RESUMO
Accumulating evidence has shown that some hallucinogens, such as LSD, have fast and persistent effects on anxiety and depression. According to a proposed mechanism, LSD activates the TrkB and HTR2A signaling pathways, which enhance the density of neuronal dendritic spines and synaptic function, and thus promote brain function. Moreover, TrkB signaling is also known to be crucial for neural stem cell (NSC)-mediated neuroregeneration to repair dysfunctional neurons. However, the impact of LSD on neural stem cells remains to be elucidated. In this study, we observed that LSD and BDNF activated the TrkB pathway in human NSCs similarly to neurons. However, unlike BDNF, LSD did not promote NSC proliferation. These results suggest that LSD may activate an alternative mechanism to counteract the effects of BDNF-TrkB signaling on NSCs. Our findings shed light on the previously unrecognized cell type-specificity of LSD. This could be crucial for deepening our understanding of the mechanisms underlying the effects of LSD.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Alucinógenos , Dietilamida do Ácido Lisérgico , Células-Tronco Neurais , Receptor trkB , Transdução de Sinais , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Alucinógenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor trkB/metabolismo , Dietilamida do Ácido Lisérgico/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/citologia , Glicoproteínas de MembranaRESUMO
We reported that infiltrated Ly6C+ macrophages express brain-derived neurotrophic factor (BDNF) only at the cerebral cortex infarct in a rat dMCAO model. However, the changein neuron-expressed BDNF, the niche components that induce the Ly6C+ cells to express BDNF, and the cellular sources of these components, remain unclear. In this study, immunofluorescence double staining was performed to label BDNF and Ly6C on brain sections at 3, 24, and 48 h following distal middle cerebral artery occlusion (dMCAO) of male rats, and to stain BDNF with Ly6C, IL-4R, and IL-10R. A neutralizing anti-IL-4 antibody was injected into the infarct, and the IL-4 and BDNF concentrations in the subareas of the infarct were determined using enzyme-linked immunosorbent assay. To find out the cellular sources of IL-4, the markers for microglia, T cells, and neurons were co-stained with IL-4 separately. In certain infarct subareas, the main BDNF-expressing cells shifted quickly from NeuN+ neurons to Ly6C+ cells during 24-48 h post-stroke, and the Ly6C+/BDNF+ cells mostly expressed IL-4 receptor. Following IL-4 neutralizing antibody injection, the BDNF, IL-4 protein levels, and BDNF+/Ly6C+ cells decreased significantly. The main IL-4-expressing cell type in this infarct subarea is not neuron either, but immune cells, including microglia, monocyte, macrophages, and T cells. The neurons, maintained BDNF and IL-4 expression in the peri-infarct area. In conclusion, in a specific cerebral subarea of the rat dMCAO model, IL-4 secreted by immune cells is one of the main inducers for Ly6C+ cells to express BDNF.
Assuntos
Isquemia Encefálica , Fator Neurotrófico Derivado do Encéfalo , Interleucina-4 , Macrófagos , Animais , Masculino , Ratos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Interleucina-4/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-DawleyRESUMO
Throughout our evolutionary history, physical activity has played a significant role in shaping our physiology. Advances in exercise science have further reinforced this concept by highlighting how exercise can change gene expression and molecular signaling to achieve various beneficial outcomes. Several studies have shown that exercise can alter neuronal functions to prevent neurodegenerative conditions like Parkinson's and Alzheimer's diseases. However, individual genotypes, phenotypes, and varying exercise protocols hinder the prescription of exercise as standard therapy. Moreover, exercise-induced molecular signaling targets can be double-edged swords, making it difficult to use exercise as the primary candidate for beneficial effects. For example, activating PGC-1 alpha and BDNF through exercise could produce several benefits in maintaining brain health, such as plasticity, neuronal survival, memory formation, cognition, and synaptic transmission. However, higher expression of BDNF might play a negative role in bipolar disorder. Therefore, further understanding of a specific mechanistic approach is required. This review focuses on how exercise-induced activation of these molecules could support brain health and discusses the potential underlying mechanisms of the effect of exercise-induced PGC-1 alpha and BDNF on brain health.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Encéfalo , Exercício Físico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Exercício Físico/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Animais , Plasticidade Neuronal/fisiologiaRESUMO
High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds' potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain-derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward. Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti-inflammatory properties, among others. This work aims to examine the potential anxiety-reducing properties of CBD in a well-established experimental mouse model of anxiety-like behavior induced by high doses of nicotine on male C57BL/6 mice. In this context, the open-field behavioral test was specially conducted to assess CBD's effects on anxiety-like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood's metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro-inflammatory cytokine assessments were conducted to evaluate redox status and immune system function. Our research suggests that CBD shows potential in reducing anxiety-like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue's systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro-inflammatory cytokines (TNF-alpha and IL-6).
