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1.
Braz J Med Biol Res ; 54(5): e10717, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33825777

RESUMO

Scorpion venom is a Chinese medicine for epilepsy treatment, but the underlying mechanism is not clear. Scorpion venom heat-resistant peptide (SVHRP), a peptide isolated from the venom of Buthus martensii Karsch, has an anti-epileptic effect by reducing seizure behavior according to a modified Racine scale. The present study aimed to investigate the molecular mechanism of SVHRP on temporal lobe epilepsy. The hippocampus and hippocampal neurons from kainic acid-induced epileptic rats were treated with SVHRP at different doses and duration. Quantitative RT-PCR and immunoblotting were used to detect the expression level of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), cAMP-response element binding protein (CREB), stromal interaction molecule (STIM), and calcium release-activated calcium channel protein 1 (ORAI1). In the hippocampal tissues and primary hippocampal neuron cultures, SVHRP treatment resulted in increased mRNA and protein levels of BDNF and NPY under the epileptic condition. The upregulation of BDNF and NPY expression was positively correlated with the dose level and treatment duration of SVHRP in hippocampal tissues from kainic acid-induced epileptic rats. On the other hand, no significant changes in the levels of CREB, STIM, or ORAI1 were observed. SVHRP may exhibit an anti-epileptic effect by upregulating the expression of BDNF and NPY in the epileptic hippocampus.


Assuntos
Epilepsia , Venenos de Escorpião , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Hipocampo/metabolismo , Temperatura Alta , Ácido Caínico/toxicidade , Neurônios , Peptídeos , Ratos , Venenos de Escorpião/toxicidade
2.
Life Sci ; 273: 119308, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667520

RESUMO

AIMS: Brain-derived neurotrophic factor (BDNF) is vital in the pathogenesis of mechanical allodynia with a paucity of reports available regarding diabetic neuropathy pain (DNP). Herein we identified the involvement of BDNF in driving mechanical allodynia in DNP rats via the activation of transient receptor potential canonical 6 (TRPC6) channel. MATERIALS AND METHODS: The DNP rat model was established via streptozotocin (STZ) injection, and allodynia was assessed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). The expression profiles of BDNF and TRPC6 in dorsal root ganglia (DRG) and spinal cord were illustrated by immunofluorescence and Western blotting. Intrathecal administration of K252a or TrkB-Fc was performed to inhibit BNDF/TrkB expression, and respective injection of GsMTX-4, BTP2 and TRPC6 antisense oligodeoxynucleotides (TRPC6-AS) was likewise conducted to inhibit TRPC6 expression in DNP rats. Calcium influx in DRG was monitored by calcium imaging. KEY FINDINGS: The time-dependent increase of BDNF and TRPC6 expression in DRG and spinal cord was observed since the 7th post-STZ day, correlated with the development of mechanical allodynia in DNP rats. Intrathecal administration of K252a, TrkB-Fc, GsMTX-4 and BTP2 prevented mechanical allodynia in DNP rats. Pre-treatment of TRPC6-AS reversed the BDNF-induced pain-like responses in DNP rats rather than the naïve rats. In addition, the TRPC6-AS reversed BDNF-induced increase of calcium influx in DRG neurons in DNP rats. SIGNIFICANCE: The intrathecal inhibition of TRPC6 alleviated the BDNF-induced mechanical allodynia in DNP rat model. This finding may validate the application of TRPC6 antagonists as interesting strategy for DNP management.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/complicações , Modelos Animais de Doenças , Hiperalgesia/etiologia , Neuralgia/complicações , Canais de Cátion TRPC/metabolismo , Animais , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPC/genética
3.
J Biomed Nanotechnol ; 17(1): 37-52, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33653495

