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1.
Biol Bull ; 237(1): 48-62, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31441698

RESUMO

Anthropogenic activities and climate change have resulted in an increase of hypoxic conditions in nearshore ecosystems worldwide. Depending on the persistence of a hypoxic event, the survival of aquatic animals can be compromised. Temperate fish exposed to hypoxia display a reduction in the probability of eliciting startle responses thought to be important for escape from predation. Here we examine the effect of hypoxia on the probability of eliciting fast-startle responses (fast-starts) of a tropical fish, the white grunt (Haemulon plumieri), and whether hypoxia has a prolonged impact on behavior once the fish are returned to normoxic conditions. White grunts collected from the San Juan Bay Estuary in Puerto Rico were exposed to an oxygen concentration of 2.5 mg L-1 (40% dissolved oxygen). We found a significant reduction in auditory-evoked fast-starts that lasted for at least 24 hours after fish were returned to normoxic conditions. Accessibility to the neuronal networks that underlie startle responses was an important motivator for this study. Mauthner cells are identifiable neurons found in most fish and amphibians, and these cells are known to initiate fast-starts in teleost fishes. The assumption that most of the short-latency responses in this study are Mauthner cell initiated provided the impetus to characterize the white grunt Mauthner cell. The identification of the cell provides a first step in understanding how low oxygen levels may impact a single cell and its circuit and the behavior it initiates.


Assuntos
Comportamento Animal/fisiologia , Hipóxia/fisiopatologia , Perciformes/fisiologia , Reflexo de Sobressalto/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Oxigênio/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Clima Tropical
2.
Adv Exp Med Biol ; 1155: 747-754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468445

RESUMO

Arsenate, a well known toxicant, can induce injury in nerve system via oxidative stress and apoptosis. This study was designed to explore the protective effect of taurine against arsenite-induced neurotoxicity and its related mechanism in primary cortical neurons. The cells were treated with arsenite with or without taurine. Twenty-Four hours later, cell viability was examined using the MTT assay. The activity of caspase-3 was analyzed and the level of Akt and p-Akt were examined by western blot. The results show that taurine treatment significantly attenuates the decrease in cell viability of arsenite-exposed primary cortical neurons. Taurine also reversed the arsenite-induced increase in caspase-3 activity. The decrease in p-Akt levels induced by arsenite exposure was prevented by taurine treatment. Thus, taurine attenuated the effect of arsenite on primary cortical neurons, an effect that may involve the Akt pathway.


Assuntos
Apoptose , Arsênico/toxicidade , Neurônios/efeitos dos fármacos , Taurina/farmacologia , Caspase 3 , Humanos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais
3.
Adv Exp Med Biol ; 1155: 869-874, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468453

RESUMO

Our group previously reported that taurine has a protective capacity on the hippocampus and cerebellum of arsenic (As)-exposed mouse. In the present study, we explore whether taurine demonstrates protection against As toxicity in primary cortical neurons. Primary cortical neurons were exposed to various concentrations of arsenite and cell viability was assessed to confirm the toxicity of As on cortical neurons. The protection of taurine was examined after primary cortical neurons were treating with arsenite and taurine for 24 h. The cell viability was examined by MTT and caspase-3 activity assay. The expression of Bax and Bcl-2 was determined by western blot. The results showed that As exposure reduced cell viability and enhanced the activity of caspase-3, which were markedly inhibited by taurine treatment. The expression of Bax and Bcl-2 were disturbed by As exposure, which were reversed by taurine. These results indicated that taurine expose protective effect on As-exposed primary cortical neurons and its mechanism maybe involved the regulation of Bax/Bcl-2.


Assuntos
Arsênico/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Taurina/farmacologia , Animais , Apoptose , Sobrevivência Celular , Células Cultivadas , Camundongos , Neurônios/citologia , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
4.
Adv Exp Med Biol ; 1155: 889-903, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468455