Assuntos
Ansiedade , Fator Neurotrófico Derivado do Encéfalo , Canabidiol , Camundongos Endogâmicos C57BL , Nicotina , Estresse Oxidativo , Animais , Canabidiol/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Camundongos , Nicotina/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/induzido quimicamente , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Animal/efeitos dos fármacosRESUMO
Depression is a prevalent mental disorder, but the side effects of antidepressants also make depressed patients resistant. Effective and safe antidepressants should be developed from traditional herbs, with the aim of reducing the side effects of antidepressants and improving the efficacy of drugs. In this study, the new macamide compound-4 (NMC-4) was synthesized for the first time, addressing the problem of difficult extraction, isolation, and low content of natural macamide. NMC-4 was characterized using mass spectrometry, nuclear magnetic resonance, and infrared spectroscopy. The protective effect of NMC-4 against cell injury was demonstrated to be stronger than that of natural macamide (N-benzylhexadecanamide, XA) using a PC12 cell injury model. The study explored the effects of NMC-4 on chronic unpredictable mild stress (CUMS)-induced depressive symptoms. NMC-4 significantly improved depressive-like behaviors. NMC-4 ameliorated CUMS-induced depressive-like behaviors by mitigating neuroinflammation and modulating the NF-κB/Nrf2 and BDNF/PI3K/Akt pathways.
Assuntos
Antidepressivos , Depressão , Animais , Depressão/tratamento farmacológico , Ratos , Células PC12 , Masculino , Antidepressivos/farmacologia , Antidepressivos/química , Antidepressivos/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , NF-kappa B/metabolismo , Camundongos , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: The hippocampus is susceptible to damage, leading to negative impacts on cognition. Conditioned medium (CM) obtained from adipose tissue-derived mesenchymal stem cells (MSCs) and acetylsalicylic acid (ASA) have shown neuroprotective effects independently. This study explored the synergistic potential of ASA and CM from adipose-derived MSCs against hippocampal injury. METHODS: Adult male Wistar rats received bilateral hippocampal ethidium bromide (EB) injections to induce hippocampal damage. Rats were treated with ASA and/or CM derived from adipose tissue MSCs every 48 h for 16 days. Behavioral tests (open field test, Morris water maze, novel object recognition, and passive avoidance), oxidative stress, Western blot analysis of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) expression, and hippocampal histological investigation were conducted. RESULTS: Administration of EB caused impairments in spatial, recognition, and passive avoidance memory, as well as heightened oxidative stress, reduced BDNF/CDNF expression, and pyramidal cell loss in the hippocampal CA1 region. Administration of ASA, CM, or a combination of both mitigated these hippocampal damages and cognitive deficits, elevated BDNF and CDNF levels, and alleviated the CA1 necrosis caused by EB. Moreover, co-administering ASA and CM resulted in greater improvements in spatial memory compared to administering ASA alone, suggesting possible synergistic interactions. CONCLUSIONS: The ability of ASA, CM obtained from adipose tissue-derived MSCs, and their combination therapy to alleviate hippocampal injuries highlights their promising therapeutic potential as a neuroprotection strategy against brain damage. Our findings provide preliminary evidence of the potential synergistic effects of ASA and CM, which warrants further investigations.
