RESUMO
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.
Assuntos
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
Neospora caninum is a parasite that infects many animal species and has tropism for various tissues, particularly the nervous system, where it generally remains in cysts. Under N. caninum infection, glial cells activate immune responses by a Th2 profile, suggesting an immunologically privileged environment that controls parasite proliferation, with neuronal preservation. In this study, we investigated the role of soluble neurotrophic factors released by glial cells on neuronal integrity during N. caninum infection in vitro. Primary cultures of rat glial cells enriched in astrocytes were infected with N. caninum tachyzoites (1:1) for 24 hr. Neuron-glia co-cultures were cultured for 24 hr with conditioned medium from glial cells infected with N. caninum (CMNc) and from uninfected cultures (control). Cell viability was determined through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test; astrocyte morphology and reactivity were determined through immunocytochemistry for glial fibrillar acid protein (GFAP) and the integrity of neurons through immunocytochemistry for ß-tubulin III. Expression of inflammatory cytokines and neurotrophic factors was determined through RT-qPCR. The MTT test demonstrated that 1:1 was the best parasite/host cell ratio, considering that it was enough to increase metabolism of glial cells when compared with control cultures and was not cytotoxic after 48 hr infection. N. caninum-infected glial cultures responded with astrogliosis characterized by an increase in GFAP expression and increase in IL-10 (2-fold), BDNF (1.6-fold), and NGF (1.7-fold) gene expression. In the neuron/glia co-cultures, it was observed that treatment with CMNc induced neuritis outgrowth without toxicity. Together, these results show that modulatory mechanisms by neurotrophic factors derived from glial cells, primarily astrocytes during the N. caninum infection, can favor neuroprotection.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neospora/fisiologia , Fator de Crescimento Neural/metabolismo , Neuroglia/parasitologia , Análise de Variância , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/citologia , Chlorocebus aethiops , Técnicas de Cocultura , Meios de Cultivo Condicionados , DNA Complementar/biossíntese , Neospora/genética , Fatores de Crescimento Neural/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Neurotrofina 3/metabolismo , RNA de Protozoário/genética , RNA de Protozoário/isolamento & purificação , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Células VeroRESUMO
Despite advances in technology and rehabilitation, no effective therapies are available for patients with SCI, which remains a major medical challenge. This study compared the efficacy of 3 different doses of mesenchymal stem cells (MSCs) administered by intraperitoneal injection as a therapeutic strategy for compressive SCI. We used adult female C57BL/6 mice that underwent laminectomy at the T9 level, followed by spinal-cord compression for 1â¯min with a 30-g vascular clip. The animals received an intraperitoneal (i.p.) injection of MSCs (8â¯×â¯104, 8â¯×â¯105 or 8â¯×â¯106 in 500⯵l) or DMEM (500⯵l), one week after SCI. The cells of the three MSC doses administered i.p. were able to migrate to the injury site, increase local expression of trophic factors, and enhance fiber sparing and/or regeneration, accompanied by substantial improvement in locomotor performance. Cell transplantation at 8â¯×â¯105 density showed the best therapeutic potential, leading to significant tissue and functional improvements compared to the other two doses. These findings indicate that i.p. application of MSCs at the density of 8â¯×â¯105 yielded the best results, suggesting that this dose is a good choice for SCI treatment.
Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Recuperação de Função Fisiológica , Compressão da Medula Espinal/fisiopatologia , Compressão da Medula Espinal/cirurgia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Gliose/etiologia , Locomoção , Camundongos Endogâmicos C57BL , Fibras Nervosas Mielinizadas/fisiologia , Neurotrofina 3/metabolismo , Compressão da Medula Espinal/complicaçõesRESUMO
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.
Assuntos
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
BACKGROUND: After spinal cord (SC)-injury, a non-modulated immune response contributes to the damage of neural tissue. Protective autoimmunity (PA) is a T cell mediated, neuroprotective response induced after SC-injury. Immunization with neural-derived peptides (INDP), such as A91, has shown to promote-in vitro-the production of neurotrophic factors. However, the production of these molecules has not been studied at the site of injury. RESULTS: In order to evaluate these issues, we performed four experiments in adult female Sprague-Dawley rats. In the first one, brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) concentrations were evaluated at the site of lesion 21 days after SC-injury. BDNF and NT-3 were significantly increased in INDP-treated animals. In the second experiment, proliferation of anti-A91 T cells was assessed at chronic stages of injury. In this case, we found a significant proliferation of these cells in animals subjected to SC-injury + INDP. In the third experiment, we explored the amount of BDNF and NT3 at the site of injury in the chronic phase of rats subjected to either SC-contusion (SCC; moderate or severe) or SC-transection (SCT; complete or incomplete). The animals were treated with INDP immediately after injury. Rats subjected to moderate contusion or incomplete SCT showed significantly higher levels of BDNF and NT-3 as compared to PBS-immunized ones. In rats with severe SCC and complete SCT, BDNF and NT-3 concentrations were barely detected. Finally, in the fourth experiment we assessed motor function recovery in INDP-treated rats with moderate SC-injury. Rats immunized with A91 showed a significantly higher motor recovery from the first week and up to 4 months after SC-injury. CONCLUSIONS: The results of this study suggest that PA boosted by immunization with A91 after moderate SC-injury can exert its benefits even at chronic stages, as shown by long-term production of BDNF and NT-3 and a substantial improvement in motor recovery.