RESUMO

Diabetes causes memory loss. Hippocampus is responsible for memory and increased apoptosis was found in diabetes patients. Taurine improved memory in diabetes condition. However, mechanism is unclear. In current study, hippocampal cell line HT-22 cells were subjected to analysis as five groups i.e. Control, High glucose (HG) at concentration of 150 mM, HG + 10 mM (T1), 20 mM (T2) and 40 mM (T3) taurine solution. TUNEL assay showed that HG increased the number of apoptotic cell significantly while taurine reduced apoptosis. Taurine increased phosphorylation of Akt in HT-22 cell treated with HG, and increased phosphorylation of Bad (p-Bad) was seen suggesting involvement of Akt/Bad signaling pathway. Expression of Bcl-2 was reduced in HG group but taurine improved this. Bax expression showed opposite trend. This indicated that taurine may reduce apoptosis by controlling balance of Bcl-2 and Bax. When the activation of Akt was blocked by using of perifosine, the effect of taurine disappears either partially or altogether. Thus, it was clear that taurine reduces apoptosis via Akt/Bad pathway in HT-22 cells exposed to HG which further improves downstream balance of Bcl-2 and Bax. This mechanism may be involved in apoptosis of hippocampus cells in diabetic condition.


Assuntos
Apoptose , Neurônios/efeitos dos fármacos , Taurina/farmacologia , Animais , Linhagem Celular , Glucose , Hipocampo/citologia , Camundongos , Fosforilação , Transdução de Sinais
5.
Adv Exp Med Biol ; 1155: 923-934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468457

RESUMO

Diabetic neuropathy (DN) is the most common chronic complication of DM and its major pathological changes show axonal dysfunction, atrophy and loss. However, there are few reports that taurine promotes neurite growth of dorsal root ganglion (DRG) cells. In current study, DRG neurons were exposed to high glucose (HG) with or without taurine. The neurite outgrowth of DRG neurons was observed by fluorescent immunohistochemistry method. Expression of Gap-43, Akt, phosphorylated Akt, mTOR and phosphorylated mTOR was determined by Western blot assay. Our results showed that HG significantly decreased the neurite outgrowth and expression of Gap-43 in DRG neurons. Moreover, phosphorylated levels of Akt and mTOR were downregulated in DRG neurons exposed to HG. On the contrary, taurine supplementation significantly reversed the decreased neurite outgrowth and Gap-43 expression, and the downregulated phosphorylated levels of Akt and mTOR. However, the protective effects of taurine were blocked in the presence of PI3K antagonists LY294002 or Akt antagonists Perifosine. These results indicate that taurine promotes neurite outgrowth of DRG neurons exposed to HG via activating Akt/mTOR signal pathway.


Assuntos
Gânglios Espinais/citologia , Neurônios/efeitos dos fármacos , Taurina/farmacologia , Células Cultivadas , Proteína GAP-43/metabolismo , Glucose , Humanos , Neuritos/efeitos dos fármacos , Neurônios/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
6.
Life Sci ; 234: 116784, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445026

RESUMO

Tobacco smoking is recognized as a life-threatening risk factor worldwide. Initiation of smoking primarily occurs during adolescence which is a critical developmental phase characterized by specific neurobehavioral alterations. The effect of adolescent nicotine exposure on vulnerability to opioid addiction has not been previously addressed. Furthermore, lateral paragigantocellularis (LPGi) is a key modulator of opiate effects. In this study we investigated the effect of adolescent nicotine treatment on development of morphine tolerance and dependence as well as LPGi neuronal responses to morphine during adulthood. Male Wistar rats received subcutaneous injections of either nicotine or saline during adolescence and then development of morphine tolerance and dependence was assessed during adulthood by tail-flick and withdrawal tests, respectively. In vivo single-unit recording was performed to examine the LPGi neuronal activities. Results indicated that adolescent nicotine exposure significantly facilitates the development of tolerance to analgesic effect of morphine and increases the expression of morphine withdrawal signs in adulthood. Also, it was observed that following adolescent nicotine treatment, the extent of morphine-induced excitation is attenuated in LPGi neurons of adult rats. Moreover, the onset of morphine-induced inhibition was increased in these animals. Neither the baseline, nor the regularity of firing was affected in our observations. It could be concluded that nicotine challenge during adolescence may enhance the future vulnerability to opioid addiction through induction of persistent neuroadaptations in LPGi neurons.