Assuntos
Aspirina , Fator Neurotrófico Derivado do Encéfalo , Hipocampo , Células-Tronco Mesenquimais , Estresse Oxidativo , Ratos Wistar , Animais , Masculino , Aspirina/farmacologia , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Cognição/efeitos dos fármacos , Antioxidantes/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismoRESUMO
The regulation of neurogenesis, the complex process of producing and differentiating new brain tissue cells, is influenced by a complex interaction of internal and external factors. Over the past decade, extensive research has been conducted on neurotrophins and their key role in adult neurogenesis, as well as their impact on diseases such as depression. Among neurotrophins, the brain-derived neurotrophic factor (BDNF) has been the subject of comprehensive studies on adult neurogenesis, and scientific evidence supports its necessity for neurogenesis in the subventricular zone of the hippocampus. A novel area of research is the emerging role of gut microbiota as a significant contributor to neurogenesis and neurotrophin production. Studies have shown that reduced BDNF levels can lead to mood disorders, which are observed in intestinal dysbiosis, characterized by an imbalance in the composition and quantity of the intestinal microbiota. There is evidence in the literature that there is a link between brain function and gut microbiota. Physical activity, and especially the regularity and intensity of exercise, is important in relation to the level of BDNF and the intestinal microbiota. Probiotics, prebiotics and physical activity may have a positive effect on the intestinal microbiota, and therefore also on the level of the brain-derived neurotrophic factor.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Exercício Físico , Microbioma Gastrointestinal , Probióticos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiologia , Humanos , Exercício Físico/fisiologia , Neurogênese , Animais , Disbiose , Prebióticos , Encéfalo/metabolismo , Eixo Encéfalo-Intestino/fisiologiaRESUMO
BACKGROUND: The choroid plexus (CP) is an understudied tissue in the central nervous system and is primarily implicated in cerebrospinal fluid (CSF) production. CP also produces numerous neurotrophic factors (NTF) which circulate to different brain regions. Regulation of NTFs in the CP during natural aging is largely unknown. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and the water channel protein Aquaporin (AQP1). METHODS: Male and female mice were used for our study. Age-related transcriptional changes were analyzed using quantitative PCR at three different time points: mature adult, middle-aged, and aged. Transcriptional changes during aging were further confirmed with digital droplet PCR. Additionally, we used immunohistochemical analysis (IHC) for the evaluation of in vivo protein expression. We further investigated the cellular phenotype of these NTFS, TJP, and water channel proteins in the mouse CP by co-labeling them with the classical vascular marker, Isolectin B4, and epithelial cell marker, Plectin. RESULTS: Aging significantly altered NTF gene expression in the CP. Brain-derived neurotrophic factor (BDNF), Midkine (MDK), VGF, Insulin-like growth factor (IGF1), IGF2, Klotho (KL), Erythropoietin (EPO), and its receptor (EPOR) were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression was unchanged in the aged CP, while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJP's JAM, CLAUDIN1, CLAUDIN2 and CLAUDIN5 were reduced in aged mice. CONCLUSIONS: Our study highlights transcriptional level changes in the CP during aging. The age-related transcriptional changes exhibit similarities as well as gene-specific differences in the CP of males and females. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging.
Assuntos
Envelhecimento , Plexo Corióideo , Proteínas de Junções Íntimas , Animais , Plexo Corióideo/metabolismo , Envelhecimento/metabolismo , Feminino , Masculino , Camundongos , Proteínas de Junções Íntimas/metabolismo , Proteínas de Junções Íntimas/genética , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/genética , Camundongos Endogâmicos C57BL , Expressão Gênica , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Aquaporina 1/metabolismo , Aquaporina 1/genéticaRESUMO
There is substantial evidence supporting the neuroprotective effects of the MIND diet in neurodegenerative diseases like Parkinson's and Alzheimer's. Our aim was to evaluate the impact of a nutritional intervention (NI) with this diet on multiple sclerosis (MS) patients. The study was conducted in two stages. In the first stage, two groups were included: MS patients before the NI (group A) and healthy control subjects (group B). In this stage, groups (A) and (B) were compared (case-control study). In the second stage, group (A) was assessed after the NI, with comparisons made between baseline and final measurements (before-and-after study). In the case-control stage (baseline evaluation), we found significant differences in fatigue scores (p < 0.001), adherence to the MIND diet (p < 0.001), the serum levels of brain-derived neurotrophic factor (BDNF) (p < 0.001), and higher oxidative status in the MS group, with lower levels of reduced glutathione (p < 0.001), reduced/oxidised glutathione ratio (p < 0.001), and elevated levels of lipoperoxidation (p < 0.002) and 8-hydroxy-2'-deoxyguanosine (p < 0.025). The before-and-after intervention stage showed improvements in fatigue scores (p < 0.001) and physical quality-of-life scores (MSQOL-54) (p < 0.022), along with decreases in the serum levels of glial-derived neurotrophic factor (GDNF) (p < 0.041), lipoperoxidation (p < 0.046), and 8-hydroxy-2'-deoxyguanosine (p < 0.05). Consumption of the MIND diet is linked to clinical and biochemical improvement in MS patients.