Neuropeptidases in psychiatric disorders

Psychiatric disorders (PDs), such as schizophrenia (SCZ), bipolar disorder (BD), and major depression disorder (MDD) are characterized by disturbances in the functioning of the CNS. These mental disorders have attracted the attention of researchers from different areas due to their high prevalence and extremely debilitating clinical characteristics. In spite of the many similarities observed among the PDs, not only in symptoms but also in the etiology as well, there is still a lack of knowledge in the biochemical and/or molecular pathways underlying each of these pathologies, in which better understanding could potentially help improve the diagnosis and possibilities for treatment. Several groups, including ours, have demonstrated that neuropeptidases and neuropeptidergic systems could play a fundamental role for the susceptibility of PDs such as SCZ, due to their involvement in the neurodevelopmental process (and consequent brain formation) and their recent association to disease progression. In this article, we bring an update of the main findings on neuropeptidases, such as Nuclear distribution element like-1 (NDEL1), angiotensin I-converting enzyme (ACE), and prolyl oligopeptidase (POP), with a detailed discussion on how they could be involved in the etiology of PDs. The main findings in the literature regarding alterations in neuropeptidase activity in different biological samples of patients with PDs, as well as in animal models, are presented here in order to draw the attention of general readers to the possibility of targeting this system for the discovery of new targets and/or development of novel therapies and gaining a deeper understanding of the molecular mechanisms underlying complex diseases such as PDs.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Impairments in peripheral blood T effector and T regulatory lymphocytes in bipolar disorder are associated with staging of illness and anti-cytomegalovirus IgG levels

There is now evidence that, based on cytokine profiles, bipolar disorder (BD) is accompanied by simultaneous activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), and that both components may be associated with the staging of illness. Nevertheless, no BD studies have evaluated the IRS/CIRS ratio using CD (cluster of differentiation) molecules expressed by peripheral blood activated T effector (Teff) and T regulatory (Treg) subpopulations. This study examined Teff/Treg subsets both before and after ex vivo anti-CD3/CD28 stimulation using flow cytometric immunophenotyping in 25 symptomatic remitted BD patients and 21 healthy controls and assessed human cytomegalovirus (HCMV)-specific IgG antibodies. BD is associated with a significantly lowered frequency of unstimulated CD3 + CD8 + CD71+ and CD4 + CD25 + FOXP3 and increased CD4 + CD25 + FOXP3 + CD152+ frequencies and with lowered stimulated frequencies of CD3 + CD8 + CD71+, CD4 + CD25 + FOXP3 + CD152+, and CD4 + CD25 + FOXP3 + GARP cells and, consequently, by an increased stimulated Teff/Treg ratio. Moreover, the number of manic, but not hypomanic or depressive episodes, is significantly and negatively associated with the stimulated proportions of CD3 + CD4 + CD154+, and CD69+ and CD71+ expression on CD4+ and CD8+ cells, while duration of illness (≥ 10 years) is accompanied by a depleted frequency of stimulated CD152+ Treg, and CD154+ and CD71+ CD4+ T cells. BD and anti-human cytomegalovirus (HCMV) IgG levels significantly interact to decrease the expression of CD4 + CD25 + FOXP+GARP T phenotypes. In conclusion, in BD patients, immune injuries, staging, and HCMV seropositivity interact and cause CIRS dysfunctions and exaggerated IRS responses, which play a key role in parainflammation and neuroaffective toxicity. HCMV seropositivity contributes to an immune-risk phenotype in BD

Regulation of monoamine levels by typical and atypical antipsychotics in Caenorhabditis elegans mutant for nuclear distribution element genes

Mammalian nuclear distribution genes encode proteins with essential roles in neuronal migration and brain formation during embryogenesis. The implication of human nuclear distribution genes, namely nudC and NDE1 (Nuclear Distribution Element 1)/NDEL1 (Nuclear Distribution Element-Like 1), in psychiatric disorders including schizophrenia and bipolar disorder, has been recently described. The partial loss of NDEL1 expression results in neuronal migration defects, while ndel1 null knockout (KO) leads to early embryonic lethality in mice. On the other hand, loss-of-function of the orthologs of nuclear distribution element genes (nud) in Caenorhabditis elegans renders viable worms and influences behavioral endophenotypes associated with dopaminergic and serotoninergic pathways. In the present work, we evaluated the role of nud genes in monoamine levels at baseline and after the treatment with typical or atypical antipsychotics. Dopamine, serotonin and octopamine levels were significantly lower in homozygous loss-of-function mutant worms KO for nud genes compared with wild-type (WT) C. elegans at baseline. While treatment with antipsychotics determined significant differences in monoamine levels in WT, the nud KO mutant worms appear to respond differently to the treatment. According to the best of our knowledge, we are the first to report the influence of nud genes in the monoamine levels changes in response to antipsychotic drugs, ultimately placing the nuclear distribution genes family at the cornerstone of pathways involved in the modulation of monoamines in response to different classes of antipsychotic drugs.Department of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), Brazil.Department of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), Brazil; National Institute for Translational Medicine (INCT-TM, CNPq), BrazilDepartment of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, BrazilDepartment of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), Brazi

A system biology approach based on metabolic biomarkers and protein–protein interactions for identifying pathways underlying schizophrenia and bipolar disorder

