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1.
Nihon Shokakibyo Gakkai Zasshi ; 116(2): 145-152, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30745552

RESUMO

A ring-shaped ulcer was observed in the ileum of a 70-year-old male patient with capsule endoscopy of the small intestine performed for detailed investigation of black stools and iron deficiency anemia. Non-steroidal anti-inflammatory drugs (NSAIDs) use in patch form was considered as the etiology. The NSAIDs patches were discontinued, and protective therapy for small intestinal mucosa was initiated. The anemia improved;however, ileus originating from the site of the ulcer required surgical resection. The resected specimen showed no specific pathological findings. Based on the clinical findings, the patient was diagnosed with NSAIDs-induced small intestinal ulcer. The use of NSAIDs patches should be considered as a potential cause of injury to gastrointestinal mucosa.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Endoscopia por Cápsula , Enteropatias/induzido quimicamente , Idoso , Humanos , Enteropatias/diagnóstico , Mucosa Intestinal , Intestino Delgado , Masculino , Úlcera
2.
Nihon Shokakibyo Gakkai Zasshi ; 115(9): 804-810, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30197394

RESUMO

A 74-year-old male who was receiving endocrine therapy for prostate cancer, with multiple bone and lymph node metastases (T2bN1M1 Stage D2), underwent follow-up computed tomography (CT). The CT revealed multiple liver metastases, a high serum CEA level, and an unchanged PSA level. Upper gastrointestinal endoscopy showed an elevated lesion with mucosal erosion on the lesser curvature of the middle gastric corpus, revealed to be a metastatic prostate cancer lesion following immunohistochemical confirmation. This case demonstrates the potential for gastric metastases in patients with advanced prostate cancer and high serum CEA levels.

3.
Sci Rep ; 8(1): 13046, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158644

RESUMO

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

4.
Endosc Int Open ; 6(4): E450-E461, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29607398

RESUMO

Background and study aims: Salvage therapy for esophageal cancer following chemo-radiation therapy (CRT) has not been established. We aimed to evaluate endoscopic submucosal dissection (ESD) as a salvage therapy based on histopathological features of lesions. Patients and methods: We compared 10 lesions in eight patients with local residual, recurrent, or metachronous esophageal squamous cell carcinoma treated by ESD after CRT (CRT group) and 59 lesions treated by ESD without CRT (non-CRT group) during the same period. Results: The en bloc resection rate was 100 % while the complete resection rate was 80.0 % in the lesions after CRT, indicating no difference between the CRT and non-CRT groups. Pathological examination showed that fibrosis was more intense in the lamina propria mucosa, muscularis mucosa, and submucosa. The muscularis mucosa was thicker in both non-tumor and tumor sites in the CRT group compared to the non-CRT group. However, severe submucosal fibrosis was observed only in one lesion in the CRT group. The maximum diameter of the submucosal artery was significantly larger in the CRT group ( P  < 0.001). Conclusions: Compared to the non-CRT group, the lesions in the CRT group were accompanied by fibrosis while the muscularis mucosa were thicker; however, severe fibrosis of the submucosa was rare. It is important to dissect the muscularis mucosa appropriately during ESD, which makes successful dissection of the submucosa possible. Attention should be paid to bleeding from large arteries.

5.
Psychopharmacology (Berl) ; 234(12): 1853-1869, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28332006

RESUMO

Increased risk of attention-deficit/hyperactivity disorder (AD/HD) is partly associated with the early developmental exposure to nicotine in tobacco smoke. Emerging reports link tobacco smoke exposure or prenatal nicotine exposure (PNE) with AD/HD-like behaviors in rodent models. We have previously reported that PNE induces cognitive behavioral deficits in offspring and decreases the contents of dopamine (DA) and its turnover in the prefrontal cortex (PFC) of offspring It is well known that the dysfunction of DAergic system in the brain is one of the core factors in the pathophysiology of AD/HD. Therefore, we examined whether the effects of PNE on the DAergic system underlie the AD/HD-related behavioral changes in mouse offspring. PNE reduced the release of DA in the medial PFC (mPFC) in mouse offspring. PNE reduced the number of tyrosine hydroxylase (TH)-positive varicosities in the mPFC and in the core as well as the shell of nucleus accumbens, but not in the striatum. PNE also induced behavioral deficits in cliff avoidance, object-based attention, and sensorimotor gating in offspring. These behavioral deficits were attenuated by acute treatment with atomoxetine (3 mg/kg, s.c.) or partially attenuated by acute treatment with MPH (1 mg/kg, s.c.). Taken together, our findings support the notion that PNE induces neurobehavioral abnormalities in mouse offspring by disrupting the DAergic system and improve our understanding about the incidence of AD/HD in children whose mothers were exposed to nicotine during their pregnancy.