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Esclerose Múltipla , Humanos , Esclerose Múltipla/dietoterapia , Esclerose Múltipla/sangue , Feminino , Masculino , Adulto , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estudos de Casos e Controles , Pessoa de Meia-Idade , Estresse Oxidativo , Glutationa/sangueRESUMO
Massage is one of the oldest forms of therapy practiced since ancient times. Nowadays, it is used in sports practice, recovery from injury, or supportive therapy for various conditions. The practice of massage uses a variety of instruments that facilitate massaging while relieving the stress on the masseur. One of them is a foam roller. Although roller massage is widely used, there are still no scientific studies describing the biological mechanisms of its effects on the body. The purpose of our study was to analyze the effect of roller massage on BDNF levels in men undergoing self-massage 4x/week/7 weeks. The control group consisted of men who did not perform self-massage. Before the test and after the first, third, fifth, and seventh weeks of self-massage, the study participants' blood was drawn, the serum BDNF was determined, and the results were subjected to analysis of variance by ANOVA test. After the first week of self-massage, an increase in BDNF concentration was observed in the self-massage group compared to the control group (p = 0.023). Similarly, changes were observed in week five (p = 0.044) and week seven (p = 0.046). In the massaged group, BDNF concentrations were significantly higher after the first week of self-massage compared to baseline. In the third week of the study, BDNF decreased to a value comparable to the baseline study, then increased significantly in the fifth and seventh weeks compared to the value recorded in the third week (p = 0.049 and p = 0.029). It was significantly higher in week seven compared to week five (p = 0.03). Higher concentrations of BDNF in subjects undergoing roller self-massage may be one of the biological mechanisms justifying the therapeutic effects of massage in both sports and clinical practice. Studies analyzing the stimulation of BDNF synthesis through various massage techniques should be performed on a larger group of healthy individuals, patients after trauma of multiple origins, and sick people with indications for therapeutic massage.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Massagem , Humanos , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Massagem/métodos , Masculino , Adulto , Adulto JovemRESUMO
BACKRGROUND: Akkermansia muciniphila, a next-generation probiotic, is known as a cornerstone regulating the gut-organ axis in various diseases, but the underlying mechanism remains poorly understood. Here, we revealed the neuronal and antifibrotic effects of A. muciniphila on the gut-liver-brain axis in liver injury. RESULTS: To investigate neurologic dysfunction and characteristic gut microbiotas, we performed a cirrhosis cohort (154 patients with or without hepatic encephalopathy) and a community cognition cohort (80 participants in one region for three years) and validated the existence of cognitive impairment in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic injury mouse model. The effects of the candidate strain on cognition were evaluated in animal models of liver injury. The expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors was accessed in patients with fibrosis (100 patients) according to the fibrosis grade and hepatic venous pressure gradient. The proportion of A. muciniphila decreased in populations with hepatic encephalopathy and cognitive dysfunction. Tissue staining techniques confirmed gut-liver-brain damage in liver injury, with drastic expression of BDNF and serotonin in the gut and brain. The administration of A. muciniphila significantly reduced tissue damage and improved cognitive dysfunction and the expression of BDNF and serotonin. Isolated vagus nerve staining showed a recovery of serotonin expression without affecting the dopamine pathway. Conversely, in liver tissue, the inhibition of injury through the suppression of serotonin receptor (5-hydroxytryptamine 2A and 2B) expression was confirmed. The severity of liver injury was correlated with the abundance of serotonin, BDNF, and A. muciniphila. CONCLUSIONS: A. muciniphila, a next-generation probiotic, is a therapeutic candidate for alleviating the symptoms of liver fibrosis and cognitive impairment.
