanos , Gravidez , Feminino , Adulto , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Dronabinol/farmacologia , Poli I-C , Inflamação , Anti-InflamatóriosRESUMO
Schizophrenia is a chronic neurodevelopmental disorder with an inflammatory/prooxidant component. N-acetylcysteine (NAC) has been evaluated in schizophrenia as an adjuvant to antipsychotics, but its role as a preventive strategy has not been sufficiently explored. We aimed to evaluate the potential of NAC administration in two-time windows before the onset of symptoms in a schizophrenia-like maternal immune stimulation (MIS) rat model. Pregnant Wistar rats were injected with Poly I:C or Saline on gestational day (GD) 15. Three different preventive approaches were evaluated: 1) NAC treatment during periadolescence in the offspring (from postnatal day [PND] 35 to 49); 2) NAC treatment during pregnancy after MIS challenge until delivery (GD15-21); and 3) NAC treatment throughout all pregnancy (GD1-21). At postnatal day (PND) 70, prepulse inhibition (PPI) and anxiety levels were evaluated. In vivo magnetic resonance (MR) imaging was acquired on PND100 to assess structural changes in gray and white matter, and brain metabolite concentrations. Additionally, inflammation and oxidative stress (IOS) markers were measured ex vivo in selected brain regions. MIS offspring showed behavioral, neuroanatomical, and biochemical alterations. Interestingly, NAC treatment during periadolescence prevented PPI deficits and partially counteracted some biochemical imbalances. Moreover, NAC treatments during pregnancy not only replicated the beneficial outcomes reported by the treatment in periadolescence, but also prevented some neuroanatomical deficits, including reductions in hippocampal and corpus callosum volumes. This study suggests that early reduction of inflammation and prooxidation could help prevent the onset of schizophrenia-like symptoms, supporting the importance of anti-IOS compounds in ameliorating this disorder.
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Acetilcisteína , Esquizofrenia , Feminino , Gravidez , Ratos , Animais , Ratos Wistar , Acetilcisteína/farmacologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/prevenção & controle , Poli I-C , InflamaçãoRESUMO
Neurodevelopmental disorders (NDs) are neuropsychiatric conditions affecting central nervous system development, characterized by cognitive and behavioural alterations. Inflammation has been recently linked to NDs. Animal models are essential for understanding their pathophysiology and identifying therapeutic targets. Double-hit models can reproduce neurodevelopmental and neuroinflammatory impairments. Sixty-seven newborn rats were assigned to four groups: Control, Maternal deprivation (MD, 24-h-deprivation), Isolation (Iso, 5 weeks), and Maternal deprivation â+ âIsolation (MD â+ âIso, also known as double-hit). Cognitive dysfunction was assessed using behavioural tests. Inflammasome, MAPKs, and TLRs inflammatory elements expression in the frontal cortex (FC) and hippocampus (HP) was analysed through western blot and qRT-PCR. Oxidative/nitrosative (O/N) evaluation and corticosterone levels were measured in plasma samples. Double-hit group was affected in executive and working memory. Most inflammasomes and TLRs inflammatory responses were increased in FC compared to the control group, whilst MAPKs were downregulated. Conversely, hippocampal inflammasome and inflammatory components were reduced after the double-hit exposure, while MAPKs were elevated. Our findings reveal differential regulation of innate immune system components in FC and HP in the double-hit group. Further investigations on MAPKs are necessary to understand their role in regulating HP neuroinflammatory status, potentially linking our MAPKs results to cognitive impairments through their proliferative and anti-inflammatory activity.
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Lobo Frontal , Inflamassomos , Ratos , Animais , Inflamassomos/metabolismo , Lobo Frontal/metabolismo , Anti-Inflamatórios/metabolismo , Sistema Imunitário/metabolismo , Hipocampo/metabolismoRESUMO
Neutrophil to lymphocyte ratio (NLR) has been proposed as an emerging marker of the immune system alterations in psychotic disorders. However, it is not entirely clear whether NLR elevation is a characteristic of the psychotic disorder itself, which inflammatory pathways activation is detecting, or which possible confounding variables could alter its interpretation. We aimed to analyze the relationship of NLR values with a panel of inflammatory and oxidative/nitrosative stress biomarkers and main potential confounding factors in a well-characterized cohort of 97 patients with a first episode of psychosis (FEP) and 77 matched healthy controls (HC). In the FEP group, NLR values presented a moderate, positive correlation with the pro-inflammatory mediator Prostaglandin E2 levels (r = 0.36, p < 0.001) and a small but significant, positive correlation with cannabis use (r = 0.25, p = 0.017). After controlling for cannabis use, the association between NLR and PGE2 remained significant (beta = 0.31, p = 0.012). In the HC group, NLR values negatively correlated with body mass index (BMI, r = -0.24, p = 0.035) and positively correlated with tobacco use (r = 0.25, p = 0.031). These findings support a relationship between the elevation of NLR values and an elevated expression of proinflammatory pathways related to stress response in patients with a FEP. In addition, our study highlights the importance of considering variables such as cannabis or tobacco consumption, and BMI when interpreting the results of studies aimed to establish a clinical use of NLR. These considerations may help future research to use NLR as a reliable biomarker to determine immune system status in this population.
