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1.
J Pharmacol Exp Ther ; 363(3): 377-393, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28954811

RESUMO

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 µM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Organofosfatos/uso terapêutico , Piperidinas/uso terapêutico , Pró-Fármacos/uso terapêutico , Pirrolidinonas/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo , Administração Intravenosa , Regulação Alostérica , Animais , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Ondas Encefálicas/efeitos dos fármacos , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Transtornos Dissociativos/induzido quimicamente , Macaca fascicularis , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Organofosfatos/efeitos adversos , Organofosfatos/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Ensaio Radioligante , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Xenopus
2.
Brain Res ; 1670: 86-95, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28501494

RESUMO

Ketamine produces rapid and long-lasting antidepressant effects in depressive patients. Preclinical studies demonstrate that ketamine stimulates AMPA receptor transmission and activates BDNF/TrkB-Akt/ERK-mTOR signaling cascades, leading to a sustained increase in synaptic protein synthesis and strengthening of synaptic plasticity, a potential mechanism underlying the antidepressant effects. The purpose of this study was to develop an immunohistochemistry (IHC) assay to map the distribution of extracellular signal-regulated kinase (ERK) phosphorylation in the mouse brain in response to systemic ketamine treatment. We established a focused microwave irradiation-assisted IHC assay to detect phosphorylated (phospho) proteins including phospho-ERK, phospho- cAMP-response- element-binding protein (CREB), phospho- glutamate receptor 1 (GluR1) and phospho- calcium/calmodulin-dependent protein kinase II (CaMKII) with greater sensitivity and reproducibility in comparison to conventional IHC methods. A single dose of ketamine produced a robust, dose- and time-dependent increase in phospho-ERK immunoreactive (phospho-ERK-ir) neurons in the medial prefrontal cortex (mPFC) and the central nucleus of the amygdala. Phospho-ERK-ir neurons in the mPFC were primarily located in the prelimbic and anterior cingulate subregions with the morphology resembling pyramidal neurons. An increase in phospho-ERK-ir was also observed in the brainstem dorsal raphe nucleus and locus coeruleus. The NMDA GluN2B subtype receptor antagonist Ro 25-6981 increased phospho-ERK expression in the brain in a similar pattern as ketamine. In summary, we have established a sensitive and reliable focused microwave irradiation-assisted IHC assay, and defined the activation pattern of ERK, in response to systemic ketamine and Ro 25-6981 treatment, in brain regions that are potentially responsible for mediating the antidepressant effects.


Assuntos
Imuno-Histoquímica/métodos , Ketamina/farmacologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Animais , Antidepressivos/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Núcleo Dorsal da Rafe/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Camundongos , Micro-Ondas , Fenóis/farmacologia , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Córtex Pré-Frontal/fisiologia , Receptores de AMPA/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos
3.
Stem Cell Res ; 20: 67-69, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28395743

RESUMO

Human fibroblast cells collected from a 3-year old, female Rett Syndrome patient with a 32bp deletion in the X-linked MECP2 gene were obtained from the Coriell Institute. Fibroblasts were reprogrammed to iPSC cells using a Sendai-virus delivery system expressing human KOSM transcription factors. Cell-line pluripotency was demonstrated by gene expression, immunocytochemistry, in-vitro differentiation trilineage capacity and was of normal karyotype. Interestingly, subsequent clones retained the epigenetic memory of the parent fibroblasts allowing for the segregation of wild-type and mutant expressing clones. This MECP2 mutant expressing clone may serve as a model for investigating MECP2 reactivation in Rett's Syndrome.


Assuntos
Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/patologia , Alelos , Diferenciação Celular , Linhagem Celular , Pré-Escolar , Corpos Embrioides/metabolismo , Corpos Embrioides/patologia , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Deleção de Genes , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Genótipo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Cariótipo , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Vírus Sendai/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
J Med Chem ; 59(24): 11138-11147, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28002964

RESUMO

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Naftalenos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
5.
ACS Med Chem Lett ; 7(3): 289-93, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26985317

RESUMO

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.