Assuntos
Akkermansia , Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Microbioma Gastrointestinal , Cirrose Hepática , Fígado , Probióticos , Serotonina , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Serotonina/metabolismo , Camundongos , Disfunção Cognitiva/metabolismo , Masculino , Probióticos/uso terapêutico , Feminino , Fígado/metabolismo , Cirrose Hepática/metabolismo , Pessoa de Meia-Idade , Eixo Encéfalo-Intestino/fisiologia , Encefalopatia Hepática/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , IdosoRESUMO
In the present study, we aimed to establish and characterize a mature cortical spheroid model system for Kleefstra syndrome (KS) using patient-derived iPSC. We identified key differences in the growth behavior of KS spheroids determined by reduced proliferation marked by low Ki67 and high E-cadherin expression. Conversely, in the spheroid-based neurite outgrowth assay KS outperformed the control neurite outgrowth due to higher BDNF expression. KS spheroids were highly enriched in VGLUT1/2-expressing glutamatergic and ChAT-expressing cholinergic neurons, while TH-positive catecholamine neurons were significantly underrepresented. Furthermore, high NMDAR1 expression was also detected in the KS spheroid, similarly to other patients-derived neuronal cultures, denoting high NMDAR1 expression as a general, KS-specific marker. Control and KS neuronal progenitors and neurospheres were exposed to different toxicants (paraquat, rotenone, bardoxolone, and doxorubicin), and dose-response curves were assessed after acute exposure. Differentiation stage and compound-specific differences were detected with KS neurospheres being the most sensitive to paraquat. Altogether this study describes a robust 3D model system expressing the disease-specific markers and recapitulating the characteristic pathophysiological traits. This platform is suitable for testing developing brain-adverse environmental effects interactions, drug development, and screening towards individual therapeutic strategies.
Assuntos
Diferenciação Celular , Deleção Cromossômica , Cromossomos Humanos Par 9 , Células-Tronco Pluripotentes Induzidas , Esferoides Celulares , Humanos , Cromossomos Humanos Par 9/genética , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Diferenciação Celular/efeitos dos fármacos , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/metabolismo , Deficiência Intelectual/metabolismo , Proliferação de Células/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/efeitos dos fármacos , Células Cultivadas , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/efeitos dos fármacos , Rotenona/toxicidade , Cardiopatias Congênitas , Proteínas do Tecido NervosoRESUMO
OBJECTIVE: This study aimed to explore the mechanism by which noise contributes to the development of Alzheimer's disease (AD)-like lesions. METHOD: Male Wistar rats (24 months) were allocated into two groups (n = 6 per groups): a noise group exposed to 98 dB sound pressure-level white noise for 4 hours daily from 8:00 to 12:00 for 30 days, and a control group without noise exposure. The cognitive functions of the rats were assessed using new-object recognition and Morris water maze tests. Then, hippocampal tissues were collected, and the levels of amyloid ß 1-42 (Aß1-42), Aß1-40, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) were measured using enzyme-linked immunosorbent assay (ELISA). Protein expression was evaluated through Western blot. RESULTS: Noise exposure significantly impaired cognitive and recognition abilities, increased the escape latency, and decreased the number of crossings through the platform quadrant intersection and the time spent in the target quadrant (P < 0.01). The new-object exploration and recognition index of the rats in the noise group markedly decreased (P < 0.01). ELISA results indicated increases in Aß1-40 and Aß1-42 levels and decreases in BDNF and TrkB levels in the rat hippocampus in the noise group (P < 0.01). Western blot analyses revealed that beta-site amyloid precursor protein (APP) cleaving enzyme 1, phosphorylated tau protein, gamma-H2A histone family, member X, checkpoint kinase 2, p53, and p21 were remarkably elevated in the noise group (P < 0.01). CONCLUSION: Chronic noise exposure can cause hippocampal genetic damage in aged rats, leading to cognitive disorders and the development of lesions similar to those observed in AD. Thus, noise is a potential risk factor for neurodegenerative disorders.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Fator Neurotrófico Derivado do Encéfalo , Dano ao DNA , Hipocampo , Ruído , Ratos Wistar , Animais , Doença de Alzheimer/etiologia , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ruído/efeitos adversos , Peptídeos beta-Amiloides/metabolismo , Ratos , Hipocampo/metabolismo , Hipocampo/patologia , Fragmentos de Peptídeos/metabolismo , Receptor trkB/metabolismo , Modelos Animais de Doenças , Aprendizagem em Labirinto/fisiologiaRESUMO
