Assuntos
Envelhecimento , Conservadores da Densidade Óssea/uso terapêutico , Cálcio/uso terapêutico , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Vitamina D/uso terapêutico , Absorciometria de Fóton/métodos , Idoso , Feminino , Humanos , Masculino , Osteoporose/diagnóstico por imagem , Resultado do TratamentoRESUMO
The cellular pathology of Alzheimer's disease is progressive and protracted leading eventually to considerable neuronal death. The underlying mechanisms of the pathology are complex but changes in the control of intracellular Ca2+ are believed to contribute to the demise of neurons. In this study, we investigated the functional consequences of an increase in the expression of the type 3 isoform of the ryanodine receptor (RyR3). We found that although cortical neurons from TgCRND8 mice secreted significantly more amyloid beta protein and showed significantly increased RyR3 expression, they were no more sensitive to cell stress than non-transgenic neurons. Furthermore, despite increased intracellular Ca2+ release in response to ryanodine, we found that basal Ca2+, K+-evoked Ca2+ responses, and capacitative Ca2+ entry were no different in TgCRND8 neurons compared with non-transgenic neurons. Therefore, as RyR3 up-regulation did not affect neuronal health or global Ca2+ homeostasis, we investigated the effect of reducing RyR3 expression using small interfering RNA. Surprisingly, a reduction of RyR3 expression in TgCRND8, but not in non-transgenic, neurons increased neuronal death. These data reveal a new role for RyR3 and indicate a novel potential therapeutic target to delay or prevent the progression of Alzheimer's disease.
Assuntos
Doença de Alzheimer/metabolismo , Neurônios/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Regulação para Cima/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática/métodos , Ácido Glutâmico/farmacologia , Proteínas de Fluorescência Verde/genética , Humanos , Camundongos , Camundongos Transgênicos , Mutação/genética , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Potássio/farmacologia , Presenilina-1/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Sais de Tetrazólio , Tiazóis , Regulação para Cima/efeitos dos fármacosRESUMO
LC-MS/MS-based screening of the dichloromethane extract of the gorgonian coral Pseudopterogorgia acerosa led to the isolation of a novel bis(pseudopterane) amine (1). The structural assignment of 1 was achieved by 1D and 2D NMR and mass spectrometry analysis. A biomimetic synthesis of 1 and the known symmetrical diterpene 2 from pseudopterolide (3) is described in this report. Bis(pseudopterane) amine showed selective growth inhibition activity against cancer cell lines with IC(50) values of 4.2 microM (HCT116) and 42 microM (HeLa).