RESUMO

Nanoparticulate titanium dioxide (nano-TiO2) is a commonly used nanoparticle material and has been widely used in the fields of medicine, cosmetics, construction, and environmental protection. Numerous studies have demonstrated that nano-TiO2 has toxic effects on neuronal development, which lead to defects in learning and memory functions. However, it is still unclear whether nano-TiO2 inhibits the development of synapse and the underlying molecular mechanism is still unknown. In this study, nano-TiO2 was administered to rat primary hippocampal neurons for 24 h to investigate the underlying molecular mechanisms behind the inhibition of neuronal synaptic development by nano-TiO2. We used hippocampal neurons as a model to study the effect of nano-TiO2 on synaptic development. Our results demonstrated that dendritic development that represented synaptic plasticity in hippocampal neurons was significantly inhibited in a concentration-dependent manner after exposure to nano-TiO2 for 24 h. Experiments with varying concentrations of nano-TiO2 (5, 15, and 30 g/mL) indicated that the apoptotic rate of hippocampal neurons increased, development of neuronal synapses were inhibited, and synaptic densities decreased by 24.29%, 54.29%, and 72.86%, respectively, in post-treatment with nano-TiO2. Furthermore, the results indicated that the expressions of Synapsin I (SYN I) and postsynaptic density 95 (PSD95) in neuron synapse were also significantly inhibited, particularly SYN I decreased by 18.43%, 37.2%, and 51.6%, and PSD95 decreased by 16.02%, 24.06%, and 38.74% after treatment with varying concentrations of nano-TiO2, respectively. In addition, experiments to assess the BDNF-TrkB signaling pathway indicated that nano-TiO2 inhibited the expressions of key proteins in the downstream MEK/ERK and PI3K/Akt signaling pathways by inhibiting the expression of BDNF. With concentrations of nano-TiO2 at 5, 15, and 30 µg/mL, the expression of BDNF decreased by 22.64%, 33.3%, and 53.58% compared with the control group. Further, the expression ratios of downstream key proteins p-CREB/CREB decreased by 3.03%, 18.11%, and 30.57%; p-ERK1/2/ERK1/2 ratios decreased by 19.11%, 28.82%, and 58.09%, and p-Akt1/Akt1 ratios decreased by 1.92%, 27.79%, and 41.33%, respectively. These results demonstrated that nano-TiO2 inhibited the normal function of the BDNF-TrkB signaling pathway, which is closely related to neuronal synapse. Thus, it can be hypothesized that the inhibition of neuronal synaptic growth by nano-TiO2 may be related to the inhibition of BDNF-TrkB signaling pathway.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Fosfatidilinositol 3-Quinases , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Proteínas Tirosina Quinases , Ratos , Receptores Proteína Tirosina Quinases , Transdução de Sinais , Sinapses/metabolismo , Titânio
4.
Medicine (Baltimore) ; 100(6): e23305, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578508

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) rs6265 polymorphism has been previously suggested to be associated with the susceptibility of type 2 diabetes mellitus (T2DM), but results remained controversial. We aim to provide a more reliable conclusion about the association between BDNF rs6265 polymorphism and T2DM risk by using a meta-analysis. METHODS: Electronic databases such as Pubmed, Embase, CNKI, and Wanfang were searched for relevant articles published up to May 06, 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the associations. Subgroup analysis was carried out according to source of controls and quality score of included studies. A trial sequential analysis was conducted to reduce the risk of type I error. RESULTS: A total of 8 case-control studies (7 conducted in China) with 1576 T2DM patients and 1866 controls were included. Overall, our results indicated no significant association between BDNF rs6265 polymorphism and T2DM risk with the random-effects model (allele model: pooled OR = 1.14, 95% CI = 0.79-1.65, homozygote model: pooled OR = 1.13, 95% CI = 0.57-2.21, heterozygote model: pooled OR = 1.07, 95% CI = 0.78-1.48, dominant model: pooled OR = 1.14, 95% CI = 0.74-1.75 and recessive model: pooled OR = 1.10, 95% CI = 0.67-1.80). Subgroup analysis by source of controls and quality score also showed no significant association between BDNF rs6265 polymorphism and T2DM risk. Trial sequential analysis results confirmed the null association and further studies were unnecessary. CONCLUSION: This meta-analysis study indicated that no significant association between BDNF rs6265 polymorphism and T2DM risk.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Alelos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estudos de Casos e Controles , China/epidemiologia , Ensaios Clínicos como Assunto , Dinamarca/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
5.
Psychopharmacology (Berl) ; 238(4): 1213-1222, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33496816

