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BACKGROUND: Neurotrophins (NTs) and their precursors (pro-NTs) are polypeptides with important roles in neuronal development, differentiation, growth, survival and plasticity, as well as apoptosis and neuronal death. Imbalance in NT levels were observed in schizophrenia spectrum disorders, but evidence in ultra-high risk for psychosis (UHR) samples is scarce. METHODS: A naturalistic sample of 87 non-help-seeking UHR subjects and 55 healthy controls was drawn from the general population. Blood samples were collected and NT-3, NT-4/5, BDNF, pro-BDNF, NGF, pro-NGF were analyzed through enzyme linked immunosorbent assay (ELISA). Information on cannabis and tobacco use was also collected. Logistic regression models and path analysis were used to control for confounders (tobacco, age, cannabis use). RESULTS: NT-4/5 was significantly decreased, and pro-BDNF was significantly increased in UHR individuals compared to controls. Cannabis use and higher NGF levels were significantly related to transition to psychiatric disorders among UHR subjects. Increased pro-BDNF and decreased NT-4/5 influenced transition by the mediation of perceptual abnormalities. CONCLUSIONS: Our study shows for the first time that NTs are altered in UHR compared to healthy control individuals, and that they can be a predictor of transition to psychiatric illnesses in this population. Future studies should employ larger naturalistic samples to confirm the findings.
Assuntos
Transtornos Mentais , Transtornos Psicóticos , Humanos , Fator Neurotrófico Derivado do EncéfaloRESUMO
During prenatal life, exposure to synthetic glucocorticoids (SGCs) can alter normal foetal development, resulting in disease later in life. Previously, we have shown alterations in the dendritic cytoarchitecture of Purkinje cells in adolescent rat progeny prenatally exposed to glucocorticoids. However, the molecular mechanisms underlying these alterations remain unclear. A possible molecular candidate whose deregulation may underlie these changes is the glucocorticoid receptor (GR) and neurotrophin 3/ tropomyosin receptor kinase C, neurotrophic complex (NT-3/TrkC), which specifically modulates the development of the neuronal connections in the cerebellar vermis. To date, no evidence has shown that the cerebellar expression levels of this neurotrophic complex are affected by exposure to a synthetic glucocorticoid in utero. Therefore, the first objective of this investigation was to evaluate the expression of GR, NT-3 and TrkC in the cerebellar vermis using immunohistochemistry and western blot techniques by evaluating the progeny during the postnatal stage equivalent to adolescence (postnatal Day 52). Additionally, we evaluated anxiety-like behaviours in progeny using the elevated plus maze and the marble burying test. In addition, an environmental enrichment (EE) can increase the expression of some neurotrophins and has anxiolytic power. Therefore, we wanted to assess whether an EE reversed the long-term alterations induced by prenatal betamethasone exposure. The major findings of this study were as follows: i) prenatal betamethasone (BET) administration decreases GR, NT-3 and TrkC expression in the cerebellar vermis ii) prenatal BET administration decreases GR expression in the cerebellar hemispheres and iii) enhances the anxiety-like behaviours in the same progeny, and iv) exposure to an EE reverses the reduced expression of GR, NT-3 and TrkC in the cerebellar vermis and v) decreases anxiety-like behaviours. In conclusion, an enriched environment applied 18 days post-weaning was able to restabilize GR, NT-3 and TrkC expression levels and reverse anxious behaviours observed in adolescent rats prenatally exposed to betamethasone.
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Introduction: Neurotrophin-3 (NT-3) is thought to play a role in the neurobiological processes implicated in mood and anxiety disorders. NT-3 is a potential pharmacological target for mood disorders because of its effects on monoamine neurotransmitters, regulation of synaptic plasticity and neurogenesis, brain-derived neurotrophic factor (BDNF) signaling boosting, and modulation of the hypothalamic-pituitary-adrenal (HPA) axis. The mechanisms underlying NT-3 anxiolytic properties are less clear and require further exploration and definition. Areas covered: The evidence that supports NT-3 as a pharmacological target for anxiety and mood disorders is presented and this is followed by a reflection on the quandaries, stumbling blocks, and future perspectives for this novel target. Expert opinion: There is evidence for miRNAs being key post-transcriptional regulators of neurotrophin-3 receptor gene (NTRK3) in anxiety disorders; however, the anxiolytic properties of NT-3 need further examination and delineation. Moreover, NT-3 expression by non-neuronal cells and its role in brain circuits that participate in anxiety and mood disorders require further scrutiny. Further work is vital before progression into clinical trials can be realized.