Mental disorders (MDs), including schizophrenia (SCZ) and bipolar disorder (BD), have attracted special attention from scientists due to their high prevalence and significantly debilitating clinical features. The diagnosis of MDs is still essentially based on clinical interviews, and intensive efforts to introduce biochemical based diagnostic methods have faced several difficulties for implementation in clinics, due to the complexity and still limited knowledge in MDs. In this context, aiming for improving the knowledge in etiology and pathophysiology, many authors have reported several alterations in metabolites in MDs and other brain diseases. After potentially fishing all metabolite biomarkers reported up to now for SCZ and BD, we investigated here the proteins related to these metabolites in order to construct a protein–protein interaction (PPI) network associated with these diseases. We determined the statistically significant clusters in this PPI network and, based on these clusters, we identified 28 significant pathways for SCZ and BDs that essentially compose three groups representing three major systems, namely stress response, energy and neuron systems. By characterizing new pathways with potential to innovate the diagnosis and treatment of psychiatric diseases, the present data may also contribute to the proposal of new intervention for the treatment of still unmet aspects in MDs.Nara Institute of Science and Technology, Ikoma, Nara, 630-0192, JapanDepartment of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, BrazilNational Institute for Translational Medicine (INCT-TM, CNPq/FAPESP/CAPES), Ribeirão Preto, BrazilChemical Biology Laboratory, Department of Organic Chemistry, Institute of Chemistry, Universidade Estadual de Campinas (Unicamp), Campinas, SP, BrazilDepartment of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazi

Decreased nuclear distribution nudE-like 1 enzyme activity in an animal model with dysfunctional disrupted-in-schizophrenia 1 signaling featuring aberrant neurodevelopment and amphetamine-supersensitivity

Background: Interaction of nuclear-distribution element-like 1 with disrupted-in-schizophrenia 1 protein is crucial for neurite outgrowth/neuronal migration, and this interaction competitively inhibits nuclear-distribution element-like 1 peptidase activity. Nuclear-distribution element-like 1 activity is reduced in antipsychotic-naïve first-episode psychosis and in medicated chronic schizophrenia, with even lower activity in treatment-resistant schizophrenia. Aims: The purpose of this study was to investigate in a rat model overexpressing human non-mutant disrupted-in-schizophrenia 1, with consequent dysfunctional disrupted-in-schizophrenia 1 signaling, the relation of nuclear-distribution element-like 1 activity with neurodevelopment and dopamine-related phenotypes. Methods: We measured cell distribution in striatum and cortex by histology and microtomography, and quantified the basal and amphetamine-stimulated locomotion and nuclear-distribution element-like 1 activity (in blood and brain) of transgenic disrupted-in-schizophrenia 1 rat vs wild-type littermate controls. Results: 3D assessment of neuronal cell body number and spatial organization of mercury-impregnated neurons showed defective neuronal positioning, characteristic of impaired cell migration, in striatum/nucleus accumbens, and prefrontal cortex of transgenic disrupted-in-schizophrenia 1 compared to wild-type brains. Basal nuclear-distribution element-like 1 activity was lower in the blood and also in several brain regions of transgenic disrupted-in-schizophrenia 1 compared to wild-type. Locomotion and nuclear-distribution element-like 1 activity were both significantly increased by amphetamine in transgenic disrupted-in-schizophrenia 1, but not in wild-type. Conclusions: Our findings in the transgenic disrupted-in-schizophrenia 1 rat allow us to state that decreased nuclear-distribution element-like 1 activity reflects both a trait (neurodevelopmental phenotype) and a state (amphetamine-induced dopamine release). We thus define here a role for decreased nuclear-distribution element-like 1 peptidase activity both for the developing brain (the neurodevelopmental phenotype) and for the adult (interaction with dopaminergic responses), and present nuclear-distribution element-like 1 activity in a novel way, as unifying neurodevelopmental with dysfunctional dopamine response phenotypes

Effects of psychostimulants and antipsychotics on serum lipids in an animal model for schizophrenia

Schizophrenia (SCZ) treatment is essentially limited to the use of typical or atypical antipsychotic drugs, which suppress the main symptoms of this mental disorder. Metabolic syndrome is often reported in patients with SCZ under long-term drug treatment, but little is known about the alteration of lipid metabolism induced by antipsychotic use. In this study, we evaluated the blood serum lipids of a validated animal model for SCZ (Spontaneously Hypertensive Rat, SHR), and a normal control rat strain (Normotensive Wistar Rat, NWR), after long-term treatment (30 days) with typical haloperidol (HAL) or atypical clozapine (CLZ) antipsychotics. Moreover, psychostimulants, amphetamine (AMPH) or lisdexamfetamine (LSDX), were administered to NWR animals aiming to mimic the human first episode of psychosis, and the effects on serum lipids were also evaluated. Discrepancies in lipids between SHR and NWR animals, which included increased total lipids and decreased phospholipids in SHR compared with NWR, were similar to the differences previously reported for SCZ patients relative to healthy controls. Administration of psychostimulants in NWR decreased omega-3, which was also decreased in the first episode of psychosis of SCZ. Moreover, choline glycerophospholipids allowed us to distinguish the effects of CLZ in SHR. Thus, changes in the lipid metabolism in SHR seem to be reversed by the long-term treatment with the atypical antipsychotic CLZ, which was under the same condition described to reverse the SCZ-like endophenotypes of this validated animal model for SCZ. These data open new insights for understanding the potential influence of the treatment with typical or atypical antipsychotics on circulating lipids. This may represent an outcome effect from metabolic pathways that regulate lipids synthesis and breakdown, which may be reflecting a cell lipids dysfunction in SCZ.Instituto de Química, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-970, BrazilNational Institute for Translational Medicine (INCT-TM, CNPq), Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), São Paulo 14049-900, BrazilDepartamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo 04044-020, Brazil.Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo 04044-020, Brazil