RESUMO

RATIONALE: B vitamins play essential roles in brain development and functionality; however, the effects of their deficiency during early life on mental health are not thoroughly understood. OBJECTIVES: The objective of this study is to investigate the effects of a maternal deficiency of vitamin B6, B9 (folate), and B12 on behavioral changes in adult offspring. METHODS: Female C57BL/6 J mice were put on a diet lacking vitamin B6, B9, B12, or the above three vitamins from pregnancy to weaning. The growth and developmental characteristics of both the pregnant mothers and offspring were collected. In the adult offspring, the serum levels of neuroactive substances were measured using an enzyme-linked immunosorbent assay. The level of BDNF and dimethylated lysine 9 on histone H3 (H3K9me2) was detected by immunohistochemical staining. In addition, their depressive-like behaviors, anxiety-like behaviors, and sociability were recorded using sucrose preference, a forced swim, social interaction, tail suspension, and open field tests. RESULTS: The maternal deficiency of the three B vitamins delayed offspring development. Compared to the controls, all of the groups showed decreased serum levels of 5-HT and neuropeptide Y. In the groups with deficiency of B9 or the three B vitamins, there were significant changes in sociability and social novelty preference. In groups with deficiencies in B9, B12, or all three B vitamins, the expression levels of BDNF and H3K9me2 in the hippocampus were significantly decreased. CONCLUSIONS: Maternal deficiencies of the major B vitamins caused changes in social behaviors in adult mice accompanied with epigenetic alterations in the brain and changes in the serum levels of neuroactive substances.


Assuntos
Comportamento Animal , Epigênese Genética/genética , Deficiência de Vitaminas do Complexo B/genética , Deficiência de Vitaminas do Complexo B/psicologia , Animais , Química Encefálica/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Elevação dos Membros Posteriores , Histonas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Neuropeptídeo Y/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia
6.
Chem Biol Interact ; 337: 109392, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33497687

RESUMO

Arsenic is a toxic metalloid abundantly found in nature and used in many industries. Consumption of contaminated water mainly results in human exposure to arsenic. Toxicity (arsenicosis) resulting from arsenic exposure causes cerebral neurodegeneration. Protocatechuic acid (PCA), a phenol derived from edible plants, has antioxidant properties. The present study investigated the neuroprotective potential of PCA against arsenic-induced neurotoxicity in mice. Male Swiss albino mice were divided into four groups: (i) orally administered physiological saline, (ii) orally administered 100 mg/kg PCA, (iii) orally administered 5 mg/kg NaAsO2, and (iv) orally administered 100 mg/kg PCA 120 min prior to oral administration of 5 mg/kg NaAsO2. Each group received its respective treatment for 1 week, after which cortical tissues from each group were analyzed for various parameters of oxidative stress, proinflammatory cytokines, apoptosis-related proteins, and changes in histopathology. NaAsO2-treatment resulted in a significant increase in lipid peroxidation (LPO), inducible nitric oxide synthetase (iNOs), and NO levels, with a decrease in the levels of both enzymatic (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) and non-enzymatic (glutathione) antioxidant markers. Arsenic increased proinflammatory cytokine (tumor necrosis factor-α and interleukin-1ß) levels, enhanced caspase-3 and Bax expression, and reduced Bcl-2 expression. Furthermore, arsenic-exposure in mice decreased significantly acetylcholinesterase activity and brain-derived neurotrophic factor level in the cerebral cortex. Histopathological examination revealed changes in nerve cell cyto-architecture and distribution in arsenic-exposed brain tissue sections. PCA treatment before arsenic administration resulted in a positive shift in the oxidative stress and cytokine levels with decreased levels of LPO, iNOS, and NO. PCA pre-treatment considerably attenuated arsenic-associated histopathological changes in murine brain tissue. This study suggested that the presence of PCA may be responsible for the prevention of arsenic-induced neurotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Arseniatos/toxicidade , Hidroxibenzoatos/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Citocinas/genética , Citocinas/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Superóxido Dismutase/metabolismo
7.
Biomed Pharmacother ; 133: 111062, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378965