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Transtornos de Ansiedade/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Neurotrofina 3/metabolismo , Animais , Transtornos de Ansiedade/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Humanos , MicroRNAs/genética , Terapia de Alvo Molecular , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/fisiopatologia , Receptor trkC/genéticaRESUMO
ABSTRACT Objective: The aim of the present study was to investigate the depressive symptoms and changes in neurotrophins (BDNF, NGF, NT-3), and cortisol levels in serum of peripheral blood from ostomy patients compared to healthy control group. Methods: We evaluated ostomy (n = 29) and healthy control (n = 30) patients. The neurotrophin (BDNF, NGF, NT-3), and cortisol levels were assessed by ELISA in serum of peripheral blood. Depressive symptoms were defined based on the Hamilton Depression Rating Scale (HDRS), and major depression disorder was based on clinical interviews and was confirmed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Results: The results showed a significant decrease in BDNF levels and, a significant increase in NT-3 levels in serum of peripheral blood from ostomy patients when compared to healthy controls. The levels of NGF and cortisol showed no significant differences between groups. The depressive symptom evaluations by HDRS demonstrated a significant increase in ostomy patients when compared to healthy controls. The major depression disorder diagnosis by SCID-I showed no significant difference between groups. Conclusion: Our results suggest ostomy triggers significant depressive symptoms and alterations in neurotrophins levels in serum of peripheral blood samples collected from these patients.
RESUMO Objetivo: O objetivo do presente estudo foi investigar os sintomas depressivos e alterações nos níveis de neurotrofinas (BDNF, NGF, NT-3) e cortisol em soro de sangue periférico de pacientes ostomizados em comparação com grupo controle saudável. Métodos: Foram avaliados pacientes ostomizados (n = 29) e controles saudáveis (n = 30). Os níveis de neurotrofinas (BDNF, NGF, NT-3) e cortisol foram avaliados por kit ELISA em soro de sangue periférico. Os sintomas depressivos foram definidos com base na Hamilton Depression Rating Scale (HDRS), e o transtorno depressivo maior foi baseado em entrevistas clínicas e confirmado pela Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Resultados: Os resultados mostraram diminuição significativa nos níveis de BDNF e aumento significativo nos níveis de NT-3 no soro de sangue periférico de pacientes ostomizados quando comparados com controles saudáveis. Os níveis de NGF e cortisol não apresentaram diferenças significativas entre os grupos. As avaliações dos sintomas depressivos pela HDRS demonstraram aumento significativo em pacientes ostomizados quando comparados com controles saudáveis. O diagnóstico de transtorno depressivo maior pela SCID-I não mostrou diferença significativa entre os grupos. Conclusão: Nossos resultados sugerem que a ostomia desencadeia sintomas depressivos significativos e alterações nos níveis de neurotrofinas no soro de sangue periférico coletadas desses pacientes
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Several pathogens have been suspected of playing a role in the pathogenesis of schizophrenia. Chronic inflammation has been proposed to occur as a result of persistent infection caused by Chlamydophila pneumoniae cells that reside in brain endothelial cells for many years. It was recently hypothesized that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may play prominent roles in the development of schizophrenia. NT-3 and BDNF levels have been suggested to change in response to various manifestations of infection. Therefore, we aimed to elucidate the roles of BDNF and NT3 in the schizophrenia-C. pneumoniae infection relationship. RT-PCR, immunofluorescence and ELISA methods were used. Fifty patients suffering from schizophrenia and 35 healthy individuals were included as the patient group (PG) and the healthy control group (HCG), respectively. We detected persistent infection in 14 of the 50 individuals in the PG and in 1 of the 35 individuals in the HCG. A significant difference was found between the two groups (p<0.05). Twenty-two individuals in the PG and 13 in the HCG showed seropositivity for past C. pneumoniae infection, and no difference was observed between the groups (p>0.05). C. pneumoniae DNA was not detected in any group. A significant difference in NT-3 levels was observed between the groups, with very low levels in the PG (p<0.001). A significant difference in BDNF levels was also found, with lower levels in the PG (p<0.05). The mean serum NT-3 level was higher in the PG cases with C. pneumoniae seropositivity than in seronegative cases; however, this difference was not statistically significant (p>0.05). In conclusion, we suggest that NT-3 levels during persistent C. pneumoniae infection may play a role in this relationship.