Assuntos
Tronco Encefálico/efeitos dos fármacos , Dependência de Morfina/etiologia , Neurônios/efeitos dos fármacos , Nicotina/efeitos adversos , Envelhecimento , Animais , Tronco Encefálico/citologia , Tronco Encefálico/fisiopatologia , Masculino , Dependência de Morfina/fisiopatologia , Neurônios/patologia , Transtornos Relacionados ao Uso de Opioides/etiologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Ratos Wistar , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/fisiopatologia
7.
Life Sci ; 232: 116647, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301416

RESUMO

AIM: Brain injury after sepsis leads to high mortality and long-term brain dysfunction in patients. Previous studies revealed that borneol has a protective effect on the brain, but its function on sepsis associated encephalopathy (SAE) remains unknown. Herein, we investigated the protective effect of borneol against sepsis-related brain injury. MAIN METHODS: Lipopolysaccharide (LPS)-induced sepsis mice and cells were treated with borneol at the dose of 100 mg/kg by gavage or 10 µg/ml in culture, respectively. The protective effect of borneol on neurons and the microglia were assessed in vivo and in vitro. KEY FINDINGS: We observed that borneol attenuated brain neuronal and microglial inflammation in LPS-induced sepsis mice with a suppression of p-p65 and p38 signaling that were initially activated by LPS in the brain. In vitro examination confirmed that the protective effect of borneol on both neurons and microglia, and its suppressive effect on p-p65 and p38 pathways were, at least in part, direct. SIGNIFICANCE: An early protection of neurons and microglia from bacterial endotoxin during sepsis is beneficial, and borneol has the potential to protect these cells.


Assuntos
Bornanos/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Endotoxinas/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Sepse/complicações , Animais , Bornanos/administração & dosagem , Bornanos/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia
8.
Life Sci ; 232: 116621, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31269415

RESUMO

Kainate (KA) mouse model induced by intraperitoneal injection has been widely used for epilepsy and neurodegeneration studies. KA elicits sustained epileptic activity in mouse brain revealed by recurrent behavioral seizures, deteriorative neurodegeneration and various neurological deficits. However, to date, the vast majority of the studies used male mice only, and few studies on the comparison of brain injury between male and female mice in this model were reported. Epidemiological studies indicate that sex may affect the susceptibility to seizure response and neurodegeneration process. Therefore, this study focused on the effect of sex difference on KA-induced recurrent seizures and mortality, locomotor activity and cognitive impairment, and hippocampal neurodegeneration and reactive gliosis in mice. Our results showed that, compared to females, adult male mice exhibited worse performance in mortality rate, severity of epileptic seizures, and cognitive impairment indicated by novel object recognition task. Unexpectedly, post-KA male and female mice underwent similar decline and recovery of locomotor activity. KA-induced neurodegeneration in the whole hippocampus, particularly in CA1 and CA3 subregions, along with the deteriorative reactive gliosis in astrocytes and microglia, was more severe in males than that in females. These data provided the direct in vivo evidence that indicates the key role of sex difference in studies with KA mouse model, and this could be beneficial for optimizing the design of future studies.


Assuntos
Ácido Caínico/efeitos adversos , Ácido Caínico/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Feminino , Gliose/induzido quimicamente , Hipocampo/efeitos dos fármacos , Ácido Caínico/farmacologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Fatores Sexuais
9.
Nature ; 571(7764): 198-204, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292557

RESUMO

Slow-wave sleep and rapid eye movement (or paradoxical) sleep have been found in mammals, birds and lizards, but it is unclear whether these neuronal signatures are found in non-amniotic vertebrates. Here we develop non-invasive fluorescence-based polysomnography for zebrafish, and show-using unbiased, brain-wide activity recording coupled with assessment of eye movement, muscle dynamics and heart rate-that there are at least two major sleep signatures in zebrafish. These signatures, which we term slow bursting sleep and propagating wave sleep, share commonalities with those of slow-wave sleep and paradoxical or rapid eye movement sleep, respectively. Further, we find that melanin-concentrating hormone signalling (which is involved in mammalian sleep) also regulates propagating wave sleep signatures and the overall amount of sleep in zebrafish, probably via activation of ependymal cells. These observations suggest that common neural signatures of sleep may have emerged in the vertebrate brain over 450 million years ago.