RESUMO

Diabetic peripheral neuropathy (DPN) is the common complication of diabetes mellitus. Histone deacetylase (HDAC) inhibitor trichostatin A (TSA) is reported to ameliorate the peripheral nerves degeneration of DPN. However, the exact mechanism is still not well elucidated. Here, we first revealed that TSA promoted nerve conduction and brain derived neurotrophic factor (BDNF) expression in the sciatic nerves of diabetic mice. In line, TSA also reversed high glucose-reduced mature BDNF expression in vitro cultured rat Schwann cells (RSC96). Then unexpectedly, the downstream targets of TSA HDAC1 and HDAC5 were not involved in TSA-improved BDNF expression. Furthermore, unfolded protein response (UPR) chaperone GRP78 was revealed to be downregulated with high glucose stimulation in RSC96 cells, which was avoided with TSA treatment. Also, GRP78 upregulation mediated TSA-improved mature BDNF expression in high glucose-cultured RSC96 cells by binding with BDNF. As well, TSA treatment enhanced the binding of GRP78 with BDNF in RSC96 cells. Again, UPR-associated transcription factors XBP-1s and ATF6 were involved in TSA-increased GRP78 expression in high glucose-stimulated RSC96 cells. Finally, conditioned medium from high glucose-cultured RSC96 cells delayed neuron SH-SY5Y differentiation and that from TSA-treated high glucose-cultured RSC96 cells promoted SH-SY5Y cell differentiation. Taken together, our findings suggested that TSA increased BDNF expression to ameliorate DPN by improving XBP-1s/ATF6/GRP78 axis in Schwann cells.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Proteínas de Choque Térmico/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Proteína 1 de Ligação a X-Box/metabolismo , Fator 6 Ativador da Transcrição/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Linhagem Celular Tumoral , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/metabolismo , Proteínas de Choque Térmico/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Ratos , Células de Schwann/metabolismo , Nervo Isquiático/metabolismo , Transdução de Sinais , Regulação para Cima , Proteína 1 de Ligação a X-Box/genética
8.
Zhongguo Zhong Yao Za Zhi ; 45(20): 4971-4977, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33350271

RESUMO

This study aimed to investigate the antidepressant effects of Puyu Capsules and its potential mechanism. The antidepressant activity of Puyu Capsules was evaluated by forced swimming test(FST) and tail suspension test(TST) after subchronic administration in mice. Next, the mice were subjected to a chronic unpredictable stress(CUS) protocol for a period of 28 d to induce depressive-like behaviors. Then, a sucrose preference test, open-field test and novelty-suppressed feeding test were performed to evaluate the antidepressant effect of Puyu Capsules. After the behavioral test, the adrenal index was calculated; the levels of serum corticosterone(CORT) and adrenocorticotropic hormone(ACTH) were detected by enzyme-linked immunosorbent assay(ELISA); the levels of glucocorticoid receptor(GR), protein expression of brain-derived neurotrophic factor(BDNF), and the ratio of phosphorylated cAMP response element binding protein(CREB) to total CREB were detected by Western blot to explore the antidepressant function and mechanism of Puyu Capsules. The results suggested that Puyu Capsules had significant antidepressant effects on both the depression model and CUS model. At the same time, the drug could prevent the change of adrenal index induced by CUS and reverse the abnormal activation of CORT and ACTH in the serum of depressed mice. Finally, Puyu Capsules could also reverse the lower expression of pCREB, BDNF and GR in the hippocampus of CUS mice. In conclusion, Puyu Capsules produced significant antidepressant effects, and the mechanism was closely related to hypothalamic pituitary adrenal(HPA) axis activity, GR and CREB-BDNF pathway expression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Sistema Hipotálamo-Hipofisário , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cápsulas , Depressão/tratamento farmacológico , Depressão/genética , Modelos Animais de Doenças , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Camundongos , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico
9.
Molecules ; 26(1)2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33379243