Assuntos
Cloridrato de Atomoxetina/toxicidade , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Dopamina/metabolismo , Nicotina/toxicidade , Córtex Pré-Frontal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Inibidores da Captação Adrenérgica/toxicidade , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/psicologia
6.
Neuroscience ; 351: 15-23, 2017 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-28344071

RESUMO

Diphtheria toxin (DT) administration into transgenic mice that express the DT receptor (DTR) under control of specific promoters is often used for cell ablation studies in vivo. Because DTR is not expressed in mice, DT injection has been assumed to be nontoxic to cells in vivo. In this study, we demonstrated that DT application during the juvenile stage leads to hearing loss in wild-type mice. Auditory brainstem response measurement showed severe hearing loss in C57BL/6 mice administered DT during the juvenile period, and the hearing loss persisted into adulthood. However, ototoxicity did not occur when DT was applied on postnatal day 28 or later. Histological studies demonstrated that hearing loss was accompanied by significant degeneration of inner and outer hair cells (HCs), as well as spiral ganglion neurons. Scanning electron microscopy showed quick degeneration of inner HCs within 3days and gradual degeneration of outer HCs within 1week. These results demonstrated that DT has ototoxic action on C57BL/6 mice during the juvenile period, but not thereafter, and the hearing loss was due to degeneration of inner and outer HCs by unknown DT-related mechanisms.


Assuntos
Toxina Diftérica/farmacologia , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Células Ciliadas Auditivas Internas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Perda Auditiva/patologia , Envelhecimento , Animais , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Células Ciliadas Auditivas Internas/patologia , Perda Auditiva/induzido quimicamente , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gânglio Espiral da Cóclea/efeitos dos fármacos , Gânglio Espiral da Cóclea/patologia
7.
J Nutr Sci Vitaminol (Tokyo) ; 62(2): 81-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27264091

RESUMO

Biotin is a water-soluble vitamin that functions as a cofactor for biotin-dependent carboxylases. The biochemical and physiological roles of biotin in brain regions have not yet been investigated sufficiently in vivo. Thus, in order to clarify the function of biotin in the brain, we herein examined biotin contents, biotinylated protein expression (e.g. holocarboxylases), and biotin-related gene expression in the brain of biotin-deficient rats. Three-week-old male Wistar rats were divided into a control group, biotin-deficient group, and pair-fed group. Rats were fed experimental diets from 3 wk old for 8 wk, and the cortex, hippocampus, striatum, hypothalamus, and cerebellum were then collected. In the biotin-deficient group, the maintenance of total biotin and holocarboxylases, increases in the bound form of biotin and biotinidase activity, and the expression of an unknown biotinylated protein were observed in the cortex. In other regions, total and free biotin contents decreased, holocarboxylase expression was maintained, and bound biotin and biotinidase activity remained unchanged. Biotin-related gene (pyruvate carboxylase, sodium-dependent multivitamin transporter, holocarboxylase synthetase, and biotinidase) expression in the cortex and hippocampus also remained unchanged among the dietary groups. These results suggest that biotin may be related to cortex functions by binding protein, and the effects of a biotin deficiency and the importance of biotin differ among the different brain regions.


Assuntos
Biotina/deficiência , Encéfalo/metabolismo , Animais , Biotinidase/genética , Biotinidase/metabolismo , Carbono-Nitrogênio Ligases/genética , Carbono-Nitrogênio Ligases/metabolismo , Regulação da Expressão Gênica , Masculino , Piruvato Carboxilase/genética , Piruvato Carboxilase/metabolismo , Ratos , Ratos Wistar , Simportadores/genética , Simportadores/metabolismo
8.
Neuropsychopharmacology ; 41(2): 578-89, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26105135

RESUMO

Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2'-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.


