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1.
Braz J Med Biol Res ; 54(5): e10717, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33825777

RESUMEN

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.


Asunto(s)
Epilepsia , Venenos de Escorpión , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Hipocampo/metabolismo , Calor , Ácido Kaínico/toxicidad , Neuronas , Péptidos , Ratas , Venenos de Escorpión/toxicidad
2.
Ecotoxicol Environ Saf ; 215: 112108, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33799132

RESUMEN

Fluoride which is widespread in our environment and food due to its geological origin and industrial pollution has been identified as a developmental neurotoxicant. Gut-brain axis provides new insight into brain-derived injury. We previously found the psychoactive effects of a probiotic strain, Lactobacillus johnsonii BS15 against fluoride-induced memory dysfunction in mice by modulating the gut-brain axis. In this study, we aimed to detect the link between the reconstruction of gut microbiota and gut-brain axis through which probiotic alleviate fluoride-induced memory impairment. We also added an hour of water avoidance stress (WAS) before behavioral tests and sampling, aiming to demonstrate the preventive effects of the probiotic on fluoride-induced memory impairment after psychological stress. Mice were given fluoridated drinking water (sodium fluoride 100 ppm, corresponding to 37.8 ± 2.4 ppm F¯) for 70 days and administered with PBS or a probiotic strain, Lactobacillus johnsonii BS15 for 28 days prior to and throughout a 70 day exposure to sodium fluoride. Results showed that fluoride increases the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis and reduces the exploration ratio in novel object recognition (NOR) test and the spontaneous exploration during the T-maze test in mice following WAS, which were significantly improved by the probiotic. 16S rRNA sequencing showed a significant separation in ileal microbiota between the fluoride-treated mice and control mice. Lactobacillus was the main targeting bacteria and significantly reduced in fluoride-treated mice. BS15 reconstructed the fluoride-post microbiota and increased the relative abundance of Lactobacillus. D-lactate content and diamine oxidase (DAO) activity, two biomarkers of gut permeability were reduced in the serum of probiotic-inoculated mice. ZO-1, an intestinal tight junction protein was reduced by fluoride in mRNA, and its protein levels were increased by the probiotic treatment. Moreover, the hippocampus which is essential to learning and memory, down-regulated mRNA level of both the myelin-associated glycoprotein (MAG), and protein levels of brain-derived neurotrophic factor (BDNF), including the improvement of cAMP response element-binding protein (CREB) by BS15 in fluoride-exposed mice after WAS. Via spearman correlation analysis, Lactobacillus displayed significantly positive associations with the behavioral tests, levels of nerve development related factors, and intestinal tight junction proteins ZO-1, and negative association with TNF-α of the hippocampus, highlighting regulatory effects of gut bacteria on memory potential and gut barrier. These results suggested the psychoactive effects of BS15 on fluoride-induced memory dysfunction after psychological stress. In addition, there may be some correlations between fluoride-induced memory dysfunction and reconstruction of gut microbiota. AVAILABILITY OF DATA AND MATERIALS: 16S rRNA sequencing reads have uploaded to NCBI. The accession code of 16S rRNA sequencing reads in the National Center for Biotechnology Information (NCBI) BioProject database: PRJNA660154.


Asunto(s)
Fluoruros/metabolismo , Microbioma Gastrointestinal/fisiología , Probióticos/farmacología , Animales , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Lactobacillus/metabolismo , Masculino , Memoria , Trastornos de la Memoria/inducido químicamente , Ratones , Microbiota , Sistema Hipófiso-Suprarrenal/metabolismo , ARN Ribosómico 16S/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteína de la Zonula Occludens-1/metabolismo
3.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803741