RESUMO

Ferulic Acid (FA) is a highly abundant phenolic phytochemical which is present in plant tissues. FA has biological effects on physiological and pathological processes due to its anti-apoptotic and anti-oxidative properties, however, the detailed mechanism(s) of function is poorly understood. We have identified FA as a molecule that inhibits apoptosis induced by hydrogen peroxide (H2O2) or actinomycin D (ActD) in rat pheochromocytoma, PC12 cell. We also found that FA reduces H2O2-induced reactive oxygen species (ROS) production in PC12 cell, thereby acting as an anti-oxidant. Then, we analyzed FA-mediated signaling responses in rat pheochromocytoma, PC12 cells using antibody arrays for phosphokinase and apoptosis related proteins. This FA signaling pathway in PC12 cells includes inactivation of pro-apoptotic proteins, SMAC/Diablo and Bad. In addition, FA attenuates the cell injury by H2O2 through the inhibition of phosphorylation of the extracellular signal-regulated kinase (ERK). Importantly, we find that FA restores expression levels of brain-derived neurotrophic factor (BDNF), a key neuroprotective effector, in H2O2-treated PC12 cells. As a possible mechanism, FA increases BDNF by regulating microRNA-10b expression following H2O2 stimulation. Taken together, FA has broad biological effects as a neuroprotective modulator to regulate the expression of phosphokinases, apoptosis-related proteins and microRNAs against oxidative stress in PC12 cells.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Peróxido de Hidrogênio/farmacologia , Substâncias Protetoras/farmacologia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/metabolismo , Animais , Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Dactinomicina/farmacologia , MicroRNAs/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Feocromocitoma/tratamento farmacológico , Feocromocitoma/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333883

RESUMO

Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms, accompanied by massive neuronal degeneration in the striatum. In this study, we utilized solid lipid curcumin particles (SLCPs) and solid lipid particles (SLPs) to test their efficacy in reducing deficits in YAC128 HD mice. Eleven-month-old YAC128 male and female mice were treated orally with SLCPs (100 mg/kg) or equivalent volumes of SLPs or vehicle (phosphate-buffered saline) every other day for eight weeks. Learning and memory performance was assessed using an active-avoidance task on week eight. The mice were euthanized, and their brains were processed using Golgi-Cox staining to study the morphology of medium spiny neurons (MSNs) and Western blots to quantify amounts of DARPP-32, brain-derived neurotrophic factor (BDNF), TrkB, synaptophysin, and PSD-95. We found that both SLCPs and SLPs improved learning and memory in HD mice, as measured by the active avoidance task. We also found that SLCP and SLP treatments preserved MSNs arborization and spinal density and modulated synaptic proteins. Our study shows that SLCPs, as well as the lipid particles, can have therapeutic effects in old YAC128 HD mice in terms of recovering from HD brain pathology and cognitive deficits.


Assuntos
Curcumina/administração & dosagem , Doença de Huntington/metabolismo , Doença de Huntington/psicologia , Lipossomos , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Doença de Huntington/etiologia , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/patologia , Receptor trkB/metabolismo
11.
Braz J Med Biol Res ; 54(2): e10107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33331415