Assuntos
Neurogênese/fisiologia , Neurônios/fisiologia , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Córtex Pré-Frontal/crescimento & desenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Animais , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Gravidez , Distribuição Aleatória , Ácido gama-Aminobutírico/metabolismo
9.
Behav Brain Res ; 289: 69-77, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25913833

RESUMO

Alzheimer's disease (AD), the most common form of dementia among the elderly, is characterized by the progressive decline of cognitive function. Increasing evidence indicates that the production and accumulation of amyloid ß (Aß), particularly soluble Aß oligomers, is central to the pathogenesis of AD. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory-bulbectomized mice, amyloid precursor protein transgenic mice, NMDA receptor antagonist-treated mice, and senescence-accelerated mouse prone 8. Here, we present evidence that this natural compound improves cognitive impairment and reduces soluble Aß levels in a triple transgenic mouse model of AD (3XTg-AD) that progressively develops amyloid plaques, neurofibrillary tangles, and cognitive impairments. Treatment with nobiletin (30 mg/kg) for 3 months reversed the impairment of short-term memory and recognition memory in 3XTg-AD mice. Our ELISA analysis also showed that nobiletin reduced the levels of soluble Aß1-40 in the brain of 3XTg-AD mice. Furthermore, nobiletin reduced ROS levels in the hippocampus of 3XTg-AD as well as wild-type mice. These results suggest that this natural compound has potential to become a novel drug for the treatment and prevention of AD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/análise , Encéfalo/efeitos dos fármacos , Flavonas/administração & dosagem , Fragmentos de Peptídeos/análise , Doença de Alzheimer/tratamento farmacológico , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Recognição (Psicologia)/efeitos dos fármacos
10.
Int J Neuropsychopharmacol ; 17(5): 723-37, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24345457

RESUMO

Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities remain unclear. Here, we investigated the involvement of histone modification in phencyclidine-induced behavioral abnormalities and the effects of antipsychotics on these abnormalities. After repeated phencyclidine (10 mg/kg) treatment for 14 consecutive days, mice were treated with antipsychotics (clozapine or haloperidol) or the histone deacetylase inhibitor sodium butyrate for 7 d. Repeated phencyclidine treatments induced memory impairment and social deficit in the mice. The acetylation of histone H3 at lysine 9 residues decreased in the prefrontal cortex with phencyclidine treatment, whereas the expression level of histone deacetylase 5 increased. In addition, the phosphorylation of Ca²âº/calmodulin-dependent protein kinase II in the nucleus decreased in the prefrontal cortex of phencyclidine-treated mice. These behavioral and epigenetic changes in phencyclidine-treated mice were attenuated by clozapine and sodium butyrate but not by haloperidol. The dopamine D1 receptor antagonist SCH-23390 blocked the ameliorating effects of clozapine but not of sodium butyrate. Furthermore, clozapine and sodium butyrate attenuated the decrease in expression level of GABAergic system-related genes in the prefrontal cortex of phencyclidine-treated mice. These findings suggest that the antipsychotic effect of clozapine develops, at least in part, through epigenetic modification by activation of the dopamine D1 receptor in the prefrontal cortex.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Epigênese Genética/efeitos dos fármacos , Abuso de Fenciclidina/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Animais , Benzazepinas/farmacologia , Ácido Butírico/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Antagonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Alucinógenos/farmacologia , Haloperidol/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos ICR , Fenciclidina/farmacologia , Abuso de Fenciclidina/complicações , Abuso de Fenciclidina/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores
11.
Behav Brain Res ; 250: 351-60, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23714077

RESUMO

Senescence-accelerated mouse prone 8 (SAMP8) is a model of aging characterized by the early onset of learning and memory impairment and various pathological features of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory-bulbectomized mice, amyloid precursor protein transgenic mice, and NMDA receptor antagonist-treated mice. Here, we present evidence that this natural compound improves age-related cognitive impairment and reduces oxidative stress and tau phosphorylation in SAMP8 mice. Treatment with nobiletin (10 or 50mg/kg) reversed the impairment of recognition memory and context-dependent fear memory in SAMP8 mice. Treatment with nobiletin also restored the decrease in the GSH/GSSG ratio in the brain of SAMP8 mice. In addition, increases in glutathione peroxidase and manganese-superoxide dismutase activities, as well as a decrease in protein carbonyl level, were observed in the brain of nobiletin-treated SAMP8 mice. Furthermore, nobiletin reduced tau phosphorylation in the hippocampus of SAMP8 mice. Together, the markedly beneficial effects of nobiletin represent a potentially useful treatment for ameliorating the learning and memory deficits, oxidative stress, and hyperphosphorylation of tau in aging as well as age-related neurodegenerative diseases such as AD.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Flavonas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Proteínas tau/metabolismo , Envelhecimento/genética , Envelhecimento/fisiologia , Análise de Variância , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Estudos de Casos e Controles , Condicionamento (Psicologia)/efeitos dos fármacos , Condicionamento (Psicologia)/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Flavonas/química , Flavonas/farmacologia , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
12.
Anal Bioanal Chem ; 405(25): 8137-41, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23665637