Anatomical connectivity and lesion-deficit studies have shown that the dorsal and ventral hippocampi contribute to cognitive and emotional processes, respectively. However, the role of the dorsal hippocampus (dHP) in emotional or stress-related behaviors remains unclear. Here, we showed that neuronal activity in the dHP affects stress-coping behaviors in mice via excitatory projections to the medial prefrontal cortex (mPFC). The antidepressant ketamine rapidly induced c-Fos expression in both the dorsal and ventral hippocampi. The suppression of GABAergic transmission in the dHP-induced molecular changes similar to those induced by ketamine administration, including eukaryotic elongation factor 2 (eEF2) dephosphorylation, brain-derived neurotrophic factor (BDNF) elevation, and extracellular signal-regulated kinase (ERK) phosphorylation. These synaptic and molecular changes in the dHP induced a reduction in the immobility time of the mice in the tail-suspension and forced swim tests without affecting anxiety-related behavior. Conversely, pharmacological and chemogenetic potentiation of inhibitory neurotransmission in the dHP CA1 region induced passive coping behaviors during the tests. Transneuronal tracing and electrophysiology revealed monosynaptic excitatory connections between dHP CA1 neurons and mPFC neurons. Optogenetic stimulation of dHP CA1 neurons in freely behaving mice produced c-Fos induction and spike firing in the mPFC neurons. Chemogenetic activation of the dHP-recipient mPFC neurons reversed the passive coping behaviors induced by suppression of dHP CA1 neuronal activity. Collectively, these results indicate that neuronal activity in the dHP modulates stress-coping strategies to inescapable stress and contributes to the antidepressant effects of ketamine via the dHP-mPFC circuit.
Assuntos
Hipocampo , Córtex Pré-Frontal , Estresse Psicológico , Animais , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Camundongos , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Masculino , Neurônios/metabolismo , Adaptação Psicológica/fisiologia , Ketamina/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transmissão Sináptica , Camundongos Endogâmicos C57BL , Comportamento Animal , Optogenética/métodos , Capacidades de EnfrentamentoRESUMO
This study aimed to assess the effects of the timing of administering botulinum neurotoxin A (BoNT/A) on nerve regeneration in rats. Sixty 6-week-old rats with a sciatic nerve injury were randomly divided into four groups: the immediately treated (IT) group (BoNT/A injection administered immediately post-injury), the delay-treated (DT) group (BoNT/A injection administered one week post-injury), the control group (saline administered one week post-injury), and the sham group (only skin and muscle incisions made). Nerve regeneration was assessed 3, 6, and 9 weeks post-injury using various techniques. The levels of glial fibrillary acid protein (GFAP), astroglial calcium-binding protein S100ß (S100ß), growth-associated protein 43 (GAP43), neurofilament 200 (NF200), and brain-derived neurotrophic factor (BDNF) in the IT and DT groups were higher. ELISA revealed the highest levels of these proteins in the IT group, followed by the DT and control groups. Toluidine blue staining revealed that the average area and myelin thickness were higher in the IT group. Electrophysiological studies revealed that the CMAP in the IT group was significantly higher than that in the control group, with the DT group exhibiting significant differences starting from week 8. The findings of the sciatic functional index analysis mirrored these results. Thus, administering BoNT/A injections immediately after a nerve injury is most effective for neural recovery. However, injections administered one week post-injury also significantly enhanced recovery. BoNT/A should be administered promptly after nerve damage; however, its administration during the non-acute phase is also beneficial.
Assuntos
Toxinas Botulínicas Tipo A , Regeneração Nervosa , Nervo Isquiático , Animais , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/farmacologia , Nervo Isquiático/lesões , Nervo Isquiático/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ratos , Recuperação de Função Fisiológica , Ratos Sprague-Dawley , Proteína GAP-43/metabolismo , Neuropatia Ciática/tratamento farmacológico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Fatores de TempoRESUMO
Increasing research suggests a connection between gut microbiota and depressive disorders. Targeted changes to the intestinal flora may contribute to alleviating anxiety and depression. This study aimed to identify probiotics that could attenuate stress-induced abnormal behavior and explore potential mechanisms. The administration of LR.KY16 significantly reduced stress-induced abnormal behaviors and physiological dysfunction. The mechanism may be via regulating the structure of the intestinal microbiota in mice, increasing the abundance of Akkermansia muciniphila, prompting enterochromaffin cells to secrete 5-HTP in the gut, which enters the brain through the bloodstream and promotes the synthesis of 5-HT in the brain, and then activates brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) through the 5-HT1A receptor. In addition, LR.KY16 also increased the expression of claudin-7, occludin, and zonula occludens-1 (ZO-1) in the colon, inhibited microglial M1 polarization, and inhibited systemic inflammation.