RESUMO

Ketamine (KET) is an N-methyl-D-aspartate (NMDA) antagonist with rapid and long-lasting antidepressant effects, but how the drug shows its sustained effects is still a matter of controversy. The objectives were to evaluate the mechanisms for KET rapid (30 min) and long-lasting (15 and 30 days after) antidepressant effects in mice. A single dose of KET (2, 5, or 10 mg/kg, po) was administered to male Swiss mice and the forced swim test (FST) was performed 30 min, 15, or 30 days later. Imipramine (IMI, 30 mg/kg, ip), a tricyclic antidepressant drug, was used as reference. The mice were euthanized, separated into two time-point groups (D1, first day after KET injection; D30, 30 days later), and brain sections were processed for glycogen synthase kinase-3 (GSK-3), histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) immunohistochemical assays. KET (5 and 10 mg/kg) presented rapid and long-lasting antidepressant-like effects. As expected, the immunoreactivities for brain GSK-3 and HDAC decreased compared to control groups in all areas (striatum, DG, CA1, CA3, and mainly pre-frontal cortex, PFC) after KET injection. Increases in BDNF immunostaining were demonstrated in the PFC, DG, CA1, and CA3 areas at D1 and D30 time-points. GFAP immunoreactivity was also increased in the PFC and striatum at both time-points. In conclusion, KET changed brain BDNF and GFAP expressions 30 days after a single administration. Although neuroplasticity could be involved in the observed effects of KET, more studies are needed to explain the mechanisms for the drug's sustained antidepressant-like effects.


Assuntos
Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Ketamina , Animais , Astrócitos , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida , Quinase 3 da Glicogênio Sintase , Histona Desacetilases , Ketamina/farmacologia , Masculino , Camundongos
12.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322180

RESUMO

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.


Assuntos
Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Mycobacterium tuberculosis/metabolismo , Neurônios/patologia , Tuberculose Pulmonar/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/microbiologia , Sintomas Comportamentais/microbiologia , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/citologia , Encéfalo/enzimologia , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Disfunção Cognitiva/microbiologia , Depressão/metabolismo , Depressão/microbiologia , Modelos Animais de Doenças , Regulação para Baixo , Hipocampo/citologia , Hipocampo/imunologia , Hipocampo/metabolismo , Hipocampo/patologia , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/patogenicidade , Neurônios/citologia , Neurotransmissores/metabolismo , Tuberculose Pulmonar/enzimologia , Tuberculose Pulmonar/patologia , Tuberculose Pulmonar/psicologia , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333849

RESUMO

Neuropathic pain is characterized by spontaneous pain, pain sensations, and tactile allodynia. The pain sensory system normally functions under a fine balance between excitation and inhibition. Neuropathic pain arises when this balance is lost for some reason. In past reports, various mechanisms of neuropathic pain development have been reported, one of which is the downregulation of K+-Cl--cotransporter-2 (KCC2) expression. In fact, various neuropathic pain models indicate a decrease in KCC2 expression. This decrease in KCC2 expression is often due to a brain-derived neurotrophic factor that is released from microglia. However, a similar reaction has been reported in astrocytes, and it is unclear whether astrocytes or microglia are more important. This review discusses the hypothesis that astrocytes have a crucial influence on the alteration of KCC2 expression.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Neuralgia/metabolismo , Transdução de Sinais/fisiologia , Simportadores/metabolismo , Animais , Astrócitos/enzimologia , Sistema Nervoso Central/lesões , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Metaloproteinases da Matriz/metabolismo , Neuralgia/enzimologia , Receptor trkB/metabolismo , Ferimentos e Lesões/enzimologia , Ferimentos e Lesões/metabolismo
14.
Nihon Yakurigaku Zasshi ; 155(6): 381-385, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132254

RESUMO

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.


Assuntos
Ketamina , Fator A de Crescimento do Endotélio Vascular , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Ketamina/farmacologia , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato
15.
Anticancer Res ; 40(9): 5151-5158, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878803

RESUMO

BACKGROUND/AIM: Magnetic stimulation is used in the treatment of a diversity of diseases, but a complete understanding of the underlying mechanisms of action requires further investigation. We examined the effect of static magnetic stimulation (SMS) in different cell lines. MATERIALS AND METHODS: A culture plate holder with attached NeFeB magnets was developed. Different magnetic field intensities and periods were tested in tumoral and non-tumoral cell lines. To verify the cellular responses to SMS, cell viability, cell death, cell cycle and BDNF expression were evaluated. RESULTS: Exposure of SH-SY5Y cells to SMS for 24 hours led to a decrease in cell viability. Analysis 24 h after stimulation revealed a decrease in apoptotic and double-positive cells, associated with an increase in the number of necrotic cells. CONCLUSION: The effects of SMS on cell viability are cell type-specific, inducing a decrease in cell viability in SH-SY5Y cells. This suggests that SMS may be a potential tool in the treatment of neuronal tumors.


