RESUMO
Amyloid-ß (Aß) deposition in the brain is a primary biomarker of Alzheimer's disease (AD) and Aß measurement for AD diagnosis mostly depends on brain imaging and cerebrospinal fluid analyses. Blood Aß can become a reliable surrogate biomarker if issues of low concentration for conventional laboratory instruments and uncertain correlation with brain Aß are solved. Here, brain-to-blood efflux of Aß is stimulated in AD transgenic mice by orally administrating a chemical that dissociates amyloid plaques and observing the subsequent increase of blood Aß concentration. 5XFAD transgenic and wild-type mice of varying ages and genders are prepared, and blood samples of each mouse are collected six times for 12 weeks; three weeks of no treatment and additional nine weeks of daily oral administration, ad libitum, of Aß plaque-dissociating chemical agent. By the dissociation of Aß aggregates, the altered levels of plasma Aß distinguish between transgenic and wild-type mice, displaying potential as an amyloid burden marker of AD brains.
Assuntos
Doença de Alzheimer , Amiloidose , Amiloide/metabolismo , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Placa AmiloideRESUMO
Alzheimer's disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-ß. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F=46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 µM) results indicated safety of KMS80013.
Assuntos
Compostos de Anilina/química , Derivados de Benzeno/química , Estilbenos/química , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Compostos de Anilina/farmacocinética , Compostos de Anilina/uso terapêutico , Animais , Derivados de Benzeno/farmacocinética , Derivados de Benzeno/uso terapêutico , Encéfalo/metabolismo , Modelos Animais de Doenças , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estilbenos/farmacocinética , Estilbenos/uso terapêuticoRESUMO
Pathophysiological evidences of AD have indicated that aggregation of Aß is one of the principal causes of neuronal dysfunction, largely by way of inducing oxidative stresses such as free radical formation. We hypothesized that the known antioxidative attribute of SFN could be harnessed in Alzheimer's treatment. SFN is an indirect, potent antioxidant derived from broccoli that has previously been found to stimulate the Nrf2-ARE pathway and facilitate several other cytoprotective mechanisms. In this study, administration of SFN ameliorated cognitive function of Aß-induced AD acute mouse models in Y-maze and passive avoidance behavior tests. Interestingly, we found that the therapeutic effect of SFN did not involve inhibition of Aß aggregation. While the exact mechanism of interaction of SFN in AD has not yet been ascertained, our results suggest that SFN can aid in cognitive impairment and may protect the brain from amyloidogenic damages.