6.
Neuropsychopharmacology ; 41(9): 2232-40, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26837462

RESUMO

Schizophrenia patients exhibit dysfunctional gamma oscillations in response to simple auditory stimuli or more complex cognitive tasks, a phenomenon explained by reduced NMDA transmission within inhibitory/excitatory cortical networks. Indeed, a simple steady-state auditory click stimulation paradigm at gamma frequency (~40 Hz) has been reproducibly shown to reduce entrainment as measured by electroencephalography (EEG) in patients. However, some investigators have reported increased phase locking factor (PLF) and power in response to 40 Hz auditory stimulus in patients. Interestingly, preclinical literature also reflects this contradiction. We investigated whether a graded deficiency in NMDA transmission can account for such disparate findings by administering subanesthetic ketamine (1-30 mg/kg, i.v.) or vehicle to conscious rats (n=12) and testing their EEG entrainment to 40 Hz click stimuli at various time points (~7-62 min after treatment). In separate cohorts, we examined in vivo NMDA channel occupancy and tissue exposure to contextualize ketamine effects. We report a robust inverse relationship between PLF and NMDA occupancy 7 min after dosing. Moreover, ketamine could produce inhibition or disinhibition of the 40 Hz response in a temporally dynamic manner. These results provide for the first time empirical data to understand how cortical NMDA transmission deficit may lead to opposite modulation of the auditory steady-state response (ASSR). Importantly, our findings posit that 40 Hz ASSR is a pharmacodynamic biomarker for cortical NMDA function that is also robustly translatable. Besides schizophrenia, such a functional biomarker may be of value to neuropsychiatric disorders like bipolar and autism spectrum where 40 Hz ASSR deficits have been documented.


Assuntos
Córtex Cerebral/fisiologia , Potenciais Evocados Auditivos , Ritmo Gama , Receptores de N-Metil-D-Aspartato/fisiologia , Estimulação Acústica , Animais , Biomarcadores , Córtex Cerebral/efeitos dos fármacos , Maleato de Dizocilpina/farmacocinética , Eletroencefalografia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Masculino , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Processamento de Sinais Assistido por Computador
7.
Neuropharmacology ; 102: 121-35, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26522433

RESUMO

Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Animais , Sítios de Ligação , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Macaca fascicularis , Masculino , Camundongos , Camundongos Knockout , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo
8.
Eur J Pharmacol ; 766: 1-8, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26325093

RESUMO

N-methyl-D-aspartate (NMDA) receptor antagonists, including open channel blockers and GluN2B receptor subtype selective antagonists, have been developed for the treatment of depression. The current study investigated effects of systemically administered NMDA channel blockers and GluN2B receptor antagonists on NMDA receptor activity in rodents using in vivo [(3)H]MK-801 binding. The receptor occupancy of GluN2B antagonists was measured using ex vivo [(3)H]Ro 25-6981 binding. Ketamine, a NMDA receptor channel blocker, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~100%. The complete inhibition of in vivo [(3)H]MK-801 binding was also observed with NMDA receptor channel blockers, AZD6765 (Lanicemine) and MK-801 (Dizocilpine). CP-101,606 (Traxoprodil), a GluN2B antagonist, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~60%. Partial inhibition was also observed with other GluN2B antagonists including MK-0657 (CERC-301), EVT-101, Ro 25-6981 and radiprodil. For all GluN2B antagonists tested, partial [(3)H]MK-801 binding inhibition was achieved at doses saturating GluN2B receptor occupancy. Combined treatment with ketamine (10mg/kg, i.p.) and Ro 25-6981(10mg/kg, i.p.) produced a level of inhibition of in vivo [(3)H]MK-801 binding that was similar to treatment with either agent alone. In conclusion, this in vivo [(3)H]MK-801 binding study shows that NMDA receptor activity in the rodent forebrain can be inhibited completely by channel blockers, but only partially (~60%) by GluN2B receptor antagonists. At doses effective in preclinical models of depression, ketamine may preferentially inhibit the same population of NMDA receptors as Ro 25-6981, namely those containing the GluN2B subunit.