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Neutrófilos , Transtornos Psicóticos , Humanos , Neutrófilos/metabolismo , Transtornos Psicóticos/epidemiologia , Linfócitos/metabolismo , Biomarcadores/metabolismo , Inflamação/metabolismoRESUMO
INTRODUCTION: Eating disorders (ED) represent a group of very complex and serious diagnoses characterized by emotional dysregulation and impulsivity. New approaches are necessary to achieve effective diagnosis and treatments. Shifting biomarker research away from the constraints of diagnostic categories may effectively contribute to a dimensional differentiation across disorders according to neurobiology (e.g., inflammatory biomarkers). Thus, the aim of our study was to identify inflammatory profiles in patients with ED. METHODS: A sample of 100 women with an ED (23.4 ± 8.55 years) and 59 healthy controls (HC) (20.22 ± 4.18 years) was used. K-means cluster analysis was followed to identify inflammatory clusters considering seven blood biomarkers (iNOS, TNFα, COX2, p38, ERK, TBARS and PPARγ). Moreover, a wide assessment of clinical features was conducted. RESULTS: Two distinct clusters were identified. Cluster 1 patients were characterized by higher inflammatory levels of TNF-α, COX2, p38, and ERK, and had more restrictive anorexia diagnosis than cluster 2. Cluster 2 participants showed higher inflammatory levels of iNOS and were older than cluster 1 and controls and had lower BMI than HC. In addition, they had higher levels of bulimic symptoms than those from the cluster 1 and HC, and higher impulsivity than HC. All ED patients (regardless of cluster) showed higher ED symptoms and more trauma than HC. CONCLUSIONS: Our study revealed that inflammatory dysfunction may be linked with clinical endophenotypes in ED, one more restrictive (cluster 1) with an inflammation/oxidative endophenotype more cytokine and MAPK/ERK mediated, and the other more impulsive, with more bulimic symptoms (cluster 2) with NO free radical high output source iNOS. Trauma seems to be a vulnerability factor for both endophenotypes.
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Bulimia , Transtornos da Alimentação e da Ingestão de Alimentos , Humanos , Feminino , Bulimia/diagnóstico , Bulimia/psicologia , Ciclo-Oxigenase 2 , Biomarcadores , FenótipoRESUMO
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)-1ß 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.
Assuntos
Anti-Inflamatórios/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Risperidona/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Córtex Cerebral/patologia , Regulação para Baixo/efeitos dos fármacos , Encefalite/induzido quimicamente , Encefalite/tratamento farmacológico , Encefalite/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/fisiologia , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Wistar , Risperidona/uso terapêutico , Regulação para Cima/efeitos dos fármacosRESUMO
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 IL1ß 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.
Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Inflamação/psicologia , Sistema Nervoso Parassimpático/fisiopatologia , Adulto , Biomarcadores/metabolismo , Bulimia Nervosa/fisiopatologia , Bulimia Nervosa/psicologia , Núcleo Celular/metabolismo , Cotinina/sangue , Citocinas/metabolismo , Citosol/metabolismo , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Oxirredução , Estresse Oxidativo/fisiologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Espécies Reativas de Nitrogênio/metabolismo , Transdução de Sinais/fisiologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Adulto Jovem , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
BACKGROUND: Borderline personality disorder (BPD) and eating disorders (ED) are both disorders with emotional dysregulation that may share some similar biological underpinnings, leading to oxidative/inflammatory alterations. Unfortunately, to date, no studies have assessed the relationship between clinical features, inflammatory alterations and childhood trauma across these disorders. Our aim was to identify the potential common and disorder-specific inflammatory pathways and examine possible associations between these dysregulated pathways and the clinical features. METHODS: We studied a sample of 108 women (m = 27.17 years; sd = 7.64), divided into four groups: 23 patients with a restrictive ED (ED-R), 23 patients with a bingeeating/ purging ED (ED-P) and 26 patients with BPD; whereas the control group included 23 healthy subjects. Several inflammatory/oxidative parameters: tumor necrosis factor alpha (TNFα), Thiobarbituric Acid Reactive Substances (TBARS), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), p38 mitogenactivated protein kinases, ERK mitogen-activated protein kinases and c-Jun NH2- terminal kinase (JNK), and some antiinflammatory antioxidant elements: glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), Kelch-like ECHassociated protein (Keap1) were determined in plasma or peripheral blood mononuclear cells. Furthermore, clinical, impulsivity, trauma and eating behavior questionnaires were administered. RESULTS: Three main inflammatory/oxidative components were extracted using principal component analysis (59.19 % of biomarker variance explained). Disorder-specific dysfunction in the inflammatory and oxidative pathways in patients with BPD and ED were revealed by means of relationships with specific principal components (p < .01). BPD patients showed higher levels of a component featured by elevated levels of JNK and lower of GPx and SOD. ED-R and impulsivity were associated with a component featured by the activation of ERK and negative influence of Keap1. The component featured by the suppression of catalase and COX2 was associated with both ED subtypes and trauma exposure. CONCLUSION: Several risk factors such as trauma, impulsivity and eating disorder symptoms were transdiagnostically associated with some inflammatory alterations regardless of diagnosis. These findings suggest that the clinical profile comprising trauma exposure and an emotional dysregulation disorder might constitute a specific endophenotype highly linked with inflammatory alterations.
Assuntos
Transtorno da Personalidade Borderline , Transtornos da Alimentação e da Ingestão de Alimentos , Humanos , Feminino , Catalase/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transtorno da Personalidade Borderline/psicologia , Ciclo-Oxigenase 2/metabolismo , Leucócitos Mononucleares/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Comportamento Impulsivo , Superóxido Dismutase/metabolismoRESUMO
Objective: Neighborhood socioeconomic status seems to be related to functioning in patients with first episode of psychosis (FEP). The present study aimed to assess if neighborhood vulnerability and risk of social exclusion could predict functional outcomes in people with FEP after controlling for other key variables identified in previous literature.Methods: A total of 137 patients with FEP (DSM-IV-TR criteria) and 90 controls comprised the study sample from February 2013 to May 2019. Functioning was assessed with the WHO Disability Assessment Schedule. Neighborhood vulnerability was measured using a multidimensional socioeconomic deprivation index; data for the index were collected by the Madrid City Council and based on the participant's home address. Multilevel mixed-effects regression analyses were conducted to estimate the effects of neighborhood vulnerability on functioning.Results: Our results show that FEP patients could be more vulnerable to the effects of neighborhood-level characteristics than healthy controls (B = 1,570.173; z = 3.91; P < .001). In addition, our findings suggest that higher neighborhood vulnerability is related to greater functional disability in people with FEP, after controlling for other relevant confounders (B = 1,230.332; z = 2.59; P = .010).Conclusions: These results highlight the importance of incorporating contextual factors into assessment of patients with FEP, since psychosocial difficulties observed in these patients could be partially related to the quality of neighborhood social-related resources.
Assuntos
Transtornos Psicóticos , Humanos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/psicologia , Isolamento Social , Avaliação da DeficiênciaRESUMO
The attempts to clarify the origin of eating disorders (ED) have not been completely successful and their etiopathogenesis remains unknown. Current research shows an activation of the immune response in neuropsychiatric diseases, including ED. We aimed to investigate immune response parameters in patients with ED and to identify psychological factors influencing the inflammatory response. The relationship between inflammation markers and impulsivity and affective symptomatology was explored as well. Thirty-four adult female patients with current diagnosis of ED, none of them under psychopharmacological treatment (excluding benzodiazepines), were included in this study. Patients were compared with a healthy control group of fifteen adult females. The levels of inflammatory markers and indicators of oxidative/nitrosative stress were evaluated in plasma and/or in peripheral blood mononuclear cells (PBMCs). Subjects were assessed by means of different ED evaluation tools. Additionally, the Barratt Impulsiveness Scale, the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale were also employed. Patients with ED shown increased plasma levels of the pro-inflammatory nuclear factor kappa B (NFκB) and the cytokine tumor necrosis factor-alpha (TNF-α), among other factors and an increment in the oxidative/nitrosative stress as well as increased glucocorticoid receptor (GR) expression levels in their PBMCs. Moreover, the inflammatory prostaglandin E2 (PGE2) correlated with impulsiveness and the anti-inflammatory prostaglandin J2 (15d-PGJ2) correlated with depressive symptomatology. Our results point towards a relationship between the immune response and impulsiveness and between the immune response and depressive symptomatology in female adult patients with ED.