RESUMEN

Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo. Unexpectedly, immortalized murine microglia recently exhibited this de novo biosynthesis; herein, de novo neurosteroidogenesis was characterized in immortalized human microglia. The results demonstrated that C20 and HMC3 microglial cells constitutively express members of the neurosteroidogenesis multiprotein machinery-in particular, the transduceosome members StAR and TSPO, and the enzyme CYP11A1. Moreover, both cell lines produce pregnenolone and transcriptionally express the enzymes involved in neurosteroidogenesis. The high TSPO expression levels observed in microglia prompted us to assess its role in de novo neurosteroidogenesis. TSPO siRNA and TSPO synthetic ligand treatments were used to reduce and prompt TSPO function, respectively. The TSPO expression downregulation compromised the de novo neurosteroidogenesis and led to an increase in StAR expression, probably as a compensatory mechanism. The pharmacological TSPO stimulation the de novo neurosteroidogenesis improved in turn the neurosteroid-mediated release of Brain-Derived Neurotrophic Factor. In conclusion, these results demonstrated that de novo neurosteroidogenesis occurs in human microglia, unravelling a new mechanism potentially useful for future therapeutic purposes.


Asunto(s)
Microglía/metabolismo , Neuroesteroides/metabolismo , Receptores de GABA/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Línea Celular , Regulación de la Expresión Génica , Humanos , Neuroesteroides/química , Pregnenolona/química , Pregnenolona/metabolismo
4.
J Biomed Nanotechnol ; 17(1): 37-52, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33653495

RESUMEN

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.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Fosfatidilinositol 3-Quinasas , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Proteínas Tirosina Quinasas , Ratas , Proteínas Tirosina Quinasas Receptoras , Transducción de Señal , Sinapsis/metabolismo , Titanio
5.
Life Sci ; 273: 119308, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33667520

RESUMEN

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.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/complicaciones , Modelos Animales de Enfermedad , Hiperalgesia/etiología , Neuralgia/complicaciones , Canales Catiónicos TRPC/metabolismo , Animales , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Hiperalgesia/metabolismo , Hiperalgesia/patología , Masculino , Ratas , Ratas Sprague-Dawley , Canales Catiónicos TRPC/genética
6.
J Affect Disord ; 286: 248-258, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33752039

RESUMEN

BACKGROUND: Post-traumatic stress disorder (PTSD) is a debilitating mental disease with high morbidity and major social and economic relevance. No efficient treatment for PTSD has thus far been identified. Clinical research has shown that ketamine can rapidly alleviate symptoms in patients with chronic PTSD; however, its pharmacological mechanism has yet to be determined. METHODS: This study aimed to identify a model of single prolonged stress (SPS), which induced PTSD-like features in adult mice. Once the model was established, stress-related behavioral changes in the mouse model were evaluated after intraperitoneal injection of ketamine (10 mg/kg). Alterations in certain proteins (HCN1, BDNF, and PSD95) and synaptic ultrastructure in the prefrontal cortex (PFC) and hippocampus (HIP) were measured. RESULTS: The mice under the SPS model exhibited anxiety- and depression-like behaviors and induced spatial cognitive deficits, accompanied by elevated HCN1 protein expression in the PFC and HIP, reduced brain-derived neurotrophic factor (BDNF) and PSD95 proteins, and alterations in synaptic morphology. After ketamine administration, the SPS-treated mice restored their protein levels and synaptic ultrastructure in the PFC, and their PTSD-like behaviors improved. However, learning and memory in the SPS-treated mice did not improve in the water maze test, and no significant changes in protein level and synaptic ultrastructure in the HIP were shown. LIMITATIONS: The electrophysiological mechanism of the HCN1 ion channel after ketamine administration was not explored. CONCLUSION: Ketamine could generally improve SPS-induced mood dysfunction in mice but exerted no effect on the spatial cognitive function, which could be related to the alterations in synaptic morphology and function mediated by HCN1-related BDNF signaling in the PFC and HIP.