Assuntos
Maleato de Dizocilpina/farmacocinética , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitatórios/sangue , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Ensaio Radioligante , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
9.
J Neurochem ; 112(3): 599-610, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19878436

RESUMO

Myelin is highly enriched in galactocerebroside (GalCer) and its sulfated form sulfatide. Mice, unable to synthesize GalCer and sulfatide (CGT(null)) or sulfatide alone (CST(null)), exhibit disorganized paranodal structures and progressive dysmyelination. To obtain insights into the molecular mechanisms underlying these defects, we examined myelin composition of these mutants by two-dimensional differential fluorescence intensity gel electrophoresis proteomic approach and immunoblotting. We identified several proteins whose expressions were significantly altered in these mutants. These proteins are known to regulate cytoskeletal dynamics, energy metabolism, vesicular trafficking or adhesion, suggesting a disruption in these physiological processes in the absence of myelin galactolipids. Further analysis of one of these proteins, nucleotide diphosphate kinase (NDK)/Nm23, showed that it was reduced in myelin of CGT(null) and increased in CST(null), but not in whole brain homogenate. Immunostaining showed an increase in its expression in the cell bodies of CGT(null)- and a decrease in CST(null)-oligodenrocytes, together leading to the hypothesis that transport of NDK/Nm23 from oligodenrocyte cell bodies into myelin may be differentially dysregulated in the absence of these galactolipids. This study provides new insights into the changes that occur in the composition/distribution of myelin proteins in mice lacking either unsulfated and/or sulfated galactolipids and reinforces the role of these lipids in intracellular trafficking.


Assuntos
Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , N-Acilesfingosina Galactosiltransferase/deficiência , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Sulfotransferases/deficiência , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Eletroforese em Gel Bidimensional/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Proteolipídica de Mielina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Transporte Proteico/genética , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
10.
Sleep Breath ; 12(1): 33-8, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17687577

RESUMO

Respiratory events (RE) during sleep induce cortical arousals (A) and marked changes in autonomic markers in sleep apnea syndrome (SAS). The aims of the study were double. First, we assessed whether pulse wave amplitude (PWA) added to polysomnography (PSG) could improve RE and A detection; second, we wanted to know whether the quality of detection of these two parameters could be improved using PWA. Respiratory disturbance index (RDI) and A were randomly scored twice by the same observer in 12 male patients with SAS. The first scoring was done using conventional PSG signals, the second scoring adding PWA to PSG. We also measured interobserver agreement by randomly selecting and reading 100 PSG sequences of 5 min with and without PWA by two observers. Adding PWA to PSG parameters allowed to detect significantly more RDI (53.9 +/- 21.6 h(-1) versus 48.3 +/- 22.3 h(-1), p < 0.001) and more A (68.0 +/- 14.4 versus 59.4 +/- 16.5, p < 0.001). Moreover, after using PWA, there was no significant disagreement between two observers for detecting RE, showing better quality of RE detection. PWA is a simple and cheap parameter that improves the diagnostic value of conventional PSG in sleep apnea syndrome by better detecting respiratory events and A.


Assuntos
Nível de Alerta/fisiologia , Córtex Cerebral/fisiopatologia , Oximetria , Polissonografia , Apneia Obstrutiva do Sono/diagnóstico , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apneia Obstrutiva do Sono/fisiopatologia , Fases do Sono/fisiologia
11.
Sleep Breath ; 9(2): 73-81, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15875228

RESUMO

The objective of the study is to evaluate changes in finger pulse wave amplitude (PWA), as measured by photoplethysmography, and heart rate (HR), related to obstructive respiratory events and associated arousals during sleep. We analyzed 1,431 respiratory events in NREM sleep from 12 patients according to (1) the type of event (apnea, hypopnea, upper airway resistance episode) and (2) the duration of the associated EEG arousal (>10, 3-10, <3 s). Obstructive respiratory events provoked a relative bradycardia and vasodilation followed by HR increase and vasoconstriction. Relative PWA changes were significantly greater than HR changes. These responses differed significantly according to EEG-arousal grades (time x arousal interaction, p<0.0001), with longer arousals producing greater responses, but not to the type of respiratory event (time x event interaction, p = ns). Obstructive respiratory events provoke HR and PWA changes, the magnitude seemingly related to the intensity of central nervous activation, with PWA changes greater than HR. PWA obtained from a simple pulse oxymeter might be a valuable method to evaluate sleep fragmentation in sleep breathing disorders.