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Fator Neurotrófico Derivado do Encéfalo , Infecções por Chlamydophila , Chlamydophila pneumoniae , Neurotrofina 3 , Esquizofrenia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Infecções por Chlamydophila/complicações , Ensaio de Imunoadsorção Enzimática , Humanos , Neurotrofina 3/metabolismo , Esquizofrenia/microbiologiaRESUMO
Several pathogens have been suspected of playing a role in the pathogenesis of schizophrenia. Chronic inflammation has been proposed to occur as a result of persistent infection caused by Chlamydophila pneumoniae cells that reside in brain endothelial cells for many years. It was recently hypothesized that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may play prominent roles in the development of schizophrenia. NT-3 and BDNF levels have been suggested to change in response to various manifestations of infection. Therefore, we aimed to elucidate the roles of BDNF and NT3 in the schizophrenia-C. pneumoniae infection relationship. RT-PCR, immunofluorescence and ELISA methods were used. Fifty patients suffering from schizophrenia and 35 healthy individuals were included as the patient group (PG) and the healthy control group (HCG), respectively. We detected persistent infection in 14 of the 50 individuals in the PG and in 1 of the 35 individuals in the HCG. A significant difference was found between the two groups (p < 0.05). Twenty-two individuals in the PG and 13 in the HCG showed seropositivity for past C. pneumoniae infection, and no difference was observed between the groups (p > 0.05). C. pneumoniae DNA was not detected in any group. A significant difference in NT-3 levels was observed between the groups, with very low levels in the PG (p < 0.001). A significant difference in BDNF levels was also found, with lower levels in the PG (p < 0.05). The mean serum NT-3 level was higher in the PG cases with C. pneumoniae seropositivity than in seronegative cases; however, this difference was not statistically significant (p > 0.05). In conclusion, we suggest that NT-3 levels during persistent C. pneumoniae infection may play a role in this relationship.
Existe la sospecha de que algunos patógenos pueden desempeñar un papel en la patogénesis de la esquizofrenia; en ese contexto, se ha propuesto que la infección persistente causada por células de Chlamydophila pneumoniae presentes en las células endoteliales cerebrales durante muchos años lleva a la inflamación crónica. Recientemente se ha planteado la hipótesis de que el factor neurotrófico de origen cerebral (BDNF, por sus siglas en inglés) y la neurotropina-3 (NT-3) podrían estar implicados en el desarrollo de la esquizofrenia, y se ha sugerido que sus niveles se modifican en respuesta a diversas manifestaciones de la infección. En esta investigación intentamos esclarecer el papel que desempeñan el BDNF y la NT3 en la relación entre la esquizofrenia y la infección por C. pneumoniae. Se utilizaron métodos de RT-PCR, inmunofluorescencia y ELISA. Se incluyeron 50 pacientes con esquizofrenia y 35 individuos sanos como grupo de pacientes (GP) y grupo de controles sanos (GCS), respectivamente. Detectamos una infección persistente en 14 sujetos del GP y en 1 de los del GCS, lo que constituyó una diferencia significativa (p < 0,05). Veinte participantes del GP y 13 del GCS fueron seropositivos para una infección pasada por C. pneumoniae, diferencia no significativa (p > 0,05). No se detectó ADN de C. pneumoniae en ninguno de los dos grupos. Se observó una diferencia significativa entre los grupos en los niveles de NT-3, que fueron muy bajos en el GP (p < 0,001), y de BDNF, inferiores en el GP (p < 0,05). La concentración sérica media de NT-3 fue mayor en los individuos seropositivos para C. pneumoniae en comparación con los seronegativos, pero esta diferencia no alcanzó significación estadística (p > 0,05). Sugerimos que los niveles de NT-3 durante una infección persistente por C. pneumoniae pueden estar implicados en la relación de Chlamydophila pneumoniae con la esquizofrenia.