Assuntos
Neurônios/fisiologia , Sono/fisiologia , Peixe-Zebra/fisiologia , Animais , Evolução Biológica , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Epêndima/citologia , Movimentos Oculares , Fluorescência , Frequência Cardíaca , Hipnóticos e Sedativos/farmacologia , Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Neurônios/efeitos dos fármacos , Pigmentação/fisiologia , Hormônios Hipofisários/metabolismo , Polissonografia/métodos , Sono/efeitos dos fármacos , Privação do Sono/fisiopatologia , Sono REM/efeitos dos fármacos , Sono REM/fisiologia , Sono de Ondas Lentas/efeitos dos fármacos , Sono de Ondas Lentas/fisiologia
10.
Life Sci ; 232: 116611, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260683

RESUMO

PURPOSE: To observe the effect of dexmedetomidine (DEX) on mitochondrial apoptosis of hippocampal neurons in hypoxia/reoxygenation (H/R) brain injury in developing rats, and to investigate its regulatory mechanism on HIF-1α/p53 signaling pathway. METHODS: Hypoxia/reoxygenation model was used in this study. TUNEL assay was performed to detect cell apoptosis. Immunohistochemical analysis and Western-blotting analysis were conducted to detect Cytochrome-C (Cyt-c), APAF-1, Caspase-3, Neuroglobin (Ngb), HIF-1α and p53 expression. After 28 days, Morris water maze (MWM) was performed. RESULTS: 50 µg/kg DEX improved H/R-induced brain injury and inhibited mitochondrial apoptosis in rats. Western-blotting and Immunohistochemical results demonstrated that DEX could up-regulate Ngb through α2 receptor to inhibit H/R-induced mitochondrial apoptosis. In addition, by adding inhibitors yohimbine and 2-methoxyestradiol (2ME2), we found that DEX could activate HIF-1α/p53 signaling pathway. MWM test showed that DEX could enhance long-term learning and memory of H/R brain injury rats. CONCLUSION: DEX alleviates H/R-induced brain injury and mitochondrial apoptosis in developing rats through α2 receptor, which may be related to activation of HIF-1α/p53 signaling pathway to up-regulate the expression of Ngb.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipocampo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neurônios/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos
11.
Toxicol Lett ; 314: 43-52, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31310794

RESUMO

Thioredoxin is an evolutionarily conserved antioxidant protein that plays a crucial role for fundamental cellular processes and embryonic development. Growing evidence support that Thioredoxin influences cellular response to chemicals insults, particularly those accompanying oxidative stress. The mechanisms underlying the functions of Thioredoxin1 in the embryonic development under the environmental toxicant exposure remain, however, largely unexplored. We report here that thioredoxin1 becomes differentially expressed in zebrafish embryos after exposure to 9 out of 11 environmental chemicals. In situ gene expression analysis show that thioredoxin1 is expressed in neurons, olfactory epithelia, liver and swim bladder under normal conditions. After MeHg exposure, however, thioredoxin1 is ectopically induced in the hair cells of the lateral line and in epithelia cells of the pharynx. Knockdown of Thioredoxin1 induces hydrocephalus and increases cell apoptosis in the brain ventricular epithelia cells. In comparison with 5% malformation in embryos injected with control morpholino, MeHg induces more than 77% defects in Thioredoxin1 knockdown embryos. Our data suggest that there is an association between hydrocephalus and Thioredoxin1 malfunction in embryonic development, and provide valuable information to elucidate the protective role of Thioredoxin1 against chemicals disruption.


Assuntos
Encéfalo/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Hidrocefalia/induzido quimicamente , Tiorredoxinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica no Desenvolvimento , Hidrocefalia/embriologia , Hidrocefalia/genética , Hidrocefalia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxinas/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
12.
Chem Biodivers ; 16(8): e1900299, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31287220

RESUMO

The biotransformation of huperzine B (hupB), one of the characteristic bioactive constituents of the medicinal plant Huperzia serrata, by a fungal endophyte of the host plant was studied. One new compound, 8α,15α-epoxyhuperzine B (1), along with two known oxygenated hupB analogs, 16-hydroxyhuperzine B (2) and carinatumin B (3), was isolated and identified. The structures of all the isolates were deduced by spectroscopic methods including NMR, MS, IR, and UV spectra. The known compounds 2 and 3 were obtained from a microbial source for the first time. To the best of our knowledge, it is the first report on the microbial transformation of hupB and would facilitate further structural modification of hupB by chemo-enzymatic method. In the LPS-induced neuro-inflammation injury assay, 8α,15α-epoxyhuperzine B (1) exhibited moderate neuroprotective activity by increasing the viability of U251 cell lines with an EC50 of 40.1 nm.


