RESUMO
The presence of amyloid-ß (Aß) plaque and tau protein hyperphosphorylation in brain tissue is the pathological hallmark of Alzheimer's disease (AD). At least some Aß neurotoxicity is caused by the presence of excess glutamate that has been induced by Aß accumulation. Memantine is currently the only NMDA receptor inhibitor approved for treating moderate-to-severe AD patients. We utilized primary cortical neurons and DiBAC4(3), a slow-response voltage sensitive fluorescence dye, to create a novel system for screening herbal medicines that allows the identification of pure compounds able to ameliorate Aß-induced abnormal depolarization. The intensity of DiBAC4(3) fluorescence was increased when primary neurons were stimulated by Aß; furthermore, pre-treatment with memantine abolished this change. Using this system, we identified six crude extracts made from herbal medicines that effectively alleviated this Aß-induced abnormal depolarization. Among these herbal medicines, one pure compound, baicalein, which was known to be present in Scutellaria baricalensis and is known to improve memory using an AD mouse model, was identified by our assay. However, the compound's molecular mechanism remained unknown. We found that baicalein, in addition to inhibiting Aß-induced depolarization, possibly functions as an antagonist of AMPA and NMDA receptors. Taken together, we have established a system/platform to identify herbal medicines that ameliorate Aß-induced depolarization of neurons. Equally important, baicalein is a candidate drug with great potential for the treatment of AD patients.
Assuntos
Flavanonas/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de AMPA/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Peptídeos beta-Amiloides/toxicidade , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Células HEK293 , Humanos , MAP Quinase Quinase 4/metabolismo , Potenciais da Membrana/fisiologia , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/metabolismo , Neurotransmissores/farmacologia , Fragmentos de Peptídeos/toxicidade , Fitoterapia , Extratos Vegetais/farmacologia , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
As genetic information becomes more readily available, there is increasing demand from both patients and providers to develop personalized approaches to cancer care. Investigators are increasingly reporting numbers of studies correlating genomic signatures and other biomarkers to survival endpoints. The extent to which cancer-specific and non-specific effects are reported in contemporary studies is unknown. In this review of 85 high-impact studies associating genetic biomarkers with cancer outcomes, 95% reported significant associations with event-free survival outcomes, yet less than half reported effects on a cancer-specific endpoint. This methodology leaves open the possibility that observed associations are unrelated to cancer.