Assuntos
Nível de Alerta , Fotopletismografia/métodos , Respiração , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/fisiopatologia , Fases do Sono/fisiologia , Índice de Massa Corporal , Eletroencefalografia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
12.
Mol Ther ; 11(4): 523-30, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15771955

RESUMO

Small interfering RNAs (siRNAs) are potentially powerful tools for therapeutic gene regulation. DNA cassettes encoding RNA polymerase III promoter-driven hairpin siRNAs allow long-term expression of siRNA in targeted cells. A variety of viral vectors have been used to deliver such cassettes to cells. Here we report on the development and use of a self-complementary recombinant adeno-associated virus (scAAV) vector for siRNA delivery into mammalian cells. We demonstrate that this modified vector efficiently delivers siRNA into multidrug-resistant human breast and oral cancer cells and suppresses MDR1 gene expression. This results in rapid, profound, and durable reduction in the expression of the P-glycoprotein multidrug transporter and a substantial reversion of the drug-resistant phenotype. This research suggests that scAAV-based vectors can be very effective agents for efficient delivery of therapeutic siRNA.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Neoplasias da Mama/terapia , Dependovirus/genética , Resistencia a Medicamentos Antineoplásicos , Vetores Genéticos , Neoplasias Bucais/terapia , Interferência de RNA , RNA Interferente Pequeno/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proliferação de Células , Terapia Combinada , Regulação para Baixo , Doxorrubicina/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Conformação de Ácido Nucleico , RNA Mensageiro/efeitos dos fármacos , Células Tumorais Cultivadas
13.
Pharmacol Biochem Behav ; 78(1): 47-56, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15159133

RESUMO

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT(2A)/5-HT(2C)-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT(2)-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia-a clinical syndrome linked to enhanced sensitivity to N-methyl-d-aspartate (NMDA)-receptor antagonists.


Assuntos
Benzodiazepinas/administração & dosagem , Dopamina/metabolismo , Atividade Motora/efeitos dos fármacos , Fenciclidina/farmacologia , Animais , Animais Recém-Nascidos , Interações de Medicamentos , Feminino , Masculino , Atividade Motora/fisiologia , Olanzapina , Ratos , Ratos Sprague-Dawley
14.
Neuroendocrinology ; 76(2): 111-20, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12169772

RESUMO

During increases in plasma osmolality, extrinsic and intrinsic stimuli converge on the neuroendocrine cells within the supraoptic nucleus (SON) and paraventricular nucleus and evoke the release of vasopressin (VP). This release is accompanied by an increase in VP synthesis, but the signal transduction pathways that coordinate these two processes are still poorly understood. Several transcription factors have been suggested to be intermediates in this process, but their expression is often transient in spite of continued VP synthesis. Transcription factor expression during chronic neuroendocrine cell stimulation has rarely been examined. In an effort to identify sustained increases, we examined the expression of several transcription factors in the SON of normal rats and rats deprived of water for 44 h. Alpha and beta isoforms of activator protein-2 (AP-2 alpha; AP-beta), activating transcription factor-2 (ATF-2), the phosphorylated form of cyclic AMP response element binding protein and phospho-cJun were all expressed in the rat SON under basal conditions. Increases in AP-2 alpha and ATF-2 were sustained throughout the SON during water deprivation, suggesting that these transcription factors could play a role in the maintenance of VP and oxytocin gene transcription in response to dehydration.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Núcleo Supraóptico/metabolismo , Fatores de Transcrição/metabolismo , Privação de Água/fisiologia , Fator 2 Ativador da Transcrição , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas de Ligação a DNA/genética , Masculino , Ocitocina/metabolismo , Fosforilação , Regiões Promotoras Genéticas/fisiologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos , Ratos Long-Evans , Fator de Transcrição AP-2 , Fatores de Transcrição/genética , Ativação Transcricional/fisiologia , Vasopressinas/genética , Vasopressinas/metabolismo
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