Assuntos
Sobrevivência Celular/efeitos da radiação , Fenômenos Magnéticos , Apoptose/efeitos da radiação , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Especificidade de Órgãos/efeitos da radiação
16.
Am J Chin Med ; 48(6): 1409-1433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907360

RESUMO

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut-liver-brain axis.


Assuntos
Encéfalo/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Metformina/administração & dosagem , Metformina/farmacologia , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/microbiologia , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo
17.
PLoS One ; 15(9): e0239335, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970734

RESUMO

BACKGROUND: Suicide is a common phenomenon affecting people of all ages. There is a strong relationship between suicidal ideation and depressive disorders. Increasing number of studies suggest that epigenetic modifications in certain brain areas are the main mechanism through which environmental and genetic factors interact with each other contributing to the development of mental disorders. To verify this hypothesis, some epigenetic marks: H3K9/14ac, HDAC2/3, H3K27me2 and Sin3a, as well as p-S421-MeCP2/MeCP2 were examined. On the other hand, BDNF protein level were studied. MATERIALS AND METHODS: Western blot analysis were performed in the frontal cortex (FCx) and hippocampus (HP) of suicide victims (n = 14) and non-suicidal controls (n = 8). The differences between groups and correlations between selected proteins were evaluated using Mann-Whitney U-test and Spearman's rank correlation. RESULTS: Statistically significant decrease in H3K9/14ac (FCx:↓~23%;HP:↓~33%) combined with increase in HDAC3 (FCx:↑~103%;HP:↑~85% in HP) protein levels in suicides compared to the controls was shown. These alterations were accompanied by an increase in H3K27me2 (FCx:↑45%;HP:↑~59%) and Sin3a (HP:↑50%) levels and decrease in p-S421-MeCP2/MeCP2 protein ratio (HP:↓~55%;FCx:↓~27%). Moreover, reduced BDNF protein level (FCx:↓~43%;HP:↓~28%) in suicides was observed. On the other hand, some significant correlations (e.g. between H3K9/14ac and HDAC2 or between BDNF and p-S421-MeCP2/MeCP2) were demonstrated. CONCLUSIONS: Our findings confirm the role of epigenetic component and BDNF protein in suicidal behavior. Lowered BDNF protein level in suicides is probably due to decrease in histone acetylation and increased level of factors related with deacetylation and methylation processes, including MeCP2 factor, which may operate bidirectionally (an activator or inhibitor of transcription).


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epigênese Genética , Hipocampo/metabolismo , Suicídio , Adolescente , Adulto , Estudos de Casos e Controles , Lobo Frontal/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Pessoa de Meia-Idade , Complexo Correpressor Histona Desacetilase e Sin3/genética , Complexo Correpressor Histona Desacetilase e Sin3/metabolismo , Adulto Jovem
18.
PLoS Biol ; 18(8): e3000826, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776935

RESUMO

Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and ßCaMKII-deficient (αßCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αßCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αßCaMKII DKO neurons was restored by active ßCaMKII but not inactive ßCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to ßCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cálcio/metabolismo , Neurônios/metabolismo , Subunidades Proteicas/genética , Animais , Astrócitos/citologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Fosforilação , Cultura Primária de Células , Subunidades Proteicas/deficiência , Sinapses/fisiologia , Transmissão Sináptica , Imagem com Lapso de Tempo
19.
Nat Commun ; 11(1): 3946, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770055

RESUMO

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , RNA-Seq , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Life Sci ; 260: 118338, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841662

RESUMO

AIMS: Fluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. MAIN METHODS: The sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). KEY FINDINGS: The present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SIGNIFICANCE: In conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.


Assuntos
Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/administração & dosagem , Hipocampo/metabolismo , Transtornos da Memória/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Ansiedade/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Ratos , Inibidores de Captação de Serotonina/farmacologia
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