Assuntos
Depressão , Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Camundongos Endogâmicos C57BL , Probióticos , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Camundongos , Probióticos/administração & dosagem , Probióticos/farmacologia , Masculino , Depressão/metabolismo , Depressão/tratamento farmacológico , Depressão/microbiologia , Lacticaseibacillus rhamnosus/metabolismo , Humanos , Serotonina/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Akkermansia , Intestinos/microbiologia , Mucosa Intestinal/metabolismoRESUMO
A low level of Neurotrophins (NTs), their Tyrosine Kinase Receptors (Trks), Vascular Endothelial Growth Factors (VEGFs) and their receptors, mainly VEGFR1 and VEGFR2, characterizes AD brains. The use of NTs and VEGFs as drugs presents different issues due to their low permeability of the blood-brain barrier, the poor pharmacokinetic profile, and the relevant side effects. To overcome these issues, different functional and structural NT mimics have been employed. Being aware that the N-terminus domain as the key domain of NTs for the binding selectivity and activation of Trks and the need to avoid or delay proteolysis, we herein report on the mimicking ability of two cyclic peptide encompassing the N-terminus of Brain Derived Growth Factor (BDNF), (c-[HSDPARRGELSV-]), cBDNF(1-12) and of Neurotrophin3 (NT3), (c-[YAEHKSHRGEYSV-]), cNT3(1-13). The two cyclic peptide features were characterized by a combined thermodynamic and spectroscopic approach (potentiometry, NMR, UV-vis and CD) that was extended to their copper(II) ion complexes. SH-SY5Y cell assays show that the Cu2+ present at the sub-micromolar level in the complete culture media affects the treatments with the two peptides. cBDNF(1-12) and cNT3(1-13) act as ionophores, induce neuronal differentiation and promote Trks and CREB phosphorylation in a copper dependent manner. Consistently, both peptide and Cu2+ stimulate BDNF and VEGF expression as well as VEGF release; cBDNF(1-12) and cNT3(1-13) induce the expression of Trks and VEGFRs.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Encéfalo , Cobre , Neurotrofina 3 , Transdução de Sinais , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/química , Neurotrofina 3/metabolismo , Neurotrofina 3/química , Cobre/metabolismo , Cobre/química , Transdução de Sinais/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Linhagem Celular TumoralRESUMO
The plasminogen activator inhibitor-1 (PAI-1)âmature brain-derived neurotrophic factor (mBDNF) pathway plays a pivotal role in the conversion of probrain-BDNF (ProBDNF) to mBDNF, but its clinical relevance in patients with alcohol use disorder (AUD) remains unknown. Enzyme-linked immunosorbent assays were used to examine the relevant protein levels of components of the PAI-1âmBDNF pathway in plasma samples from three groups of subjects, and statistical analysis was performed using analysis of variance (ANOVA) and one-way repeated-measures ANOVA. Our findings revealed significant alterations induced by alcohol. (1) AUD was associated with significant decreases in tissue plasminogen activator (tPA), mBDNF, and tropomyosin receptor kinase B (TrkB); significant increases in PAI-1, ProBDNF, and P75 neurotrophin receptor (P75NTR); and inhibited conversion of ProBDNF to mBDNF. (2) Following abstinence, the levels of tPA, mBDNF, and TrkB in the AUD group significantly increased, whereas the levels of PAI-1, ProBDNF, and P75NTR significantly decreased, promoting the conversion of ProBDNF to mBDNF. These clinical outcomes collectively suggest that AUD inhibits the conversion of ProBDNF to mBDNF and that abstinence reverses this process. The PAI-1âmBDNF cleavage pathway is hypothesized to be associated with AUD and abstinence treatment.