RESUMO

It has been reported that repeated phencyclidine (PCP) treatment induces schizophrenia-like behavior in mice. L-Tryptophan (Trp) concentrations in brain tissues of control (n = 8) and PCP-treated mice (10 mg/kg/day, s.c., 14 days, n = 10) were determined using high-performance liquid chromatography (HPLC) with fluorescence detection. The HPLC method involved pre-column fluorescence derivatization with (R)-(-)-4-(N,N-dimethylaminosulfonyl)-7-(3-isothiocyanatopyrrolidin-1-yl)-2,1,3-benzoxadiazole (DBD-PyNCS). Eight different parts of the brain, namely, the frontal cortex, nucleus accumbens, striatum, hippocampus, amygdala, thalamus, hypothalamus, and cerebellum, of both groups were investigated. A significant decrease in the L-Trp concentration in the nucleus accumbens (p = 0.024) and hippocampus (p = 0.027) was observed in PCP-treated mice, suggesting that alteration of the L-Trp metabolism might occur in these brain parts.


Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/farmacologia , Triptofano/metabolismo , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Isotiocianatos , Masculino , Camundongos , Oxidiazóis , Fenciclidina/efeitos adversos , Esquizofrenia/induzido quimicamente , Triptofano/análise
13.
Behav Brain Res ; 239: 80-9, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23142610

RESUMO

Nicotine replacement treatments are being alternatively applied as an aid to smoking cessation during pregnancy. However, the effects of nicotine exposed at the prenatal stage on the emotional behaviors in offspring are not well understood due to the lack of systematic investigations. The current study has therefore initially aimed to evaluate emotional behaviors in young mouse offspring (postnatal day 28-36) which experienced gestational and/or perinatal nicotine exposure (GPNE) in six different time-windows. Pregnant C57BL/6J mice were exposed to nicotine via sweetened (2% sucrose) drinking water during 6 different time-windows including gestational day 0-day 13 (G0-G13), G14-perinatal day 0 (P0), G0-P0, G14-P7, G0-P7, and P0-P7. During P28-P36 days, both male and female offspring were given a battery of behavioral tests including light and dark box test, marble burying behavior test, novelty-suppressed feeding test, sociability and social novelty preference test, social avoidance tube test, and elevated plus maze test. GPNE during G0-P0, G14-P0, G14-P7, and G0-P7 induced abnormal behaviors in male and female offspring to different extent. Results indicated that nicotine at any time points of gestational and/or perinatal period impairs emotional behaviors in offspring, and suggested certain time-windows for further neurochemical or molecular studies in relation with GPNE-induced emotional abnormalities.


Assuntos
Comportamento Animal/efeitos dos fármacos , Emoções/efeitos dos fármacos , Nicotina/farmacologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Cotinina/sangue , Feminino , Masculino , Comportamento Materno/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Nicotina/farmacocinética , Gravidez , Caracteres Sexuais , Fatores de Tempo
14.
Neuropsychopharmacology ; 37(6): 1387-96, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22257896

RESUMO

N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.


Assuntos
Proliferação de Células/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ácido Glutâmico/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/patologia , Fenciclidina/efeitos adversos , Córtex Pré-Frontal/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Estimulação Acústica , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Sintomas Comportamentais/induzido quimicamente , Peso Corporal/efeitos dos fármacos , Bromodesoxiuridina/metabolismo , Embrião de Mamíferos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microdissecção , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Natação/psicologia
15.
Int J Neuropsychopharmacol ; 15(10): 1489-501, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22093154