Assuntos
Autoimunidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Básica da Mielina/imunologia , Neurotrofina 3/metabolismo , Fragmentos de Peptídeos/imunologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/terapia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Atividade Motora , Distribuição Aleatória , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Medula Espinal/imunologia , Fatores de Tempo , VacinaçãoRESUMO
INTRODUCTION: Numerous rehabilitation treatments have been shown to be useful for peripheral and central restoration after (PNI). METHODS: After sciatic nerve crush, we investigated 4 weeks of endurance training (ET) and balance and coordination training (BCT) with sciatic function index, hind-paw stride length, and spinal cord dorsal horn synaptophysin and neurotrophin-3 immunoreactivity. RESULTS: Our results demonstrated no significant differences between the non-trained (NT), ET, and BCT groups in sciatic functional index, and in stride-length analysis, but the ET showed higher values compared with the NT group. Synaptophysin immunoreactivity was higher in the BCT group compared with the NT group, and neurotrophin-3 immunoreactivity in the BCT group was greater compared with the other groups. CONCLUSION: BCT can positively affect spinal cord plasticity after a (PNI), and these modifications are important in the rehabilitation process.
Assuntos
Neurotrofina 3/metabolismo , Condicionamento Físico Animal/fisiologia , Equilíbrio Postural/fisiologia , Neuropatia Ciática/metabolismo , Medula Espinal/metabolismo , Sinaptofisina/metabolismo , Animais , Vértebras Lombares , Masculino , Atividade Motora/fisiologia , Compressão Nervosa/métodos , Neurotrofina 3/análise , Condicionamento Físico Animal/métodos , Resistência Física/fisiologia , Desempenho Psicomotor/fisiologia , Ratos , Ratos Wistar , Medula Espinal/química , Sinaptofisina/análiseRESUMO
Standard vein graft (SVG) and inside out vein graft (IOVG) techniques to promote peripheral nerve regeneration have been widely studied since last two decades. In this experimental study, we attempted to compare these two techniques and analyze the differences in the expression of the neurotrophins during peripheral nerve regeneration. Thirty-six male Wistar rats were used in this sciatic nerve transection model and were divided into two experimental groups (SVG and IOVG) and one sham operated control group. An overall defect of 10 mm was made in the sciatic nerve of the animals in the experimental groups. Each group consisted of two time intervals of 6 and 12 weeks (n = 6). After each experimental interval, sciatic functional index (SFI) along with area and diameter of the axons and fibers of each group were calculated. Muscle mass measurements were also evaluated to see any functional recovery in the groups. Expression of neurotrophins in the graft and distal stump were analyzed with the help of RT-PCR. SFI obtained from walking track analysis showed poor motor recovery in the experimental groups during both time intervals. No significant differences in the histological, morphometric (P > 0.05), and muscle mass measurements (P > 0.05) between the two experimental groups were observed. Analysis of RT-PCR data exhibited an increase in the expression of NT-3 with time in both the grafts (6 weeks 0.428 ± 0.392, 12 weeks 1.089 ± 0.455, P < 0.05) and distal stump (6 weeks 0.411 ± 0.306, 12 weeks 0.807 ± 0.303, P < 0.05) of the SVG group. The study concludes that there is no substantial difference in the nerve regeneration ability between both the techniques. Also, the difference in the level of NT-3 between SVG and IOVG suggests a distinct regulation of NT-3 in peripheral nerve regeneration.