Assuntos
Alcaloides/química , Huperzia/química , Alcaloides/metabolismo , Alcaloides/farmacologia , Biotransformação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Huperzia/metabolismo , Lipopolissacarídeos/toxicidade , Conformação Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia
13.
J Agric Food Chem ; 67(29): 8227-8234, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31299148

RESUMO

The mechanisms underlying neurodegenerative diseases are not fully understood yet. However, an increasing amount of evidence has suggested that these disorders are related to oxidative stress. We reported herein that lipoamide (LM), a neutral amide derivative of lipoic acid (LA), could resist oxidative stress-mediated neuronal cell damage. LM is more potent than LA in alleviating hydrogen peroxide- or 6-hydroxydopamine-induced PC12 cell injury. Our results reveal that LM promotes the nuclear accumulation of NFE2-related factor 2 (Nrf2), following with the activation of expression of Nrf2-governed antioxidant and detoxifying enzymes. Notably, silencing Nrf2 gene annuls the protection of LM, which demonstrates that Nrf2 is engaged in this cytoprotection. Our findings suggest that LM might be used as a potential therapeutic candidate for oxidative stress-related neurological disorders.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/análogos & derivados , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Ácido Tióctico/farmacologia
14.
Cell Tissue Res ; 377(1): 95-106, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31165247

RESUMO

A theoretical framework is proposed to gain insight into the pathogenesis of major depressive disorder (MDD). Despite being a relatively weak argument, the neurogenesis theory is suggested to compensate for the limitations of the monoamine theory. In the adult hippocampus, neurogenesis is functionally related to regulation of the hypothalamic-pituitary-adrenal (HPA) axis, inflammatory processes, cognitive functions and other aspects that contribute to etiological factors that lead to MDD and promote recovery from MDD. Despite a lack of investigation into neurogenesis and antidepressant action, it is proposed that chronic administration of antidepressant(s) can induce the recruitment and integration of newborn neurons into the dentate gyrus and, ultimately, lead to the remission of MDD. The extant body of literature indicates that the suppression of neurogenesis per se may be associated with an impaired response to antidepressant treatment rather than with the induction of depressive-like behaviors. Moreover, recent studies have shown that increasing the survival rate and incorporation of new neurons can alleviate depressive-like behaviors and promote stress resilience. According to the neurogenic reserve hypothesis, hippocampal neurogenesis supports specific cortical functions, including executive functions, pattern separation and contextual information processing, control over the HPA axis and behavioral coping mechanisms in response to stressful situations. Therefore, hippocampal neurogenesis may be a promising biological indicator of stress resilience and antidepressant response in patients with MDD.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Hipocampo/embriologia , Neurogênese , Neurônios/fisiologia , Adulto , Animais , Antidepressivos/farmacologia , Transtorno Depressivo Maior/fisiopatologia , Modelos Animais de Doenças , Humanos , Sistema Hipotálamo-Hipofisário/embriologia , Camundongos , Neurônios/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/embriologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos
15.
Nat Neurosci ; 22(7): 1061-1065, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209378

RESUMO

A key assumption of optogenetics is that light only affects opsin-expressing neurons. However, illumination invariably heats tissue, and many physiological processes are temperature-sensitive. Commonly used illumination protocols increased the temperature by 0.2-2 °C and suppressed spiking in multiple brain regions. In the striatum, light delivery activated an inwardly rectifying potassium conductance and biased rotational behavior. Thus, careful consideration of light-delivery parameters is required, as even modest intracranial heating can confound interpretation of optogenetic experiments.


Assuntos
Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Temperatura Ambiente , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/efeitos da radiação , Animais , Compostos de Bário/farmacologia , Córtex Cerebral/citologia , Cloretos/farmacologia , Corpo Estriado/citologia , Hipocampo/citologia , Temperatura Alta , Transporte de Íons/efeitos dos fármacos , Transporte de Íons/efeitos da radiação , Luz , Camundongos , Atividade Motora/efeitos da radiação , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Optogenética/métodos , Técnicas de Patch-Clamp , Potássio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/efeitos da radiação , Projetos de Pesquisa
16.
Nat Commun ; 10(1): 2746, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227712