Assuntos
Alcoolismo , Fator Neurotrófico Derivado do Encéfalo , Inibidor 1 de Ativador de Plasminogênio , Ativador de Plasminogênio Tecidual , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Alcoolismo/metabolismo , Alcoolismo/sangue , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Masculino , Adulto , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tecidual/sangue , Feminino , Transdução de Sinais , Receptores de Fator de Crescimento Neural/metabolismo , Pessoa de Meia-Idade , Receptor trkB/metabolismo , Abstinência de Álcool , Precursores de Proteínas/metabolismo , Glicoproteínas de Membrana , Proteínas do Tecido NervosoRESUMO
Anshen Dingzhi prescription (ADP) is a classic prescription of traditional Chinese medicine, which has been used in the treatment of neuropsychiatric diseases. However, its treatment of breast cancer-related post-traumatic stress disorder (BC-PTSD) lacks clinical research evidence and its mechanism is not clear. The present study investigated the efficacy and action mechanism of ADP against BC-PTSD. The results of the clinical trial showed that after 4 weeks of treatment, both groups showed reduced post-traumatic stress disorder checklist-civilian version (PCL-C), Pittsburgh sleep quality index (PSQI), self-rating depression scale (SDS) and self-rating anxiety scale (SAS) scores, and increased functional assessment of cancer therapy-breast (FACT-B) scores. The serum cortisol (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) levels were decreased and brain-derived neurotrophic factor (BDNF) level were increased, and the improvement of serum TNF-α, IL-1ß, and BDNF in treatment group was better than that of the control group. The overall treatment efficacy in the treatment group (43.90%) was superior to that in the control group (23.81%), and the overall incidence of adverse effects was lower than that in the control group. The results of network analysis and molecular docking showed that ADP blood components could act on IL1B, TNF, and BDNF. ADP contributes to the treatment of BC-PTSD symptoms, with a mechanism possibly related to its regulatory effect on TNF-α, IL-1ß, and BDNF levels.Trial registration: Chinese Clinical Trial Registry, http://www.chictr.org.cn,ChiCTR2300077801.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Neoplasias da Mama , Medicamentos de Ervas Chinesas , Simulação de Acoplamento Molecular , Farmacologia em Rede , Transtornos de Estresse Pós-Traumáticos , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Simulação de Acoplamento Molecular/métodos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Farmacologia em Rede/métodos , Pessoa de Meia-Idade , Adulto , Medicina Tradicional Chinesa/métodos , Fator de Necrose Tumoral alfa/sangue , Interleucina-1beta/sangue , Hidrocortisona/sangue , Resultado do TratamentoRESUMO
Prenatal stress (PS) affects the development and functioning of the central nervous system, but the exact mechanisms underpinning this effect have not been pinpointed yet. A promising model of PS is one based on chronic exposure of pregnant rodents to variable-frequency ultrasound (US PS), as it mimics the PS with a psychic nature that most adequately captures the human stressors in modern society. The aim of this study was to investigate the effects of US PS on the brain neurotransmitter, neuropeptide, and neurotrophic systems of newborn Wistar rats. We determined the concentration of neurotransmitters and their metabolites (serotonin, HIAA, dopamine, DOPAC, and norepinephrine), neuropeptides (α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P), and the neurotrophin brain-derived neurotrophic factor (BDNF) in rat brain tissues by HPLC-ED, ELISA, and multiplex ELISA. Correlation analysis and principal component analysis (PCA) were used to get a sense of the relationship between the biochemical parameters of the brain. The results demonstrated that US PS increases the concentration of serotonin (p=0.004) and DOPAC (p=0.04) in the hippocampus has no effect on the neurotransmitter systems of the frontal cortex, reduces the concentration of BDNF in the entirety of the brain of males (p=0.008), and increases the neuropeptides α-MSH (p=0.02), ß-endorphin (p=0.01), oxytocin (p=0.008), and substance P (p < 0.001) in the entire brain. A degree of complexity in the neurotransmitter system network in the frontal cortex and network change in the hippocampus after exposure to US PS have been observed. PCA revealed a similar pattern of neurotransmitter system interactions in the frontal cortex and hippocampus in males and females after exposure to US PS. We suggest that US PS can alter neurodevelopment, which is mediated by changes in the studied neurochemical systems that thus affect the behavioral phenotype in animals.