Asunto(s)
Ketamina , Trastornos por Estrés Postraumático , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cognición , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Ketamina/farmacología , Ratones , Canales de Potasio , Trastornos por Estrés Postraumático/tratamiento farmacológico
7.
Medicine (Baltimore) ; 100(6): e23305, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578508

RESUMEN

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.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Alelos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Estudios de Casos y Controles , China/epidemiología , Ensayos Clínicos como Asunto , Dinamarca/epidemiología , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo
8.
J Affect Disord ; 282: 1195-1202, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33601696

RESUMEN

BACKGROUND: The present study aims to evaluate the effects of ouabain on memory and neurotrophic parameters in the brains of rats. METHODS: Wistar rats received an intracerebroventricular (ICV) injection of ouabain or artificial cerebrospinal fluid (aCSF). Seven and 14 days after ICV administration, the animals were subjected to the open-field and splash tests. Furthermore, the pro-BDNF, BDNF, TrkB, and CREB were assessed in the frontal cortex and hippocampus of the rats, in both seven and 14 days after ICV injection. The memory of the animals was tested by novel object recognition test (NOR) and inhibitory avoidance task (IA), only 14 days after ICV administration. RESULTS: Ouabain increased locomotion and exploration in the animals seven days after its administration; however, 14 days after ICV, these behavioral parameters return to the basal level. Seven days after ouabain administration increased grooming behavior in the splash test; on the other hand, seven days after ouabain injection decreased the grooming behavior, which is considered an anhedonic response. Besides, ouabain decreased recognition index in the NOR and decreased aversive memory in the IA, when compared to the control group. The levels of pro-BDNF and BDNF decreased in the frontal cortex seven days after ouabain; but its receptor (TrkB) and CREB decreased seven and 14 days after ouabain, in both cerebral structures evaluated. CONCLUSION: Ouabain-induced animal model of BD is an excellent model to assess memory alteration, observed in bipolar patients. Besides, the memory impairment induced by ouabain seems to be related to BDNF signaling pathway alterations.


Asunto(s)
Trastorno Bipolar , Ouabaína , Animales , Trastorno Bipolar/inducido químicamente , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cognición , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Humanos , Ouabaína/toxicidad , Ratas , Ratas Wistar , Transducción de Señal
9.
Int J Mol Sci ; 22(3)2021 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-33503967

RESUMEN

BACKGROUND: Environmental Enrichment (EE) has been suggested as a possible therapeutic intervention for neurodevelopmental disorders such as autism. Although the benefits of this therapeutic method have been reported in some animal models and human studies, the unknown pathophysiology of autism as well as number of conflicting results, urge for further examination of the therapeutic potential of EE in autism. Therefore, the aim of this study was to examine the effects of environmental enrichment on autism-related behaviors which were induced in the maternal separation (MS) animal model. MATERIAL AND METHODS: Maternally separated (post-natal day (PND) 1-14, 3h/day) and control male rats were at weaning (PND21) age equally divided into rats housed in enriched environment and normal environment. At adolescence (PND42-50), the four groups were behaviorally tested for direct social interaction, sociability, repetitive behaviors, anxiety behavior, and locomotion. Following completion of the behavioral tests, the blood and brain tissue samples were harvested in order to assess plasma level of brain derived neurotrophic factor (BDNF) and structural plasticity of brain using ELISA and stereological methods respectively. RESULTS: We found that environmental enrichment reduced repetitive behaviors but failed to improve the impaired sociability and anxiety behaviors which were induced by maternal separation. Indeed, EE exacerbated anxiety and social behaviors deficits in association with increased plasma BDNF level, larger volume of the hippocampus and infra-limbic region and higher number of neurons in the infra-limbic area (p < 0.05). Conclusion: We conclude that environmental enrichment has a significant improvement effect on the repetitive behavior as one of the core autistic-like behaviors induced by maternal separation but has negative effect on the anxiety and social behaviors which might have been modulated by BDNF.


Asunto(s)
Trastorno Autístico/etiología , Trastorno Autístico/psicología , Privación Materna , Animales , Animales Recién Nacidos , Ansiedad , Trastorno Autístico/terapia , Conducta Animal , Biomarcadores , Encéfalo/metabolismo , Encéfalo/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Terapia Combinada , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Masculino , Oxitocina/farmacología , Ratas , Conducta Social
10.
Psychopharmacology (Berl) ; 238(4): 1213-1222, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33496816

RESUMEN

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.