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Humanos , Masculino , Feminino , Esquizofrenia/complicações , Chlamydophila pneumoniae/patogenicidade , Fator Neurotrófico Derivado do Encéfalo/análise , Neurotrofina 3/análise , Fatores de Crescimento Neural/análise , Ensaio de Imunoadsorção Enzimática/métodos , Técnica Indireta de Fluorescência para Anticorpo/métodos , Fator Neurotrófico Derivado do Encéfalo/efeitos adversos , Neurotrofina 3/efeitos adversos , Reação em Cadeia da Polimerase em Tempo Real/métodosRESUMO
Neurotrophins (NTs) have been implicated in generation and modulation of nociceptive pathways. Change in NTs levels is associated with painful conditions and neurological diseases such as migraine. Currently, it is generally recognized that migraine headaches result from the activation and sensitization of trigeminal sensory afferent fibers leading to neuropeptides release such as calcitonin gene-related peptide (CGRP) and substance P (SP). This triggers an inflammatory cascade causing a neurogenic inflammation. The agents responsible for trigeminal activation and release of neuropeptides are still unclear. It is known that the transient receptor potential vanilloid receptor-1 (TRPV1) is an important mediator of CGRP and SP release. TRPV1 is closely associated with tyrosine receptors kinases (Trk), which are NTs receptors. NTs can act on TRPV1 increasing its sensitivity to painful stimuli, therefore predisposing to hyperalgesia. Upregulation of ion channels and pain receptors in dorsal root ganglion neurons may be alternative mechanisms by which NTs contribute to pain development. Only a few studies have been performed to investigate the role of NTs in migraine. These studies have reported changes in NTs levels in migraine patients either during the migraine attack or in free-headache periods.
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Encéfalo/metabolismo , Transtornos de Enxaqueca/metabolismo , Modelos Neurológicos , Fatores de Crescimento Neural/metabolismo , Neurônios/metabolismo , Receptores de Fator de Crescimento Neural/agonistas , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/imunologia , Gânglios Espinais/metabolismo , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/imunologia , Transtornos de Enxaqueca/fisiopatologia , Fatores de Crescimento Neural/antagonistas & inibidores , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Inflamação Neurogênica/etiologia , Inflamação Neurogênica/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/imunologia , Neurônios Aferentes/metabolismo , Dor Nociceptiva/etiologia , Dor Nociceptiva/prevenção & controle , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismoRESUMO
Progenitors were discovered in the corpus striatum several years ago, but little is known about their proliferation and differentiation. The aim of this study was to analyze embryonic progenitor cells from the corpus striatum using a bioassay with trophic stimulation. Primary cells obtained from brains of rat embryos at E13-14 were dissected from striatum niches and cultured in stem cell media. These floating dispersed cells clumped together to forming floating bodies like irregular spheres (spheroids), which were placed in type I collagen gel and cultured under basal conditions or with the addition of NGF, NT-3, or NTN. Optimum growth of neurites was obtained, and after 24 and 48 h, they were measured for number and length. The expression of proliferation markers such as PCNA and Ki67, and of neural progenitor markers such as GFAP, nestin, vimentin, O4, A2B5, Pax6, S100, TubIII, and NeuN, was then analyzed. The initial behavior in cell cultures showed distinguishable spheroids that, when placed in 3D gels and with trophic support, generated neurites. A similar effect was observed in glial cell outgrowth from the spheroids. Our assay showed high reproducibility, short culture time, and high resolution for tracing neuron-neurite outgrowth or visualizing glial outgrowth in a few hours.