RESUMO

Enriched environments (EEs) during development have been shown to influence adult behaviour. Environmental conditions during childhood may contribute to the onset and/or pathology of schizophrenia; however, it remains unclear whether EE might prevent the development of schizophrenia. Herein, we investigated the effects of EE during adolescence on phencyclidine (PCP)-induced abnormal behaviour, a proposed schizophrenic endophenotype. Male ICR mice (3 wk old) were exposed to an EE for 4 wk and then treated with PCP for 2 wk. The EE potentiated the acute PCP treatment-induced hyperlocomotion in the locomotor test and prevented chronic PCP treatment-induced impairments of social behaviour and recognition memory in the social interaction and novel object recognition tests. It also prevented the PCP-induced decrease of acetylated Lys9 in histone H3-positive cells and increase of the histone deacetylase (HDAC)5 level in the prefrontal cortex. To investigate whether the histone modification during adolescence might be critical for the effect of EE, 3-wk-old mice were first treated with sodium butyrate (SB; an HDAC inhibitor) for 4 wk and then treated with PCP for 2 wk. Chronic SB treatment during adolescence mimicked the effects of EE, including potentiation of hyperlocomotion induced by acute PCP treatment and prevention of social and cognitive impairments, decrease of acetylated Lys9 in histone H3-positive cells and increase of the HDAC5 level in the prefrontal cortex associated with chronic PCP treatment. Our results suggest that EEs prevent PCP-induced abnormal behaviour associated with histone deacetylation. EEs during childhood might prove to be a novel strategy for prophylaxis against schizophrenia.


Assuntos
Meio Ambiente , Histona Desacetilases/metabolismo , Fenciclidina/toxicidade , Agitação Psicomotora/enzimologia , Agitação Psicomotora/prevenção & controle , Comportamento Social , Fatores Etários , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Agitação Psicomotora/psicologia
16.
Behav Brain Res ; 220(1): 185-93, 2011 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-21277334

RESUMO

The deficits of attention result in significant impairment in daily life, and pharmacological intervention to improve attention is the most effective treatment in clinics. However, methods which are suitable for the large scale preclinical screening of attention-improving compounds or drugs are few in the field. In this study, we have developed object-based attention task as a simple and wherever-practical method that suitable for quick drug screening in mice. Treatment with p-chlorophenylalanine (pCPA) (200mg/kg/day, i.p.) for three consecutive days reduced the prefrontal cortical content of serotonin and dopamine, and increased turn-over of dopamine while decreasing turn-over of norepinephrine in the prefrontal cortex on day 7. Auditory attention and working memory, but not long-term object memory after a long (10 min) object (two objects)-exposure period, were impaired on day 7 after the same treatment paradigm with pCPA. Novel object recognition ability immediately (<10s) after a short (3 min) object (on two objects)-exposure period was not impaired after pCPA treatment. However, novel object recognition ability immediately (<10s) after a short (3 min), but not long (6 min), object (five objects)-exposure period was impaired after pCPA treatment. For the verification, the current task, the object-based attention task, was confirmed in an attention deficit model induced by acute phencyclidine (1mg/kg, i.p.) treatment in mice. It was implied that the object-based attention task would assist the behavioral screening process of pharmacological studies on attention-improving drugs.


Assuntos
Atenção/fisiologia , Recognição (Psicologia)/fisiologia , Estimulação Acústica/métodos , Análise de Variância , Animais , Atenção/efeitos dos fármacos , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenclonina/efeitos adversos , Inibição (Psicologia) , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Testes Neuropsicológicos , Norepinefrina/metabolismo , Fenciclidina/farmacologia , Recognição (Psicologia)/efeitos dos fármacos , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia
17.
Biochim Biophys Acta ; 1636(1): 12-21, 2004 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-14984734

RESUMO

Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator generated from sphingosine by sphingosine kinase (SPHK). S1P acts both extracellularly and intracellularly as a signaling molecule, although its intracellular targets are still undefined. Intracellular level of S1P is under strict regulatory control of SPHK regulation, S1P degradation, and S1P dephosphorylation. Therefore, clarifying the mechanisms regulating SPHK activity may help us understand when and where S1P is generated. In this study, we performed yeast two-hybrid screening to search for SPHK1a-binding molecules that may be involved in the regulation of the kinase localization or activity. Platelet endothelial cell adhesion molecule-1 (PECAM-1) was identified as a protein potentially associating with SPHK1a. Their association was confirmed by co-immunoprecipitation analysis using HEK293 cells overexpressing PECAM-1 and SPHK1a. Moreover, the kinase activity appeared to be reduced in stable PECAM-1-expressing cells. PECAM-1 is expressed on the cell surface of vascular cells, and several stimuli are known to induce phosphorylation of its tyrosine residues. We found that such phosphorylation attenuated its association with SPHK1a. This association/dissociation of SPHK with PECAM-1, regulated by the phosphorylated state of the membrane protein, may be involved in the control of localized kinase activity in certain cell types.


Assuntos
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Sítios de Ligação , Linhagem Celular , Humanos , Lisofosfolipídeos/metabolismo , Mutagênese Sítio-Dirigida , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/biossíntese , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Plasmídeos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Ligação Proteica , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Aglutininas do Germe de Trigo
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