Asunto(s)
Conducta Animal , Epigénesis Genética/genética , Deficiencia de Vitamina B/genética , Deficiencia de Vitamina B/psicología , Animales , Química Encefálica/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Suspensión Trasera , Histonas/metabolismo , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Neuropéptido Y/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/psicología
11.
Chem Biol Interact ; 337: 109392, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33497687

RESUMEN

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.


Asunto(s)
Apoptosis/efectos de los fármacos , Arseniatos/toxicidad , Hidroxibenzoatos/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Catalasa/genética , Catalasa/metabolismo , Citocinas/genética , Citocinas/metabolismo , Glutatión Peroxidasa/metabolismo , Masculino , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Superóxido Dismutasa/metabolismo
12.
Biomed Pharmacother ; 133: 111062, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378965

RESUMEN

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.


Asunto(s)
Factor de Transcripción Activador 6/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Neuropatías Diabéticas/tratamiento farmacológico , Proteínas de Choque Térmico/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Células de Schwann/efectos de los fármacos , Nervio Ciático/efectos de los fármacos , Proteína 1 de Unión a la X-Box/metabolismo , Factor de Transcripción Activador 6/genética , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Línea Celular Tumoral , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/metabolismo , Proteínas de Choque Térmico/genética , Humanos , Masculino , Ratones Endogámicos C57BL , Ratas , Células de Schwann/metabolismo , Nervio Ciático/metabolismo , Transducción de Señal , Regulación hacia Arriba , Proteína 1 de Unión a la X-Box/genética
13.
Epilepsy Behav ; 115: 107660, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33328107

RESUMEN

Epilepsies are a diverse group of neurological disorders characterized by an unprovoked seizure and a brain that has an enduring predisposition to seizures. The lack of disease-modifying treatment strategies against the same has led to the exploration of novel treatment strategies that could halt epileptic seizures. In this regard, environmental enrichment (EE) has gained increased attention in recent days. EE modulates the effects of interactions between the genes and the environment on the structure and function of the brain. EE therapy can improve seizure-related symptoms in neurological diseases such as epilepsy. EE therapy can have a significant effect on cognitive disorders such as learning and memory impairments associated with seizures. EE therapy in epileptic hippocampus tissue can improve seizure-related symptoms by inducing enhanced neurogenesis and neuroprotective mechanisms. In this context, the efficiency of EE is regulated in the epilepsy by the brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK) signaling pathway regulated by extracellular signaling. Herein, we provide experimental evidence supporting the beneficial effects of EE in epileptic seizures and its underlying mechanism.


Asunto(s)
Epilepsia , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Epilepsia/complicaciones , Epilepsia/terapia , Hipocampo/metabolismo , Humanos , Neurogénesis , Convulsiones
14.
Biochem Biophys Res Commun ; 537: 36-42, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33383562

RESUMEN

Ischemia/reperfusion (I/R) is a common injury leading to ischemic stroke. At present, I/R treatment remains limited, highlighting the urgent need for the discovery and development of new protective drugs for brain injury. Here, we investigated the neuroprotective effects of short peptide OM-LV20 previously identified from amphibian against I/R rats. Results showed that intraperitoneal administration of OM-LV20 (20 ng/kg) significantly reduced infarct area formation, improved behavioral abnormalities, and protected cortical and hippocampal neurons against death caused by I/R. Moreover, the underlying molecular mechanism was involved with the regulation of the MAPK and BDNF/AKT signaling pathways, as well as the levels of cyclic adenosine monophosphate, pituitary adenylate cyclase-activating polypeptide receptor, and tryptophan hydroxylase 1. To the best of our knowledge, this research was the first report to describe the neuroprotective effects of an amphibian skin secretion-derived peptide in I/R rats and highlighted OM-LV20 as a promising drug candidate for the development of novel anti-stroke therapies.