RESUMO

Nicotinic acetylcholine receptors (nAChRs) mediate and modulate synaptic transmission throughout the brain, and contribute to learning, memory, and behavior. Dysregulation of α7-type nAChRs in neuropsychiatric as well as immunological and oncological diseases makes them attractive targets for pharmaceutical development. Recently, we identified NACHO as an essential chaperone for α7 nAChRs. Leveraging the robust recombinant expression of α7 nAChRs with NACHO, we utilized genome-wide cDNA library screening and discovered that several anti-apoptotic Bcl-2 family proteins further upregulate receptor assembly and cell surface expression. These effects are mediated by an intracellular motif on α7 that resembles the BH3 binding domain of pro-apoptotic Bcl-2 proteins, and can be blocked by BH3 mimetic Bcl-2 inhibitors. Overexpression of Bcl-2 member Mcl-1 in neurons enhanced surface expression of endogenous α7 nAChRs, while a combination of chemotherapeutic Bcl2-inhibitors suppressed neuronal α7 receptor assembly. These results demonstrate that Bcl-2 proteins link α7 nAChR assembly to cell survival pathways.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neurônios/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Motivos de Aminoácidos/genética , Animais , Benzotiazóis/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células HEK293 , Humanos , Isoquinolinas/farmacologia , Chaperonas Moleculares/metabolismo , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Ratos , Transmissão Sináptica/efeitos dos fármacos , Tiofenos/farmacologia , Regulação para Cima , Receptor Nicotínico de Acetilcolina alfa7/genética
17.
Life Sci ; 231: 116566, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31201846

RESUMO

AIMS: Diabetes mellitus can cause cognitive impairments, a state between normal aging and dementia. Effective clinical interventions are urgently needed to prevent or treat this complication. Liraglutide as a glucagon-like peptide 1 analog has been shown to exert memory-enhancing and neuroprotective effects on neurodegenerative diseases. This study aims to investigate the neuroprotective effects of liraglutide in streptozotocin (STZ)-induced diabetic mice with cognitive deficits. METHODS: Male C57BL/6J mice were intraperitoneal injected with STZ (65 mg/kg body weight daily for 5 days) to induce type 1 diabetes model. Then the mice were treated with liraglutide (250 mg/kg/day, for 6 weeks) or saline. Weekly changes of body weight and fasting blood glucose were measured. Cognitive performance was evaluated by Morris water maze test. The ultrastructure of hippocampus was observed by transmission electron microscope. The superoxide dismutase activities and malondialdehyde levels in the hippocampus were detected by biochemistry assay. Apoptosis-related proteins and phosphoinositide 3-kinase (PI3K)/protein kinase-B (Akt) signaling were detected by Western blotting. KEY FINDINGS: We found that STZ-induced diabetic mice exhibited impaired learning and memory, ultrastructure damage of hippocampal neurons and synapses, exacerbated oxidative stress and neuronal apoptosis, as compared to the control mice. These effects were attenuated by the treatment with liraglutide. Furthermore, liraglutide reversed diabetes-induced alterations in PI3K/Akt signaling pathway that plays an essential role in modulating neuronal survival, apoptosis and plasticity. SIGNIFICANCE: These data suggest that the neuroprotective effects of liraglutide on diabetes-induced cognitive impairments are associated with the improvements of hippocampal synapses and inhibition of neuronal apoptosis.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Liraglutida/farmacologia , Animais , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Cognição/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipoglicemiantes/farmacologia , Liraglutida/metabolismo , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
18.
Life Sci ; 231: 116581, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220524

RESUMO

AIMS: The aims of this study were to investigate the effect of colonic electrical stimulation (CES) on delayed colonic transit in Parkinson's disease (PD) model induced by rotenone and its possible mechanisms. MAIN METHODS: Sprague-Dawley male rats were implanted with a pair of electrodes on the serosa at the proximal colon and rotenone was subcutaneously injected for 6 weeks to induce the PD model. Behavior activity, stool volume and open-field test were recorded during the injection. Colonic propulsion rate was measured 6 weeks after rotenone injection. Colon samples of all rats were collected for the measurement of phosphorylated alpha-synuclein, choline acetyltransferase (CHAT), neuronal nitric oxide synthase (nNOS), and tyrosine hydroxylase (TH). The protocols of control rats were the same as the PD rats except that no electrodes were implanted and no rotenone was injected. KEY FINDINGS: (1) Rotenone-induced PD rats demonstrated weight loss, significant decrease of the dopaminergic neurons in substantia nigra, and impairment of colon movement. (2) CES significantly accelerated the delayed colonic transmit (91.67 ±â€¯5.58% vs 51.33 ±â€¯4.18%), superior to Macrogol-4000. (3) CES significantly upregulated the expression of CHAT, nNOS and TH protein in colon of PD rats. (4) In colon of PD rats, the phosphorylated alpha-synuclein was significantly upregulated, but CES had no significant effect on phosphorylated alpha-synuclein. SIGNIFICANCE: Our data show that CES can normalize the delayed colonic transit and this normalization may attribute to affecting enteric excitatory and inhibitory neurons.


