RESUMO
Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3ß. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD.
Assuntos
Encefalopatias , Bloqueadores dos Canais de Cálcio/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Hiper-Homocisteinemia/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Animais , Encefalopatias/tratamento farmacológico , Encefalopatias/etiologia , Encefalopatias/patologia , Modelos Animais de Doenças , Donepezila , Quimioterapia Combinada , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/ultraestrutura , Homocisteína/toxicidade , Hiper-Homocisteinemia/induzido quimicamente , Indanos/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Nifedipino/análogos & derivados , Nifedipino/uso terapêutico , Piperidinas/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/ultraestrutura , Ratos , Ratos Sprague-Dawley , Coloração pela Prata , Tacrina/análogos & derivados , Tacrina/farmacologia , Tacrina/uso terapêuticoRESUMO
Hyperphosphorylated tau is the major component of neurofibrillary tangles in Alzheimer disease (AD), and the tangle distribution largely overlaps with zinc-containing glutamatergic neurons, suggesting that zinc released in synaptic terminals may play a role in tau phosphorylation. To explore this possibility, we treated cultured hippocampal slices or primary neurons with glutamate or Bic/4-AP to increase the synaptic activity with or without pretreatment of zinc chelators, and then detected the phosphorylation levels of tau. We found that glutamate or Bic/4-AP treatment caused tau hyperphosphorylation at multiple AD-related sites, including Ser-396, Ser-404, Thr-231, and Thr-205, while application of intracellular or extracellular zinc chelators, or blockade of zinc release by extracellular calcium omission almost abolished the synaptic activity-associated tau hyperphosphorylation. The zinc release and translocation of excitatory synapses in the hippocampus were detected, and zinc-induced tau hyperphosphorylation was also observed in cultured brain slices incubated with exogenously supplemented zinc. Tau hyperphosphorylation induced by synaptic activity was strongly associated with inactivation of protein phosphatase 2A (PP2A), and this inactivation can be reversed by pretreatment of zinc chelator. Together, these results suggest that synaptically released zinc promotes tau hyperphosphorylation through PP2A inhibition.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteína Fosfatase 2/antagonistas & inibidores , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Zinco/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Zinco/farmacologiaRESUMO
Most patients with Alzheimer's disease (AD) present decreased levels of melatonin, a day-night rhythm-related hormone. To investigate the role of melatonin deficiency in AD, we used constant illumination to interrupt melatonin metabolism and measured some of the AD-like alterations in rats. Concomitant with decreased serum melatonin, the rats developed spatial memory deficits, tau hyperphosphorylation at multiple sites, activation of glycogen synthase kinase-3 and protein kinase A, as well as suppression of protein phosphatase-1. Prominent oxidative damage and organelle lesions, demonstrated by increased expression of endoplasmic reticulum (ER) stress-related proteins including BiP/GRP78 and CHOP/GADD153, decreased number of rough ER and free ribosome, thinner synapses, and increased superoxide dismutase and monoamine oxidase were also observed in the light exposed rats. Simultaneous supplement of melatonin partially arrested the behavioral and molecular impairments. It is suggested that melatonin deficiency may be an upstream effector responsible for the AD-like behavioral and molecular pathologies with ER stress-involved mechanisms.
Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Antioxidantes/uso terapêutico , Retículo Endoplasmático/patologia , Melatonina/uso terapêutico , Doença de Alzheimer/sangue , Doença de Alzheimer/complicações , Animais , Comportamento Animal , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/ultraestrutura , Quinase 3 da Glicogênio Sintase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/ultraestrutura , Iluminação/efeitos adversos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Melatonina/sangue , Microscopia Imunoeletrônica/métodos , Monoaminoxidase/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/efeitos da radiação , Superóxido Dismutase/metabolismo , Proteínas tau/metabolismoRESUMO
Derivatives of 1-(4-amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine were identified as potent and functionally active MCH-R1 antagonists. One compound with Ki = 2.3 nM demonstrated good oral bioavailability (32%) and in vivo efficacy in rats.