Asunto(s)
Fármacos Neuroprotectores/uso terapéutico , Péptidos/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Secuencia de Aminoácidos , Animales , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , AMP Cíclico/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Péptidos/administración & dosificación , Péptidos/química , Péptidos/farmacología , Estabilidad Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Triptófano Hidroxilasa/metabolismo
15.
Nutrients ; 12(12)2020 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-33322645

RESUMEN

Neuroinflammation is associated with an increased risk of depression. Lipopolysaccharide (LPS) treatment is known to induce pro-inflammatory cytokine secretion and a depressive-like phenotype in mice. Although Erythronium japonicum exhibits various health benefits, the role of E. japonicum extract (EJE) in inflammation-associated depression is unknown. This study aimed to explore the anti-inflammatory effect of EJE on LPS-induced depressive symptoms in mice using the open field test (OFT), passive avoidance test (PAT), tail suspension test (TST), and forced swim test (FST). LPS-treated mice had significantly increased immobility time in the TST and FST, decreased step-through latency time in the PAT, and decreased locomotor activity in the OFT. However, administration of 100 and 300 mg/kg of EJE significantly improved these depressive-like behaviors. EJE also prevented the increase in mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and monocyte chemoattractant protein-1 (MCP-1), and the decrease in IL-10 levels by inhibiting nuclear factor-κB (NF-κB) subunit p65 phosphorylation. Additionally, LPS-treated mice showed markedly decreased brain-derived neurotrophic factor (BDNF) levels and phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt, while EJE treatment significantly increased these levels in the hippocampus. These results suggest that EJE ameliorated LPS-induced depressive-like behavior by reducing LPS-induced neuroinflammation and activating the BDNF-PI3K/Akt pathway.


Asunto(s)
Antiinflamatorios/farmacología , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Liliaceae , Extractos Vegetales/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/inducido químicamente , Modelos Animales de Enfermedad , Suspensión Trasera , Lipopolisacáridos , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Natación
16.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-33333849

RESUMEN

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.


Asunto(s)
Astrocitos/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Neuralgia/metabolismo , Transducción de Señal/fisiología , Simportadores/metabolismo , Animales , Astrocitos/enzimología , Sistema Nervioso Central/lesiones , Citocinas/metabolismo , Humanos , Inflamación/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Neuralgia/enzimología , Receptor trkB/metabolismo , Heridas y Traumatismos/enzimología , Heridas y Traumatismos/metabolismo
17.
Molecules ; 26(1)2020 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-33379243

RESUMEN

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.


Asunto(s)
Apoptosis/efectos de los fármacos , Ácidos Cumáricos/farmacología , Peróxido de Hidrógeno/farmacología , Sustancias Protectoras/farmacología , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/metabolismo , Animales , Antioxidantes/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Línea Celular Tumoral , Dactinomicina/farmacología , MicroARNs/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Feocromocitoma/tratamiento farmacológico , Feocromocitoma/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
18.
Zhongguo Zhong Yao Za Zhi ; 45(20): 4971-4977, 2020 Oct.
Artículo en Chino | MEDLINE | ID: mdl-33350271

RESUMEN

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.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Sistema Hipotálamo-Hipofisario , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cápsulas , Depresión/tratamiento farmacológico , Depresión/genética , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Ratones , Sistema Hipófiso-Suprarrenal/metabolismo , Estrés Psicológico
19.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-33333883

RESUMEN

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.


Asunto(s)
Curcumina/administración & dosificación , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/psicología , Liposomas , Memoria/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Animales , Biomarcadores , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Enfermedad de Huntington/etiología , Aprendizaje/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Ratones , Ratones Transgénicos , Neuronas/patología , Receptor trkB/metabolismo
20.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-33322180

RESUMEN

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.


Asunto(s)
Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Mycobacterium tuberculosis/metabolismo , Neuronas/patología , Tuberculosis Pulmonar/metabolismo , Animales , Ansiedad/metabolismo , Ansiedad/microbiología , Síntomas Conductuales/microbiología , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/citología , Encéfalo/enzimología , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Disfunción Cognitiva/microbiología , Depresión/metabolismo , Depresión/microbiología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Hipocampo/citología , Hipocampo/inmunología , Hipocampo/metabolismo , Hipocampo/patología , Quinasas Janus/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/patogenicidad , Neuronas/citología , Neurotransmisores/metabolismo , Tuberculosis Pulmonar/enzimología , Tuberculosis Pulmonar/patología , Tuberculosis Pulmonar/psicología , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
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