Assuntos
Colo/metabolismo , Sistema Nervoso Entérico/efeitos dos fármacos , Doença de Parkinson/fisiopatologia , Animais , Colina O-Acetiltransferase/metabolismo , Colo/fisiopatologia , Constipação Intestinal/fisiopatologia , Modelos Animais de Doenças , Estimulação Elétrica , Motilidade Gastrointestinal/efeitos dos fármacos , Intestino Delgado/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Ratos Sprague-Dawley , Rotenona/metabolismo , Rotenona/farmacologia , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
19.
Artigo em Chinês | MEDLINE | ID: mdl-31245956

RESUMO

OBJECTIVE: To investigate the effects of dexmedetomidine (DEX) on hippocampal neuron development process and the expressions of molecules in brain-derived neurotropic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling pathway in neonatal rats. METHODS: The hippocampal neurons were isolated from neonatal rats and cultured in vitro. The cells were seeded in 96-well plates,which were divided into 4 groups (control group, 1 µmol/L DEX treatment group, 5 µmol/L DEX treatment group, 50 µmol/L DEX treatment group), six wells were set in each group, and different concentrations of dexmedetomidine 1, 5 and 50 µmol/L were administered respectively. Cell viability was detected at 2, 4, 6, 8, and 10 d after treatment, and apoptosis was detected 10 days after treatment. The mRNA expression levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) were detected by q-PCR, and the expressions of BDNF, TrkB and N-methyl-D-aspartate receptor (NMDAR) protein were analyzed. RESULTS: Compared with the control group, there was no significant difference in neuronal cell viability between the different doses of DEX treatment group. There was no significant difference in the expression of SYN and PSD95 mRNA and TrkB protein between the 1 µmol/L and 5 µmol/L DEX treatment groups (P>0.05). The expression levels of SYN and PSD95 mRNA in the 50 µmol/L DEX group were increased significantly (P<0.01), and the expression level of BDNF protein was up-regulated significantly (P<0.01), the expression of the p-N-methyl-D-aspartate receptor was increased (P<0.01). CONCLUSION: 50 µmol/L DEX has a certain effect on rat hippocampal neurons, which may be achieved by up-regulating the expression of BDNF and the phosphorylation level of N-methyl-D-aspartate receptor.


Assuntos
Dexmedetomidina , Hipocampo , Hipnóticos e Sedativos , Neurônios , Animais , Fator Neurotrófico Derivado do Encéfalo , Dexmedetomidina/farmacologia , Crescimento e Desenvolvimento , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipnóticos e Sedativos/farmacologia , Neurônios/efeitos dos fármacos , Ratos
20.
Yonsei Med J ; 60(7): 640-650, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250578

RESUMO

PURPOSE: Alzheimer's disease (AD) is the most common neurodegenerative disease, with a rising prevalence worldwide. Long noncoding RNAs (lncRNAs) have been found to play important roles in the development and treatment of AD. However, the exact role of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in neuronal damage in AD is largely unknown. MATERIALS AND METHODS: The AD model was established in SH-SY5Y and SK-N-SH cells via treatment with amyloid ß1-42 (Aß). The expression of NEAT1 and microRNA-107 (miR-107) was measured by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were detected by MTT assay, immunocytochemistry, and flow cytometry. The expression of phosphorylated tau protein (p-Tau) was measured by Western blot. The interaction between NEAT1 and miR-107 was explored by bioinformatics analysis, luciferase activity, and RNA immunoprecipitation assays. RESULTS: NEAT1 expression was enhanced in Aß-treated SH-SY5Y and SK-N-SH cells, and its knockdown attenuated Aß-induced inhibition of viability and promotion of apoptosis and p-Tau levels. NEAT1 was indicated as a decoy of miR-107. miR-107 abundance was reduced in Aß-treated cells, and its overexpression reversed Aß-induced injury. Moreover, interference of miR-107 abated silencing of NEAT1-mediated inhibition of neuronal damage in Aß-treated SH-SY5Y and SK-N-SH cells. CONCLUSION: LncRNA NEAT1 aggravated Aß-induced neuronal damage by sponging miR-107, indicating a novel avenue for treatment of AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , MicroRNAs/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/toxicidade , RNA Longo não Codificante/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Humanos , Neurônios/patologia
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