Assuntos
Regeneração Tecidual Guiada/métodos , Veias Jugulares/transplante , Fatores de Crescimento Neural/metabolismo , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/cirurgia , Nervo Isquiático/lesões , Animais , Biomarcadores/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Neurotrofina 3/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Nervo Isquiático/cirurgiaRESUMO
Experimental evidence has revealed the role of mitochondria in various aspects of neuronal physiology. Mitochondrial failure results in alterations that underlie the pathogeneses of many neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease (HD) and amyotrophic lateral sclerosis. The mitochondrial toxin 3-nitropropionic acid (3-NP) has been used to model failure; for example, systemic administration of 3-NP imitates the striatal degeneration that is exhibited in the postmortem tissue of patients afflicted with HD. We have demonstrated that low, sub-chronic doses of 3-NP are sufficient to initiate the damage to striatal neurons that is associated with changes in neurotrophin expression levels. However, the mechanisms underlying the alterations in neuronal activity and neurotransmission due to 3-NP-induced mitochondrial dysfunction remain to be elucidated. In this paper, we focus on how corticostriatal transmission and its modulation by neurotrophins are altered in vivo after 5 days of mitochondrial inhibition with 3-NP. Recordings of population spikes and a paired pulse (PP) stimulation protocol were used to document changes in corticostriatal synapses in 3-NP-treated brain slices. The corticostriatal synapses were modulated by neurotrophins but displayed differential amplitude increases in the presence of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5 (NT-4/5) under control conditions. Neurotrophin-mediated synaptic modulation was decreased in slices from 3-NP-treated mice. The protein and mRNA levels of neurotrophins and their receptors were also modified in the 3-NP-treated tissue. Neuronal structural evaluation demonstrated that synaptic length and density were reduced in the 3-NP-treated mice, which partially explained the changes in the amplitudes of the synaptic field responses. Our results demonstrate that corticostriatal synapses are differentially modulated by neurotrophins and that this modulation is altered by mitochondrial failure. Mitochondrial dysfunction also affects neurotransmitter release in corticostriatal synapses, neurotrophin availability, dendritic arborization and the lengths of the striatal medium spiny neurons (MSNs).
Assuntos
Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Mitocôndrias/fisiologia , Fatores de Crescimento Neural/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Ácido Glutâmico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais , Vias Neurais/efeitos dos fármacos , Vias Neurais/patologia , Vias Neurais/fisiologia , Neurotrofina 3/metabolismo , Nitrocompostos/toxicidade , Propionatos/toxicidade , Distribuição Aleatória , Receptores de Fator de Crescimento Neural/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/patologia , Técnicas de Cultura de TecidosRESUMO
Chemotactic cell migration is triggered by extracellular concentration gradients of molecules segregated by target fields. Neural crest cells (NCCs), paradigmatic as an accurately moving cell population, undergo wide dispersion along multiple pathways, invading with precision defined sites of the embryo to differentiate into many derivatives. This report addresses the involvement of NT-3 in early colonization by cephalic NCCs invading the optic vesicle region. The results of in vitro and in vivo approaches showed that NCCs migrate directionally up an NT-3 concentration gradient. We also demonstrated the expression of NT-3 in the ocular region as well as their functional TrkB, TrkC and p75 receptors on cephalic NCCs. On whole-mount embryo, a perturbed distribution of NCCs colonizing the optic vesicle target field was shown after morpholino cancelation of cephalic NT-3 or TrkC receptor on NCCs, as well as in situ blocking of TrkC receptor of mesencephalic NCCs by specific antibody released from inserted microbeads. The present results strongly suggest that, among other complementary cell guidance factor(s), the chemotactic response of NCCs toward the ocular region NT-3 gradient is essential for spatiotemporal cell orientation, amplifying the functional scope of this neurotrophic factor as a molecular guide for the embryo cells, besides its well-known canonical functions.
Assuntos
Quimiotaxia , Mesencéfalo/citologia , Crista Neural/citologia , Neurotrofina 3/metabolismo , Animais , Proliferação de Células , Embrião de Galinha , Galinhas , Crista Neural/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de SinaisRESUMO
It has been suggested that long-term modifications of synaptic transmission constitute the foundation of the processes by which information is stored in the central nervous system. A group of proteins called neurotrophins are considered powerful molecular mediators in central synaptic plasticity. Among these, brain-derived neurotrophic factor (BDNF) as well as neurotrophin-3 (NT-3) have emerged as having key roles in the neurobiological mechanisms related to learning and memory. In this chapter, we review the studies that have represented a significant step forward in understanding the role played by BDNF and NT-3 in long-term synaptic plasticity. The effects of BDNF and NT-3 on synaptic plasticity can be of a permissive nature, establishing the conditions under which plastic changes can take place, or it may be instructive, directly modifying the communication and morphology of synapses. The actions carried out by BDNF include its capacity to contribute to the stabilization and maturation of already-existing synapses, as well as to generate new synaptic contacts. One important finding that highlights the participation of these neurotrophins in synaptic plasticity is the observation that adding BDNF or NT-3 gives rise to drastic long-term increases in synaptic transmission, similar to the long-term potentiation in the hippocampus and neocortex of mammals. Because neurotrophins modulate both the electrical properties and the structural organization of the synapse, these proteins have been considered important biological markers of learning and memory processes.