RESUMO
Alzheimer's disease (AD) is a degenerative disorder typified by progressive deterioration of memory and the appearance of ß-amyloid peptide (Aß)-rich senile plaques. Recently we have identified a novel function of a patented formulation of modified Huanglian-Jie-Tu-Tang (HLJDT-M), a Chinese herbal medicine, in treating AD in in vitro studies (US patent No. 9,375,457). HLJDT-M is a formulation composed of Rhizoma Coptitis, Cortex Phellodendri and Fructus Gardeniae without Radix Scutellariae. Here, we assessed the efficacy of HLJDT-M on a triple transgenic mouse model of AD (3XTg-AD). Oral administration of HLJDT-M ameliorated the cognitive dysfunction of 3XTg-AD mice and lessened the plaque burden. In addition, biochemical assays revealed a significant decrease in levels of detergent-soluble and acid-soluble Aß via decreasing the levels of full length amyloid-ß precursor protein (FL-APP) and C-terminal fragments of APP (CTFs) in brain lysates of HLJDT-M-treated mice. HLJDT-M treatment also significantly reduced the levels of FL-APP and CTFs in N2a/SweAPP cells. In contrast, treatment using the classical formula HLJDT did not reduce the memory impairment of 3XTg-AD mice and, rather, increased the Aß/Fl-APP/CTFs in both animal and cell culture studies. Altogether, our study indicates that HLJDT-M is a promising herbal formulation to prevent and/or cure AD.
Assuntos
Doença de Alzheimer/complicações , Precursor de Proteína beta-Amiloide/fisiologia , Medicamentos de Ervas Chinesas/química , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/farmacocinética , Placa Amiloide/prevenção & controle , Presenilina-1/fisiologia , Proteínas tau/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Placa Amiloide/etiologia , Placa Amiloide/patologiaAssuntos
Imunização Passiva , Tauopatias/terapia , Proteínas tau/fisiologia , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Especificidade de Anticorpos , Modelos Animais de Doenças , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Humanos , Lisossomos/fisiologia , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/química , Neurônios/patologia , Fosfosserina/química , Agregação Patológica de Proteínas/etiologia , Agregação Patológica de Proteínas/prevenção & controle , Tauopatias/prevenção & controle , Proteínas tau/deficiência , Proteínas tau/metabolismoRESUMO
BACKGROUND: The aim of our research work was to quantify total flavonoid contents in the leaves of 13 plant species family Asteraceae, 8 representatives of family Lamiaceae and 9 plant species belonging to familyRosaceae, using the multiplex fluorimetric sensor. Fluorescence was measured using optical fluorescence apparatus Multiplex(R) 3 (Force-A, France) for non-destructive flavonoids estimation. The content of total flavonoids was estimated by FLAV index (expressed in relative units), that is deduced from flavonoids UV absorbing properties. RESULTS: Among observed plant species, the highest amount of total flavonoids has been found in leaves ofHelianthus multiflorus (1.65 RU) and Echinops ritro (1.27 RU), Rudbeckia fulgida (1.13 RU) belonging to the family Asteraceae. Lowest flavonoid content has been observed in the leaves of marigold (Calendula officinalis) (0.14 RU) also belonging to family Asteraceae. The highest content of flavonoids among experimental plants of family Rosaceae has been estimated in the leaves of Rosa canina (1.18 RU) and among plant species of family Lamiaceae in the leaves of Coleus blumei (0.90 RU). CONCLUSIONS: This research work was done as pre-screening of flavonoids content in the leaves of plant species belonging to family Asteraceae, Lamiaceae and Rosaceae. Results indicated that statistically significant differences (P > 0.05) in flavonoids content were observed not only between families, but also among individual plant species within one family.
Assuntos
Animais , Humanos , Camundongos , Relógios Biológicos/genética , Caseína Quinase 1 épsilon/deficiência , Ritmo Circadiano/genética , Mutação , Proteínas tau/deficiência , Proteínas tau/metabolismo , Linhagem Celular , Células Cultivadas , Caseína Quinase 1 épsilon/antagonistas & inibidores , Caseína Quinase 1 épsilon/fisiologia , Camundongos Knockout , Camundongos Transgênicos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/deficiência , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiologia , Proteínas Circadianas Period , Fosforilação , Núcleo Supraquiasmático/fisiologia , Fatores de Tempo , Proteínas tau/fisiologiaAssuntos
Doença de Alzheimer , Idoso , Envelhecimento/fisiologia , Envelhecimento/psicologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/etiologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/fisiologia , Encéfalo/fisiopatologia , China , Diagnóstico por Imagem/métodos , Humanos , Medicina Tradicional Chinesa , Modelos Neurológicos , Proteínas tau/fisiologiaRESUMO
For decades, researchers have focused primarily on a pathway initiated by amyloid beta aggregation, amyloid deposition, and accumulation in the brain as the key mechanism underlying the disease and the most important treatment target. However, evidence increasingly suggests that amyloid is deposited early during the course of disease, even prior to the onset of clinical symptoms. Thus, targeting amyloid in patients with mild to moderate Alzheimer's disease (AD), as past failed clinical trials have done, may be insufficient to halt further disease progression. Scientists are investigating other molecular and cellular pathways and processes that contribute to AD pathogenesis. Thus, the Alzheimer's Association's Research Roundtable convened a meeting in April 2012 to move beyond amyloid and explore AD as a complex multifactorial disease, with the goal of using a more inclusive perspective to identify novel treatment strategies.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Terapia de Alvo Molecular , Nootrópicos/uso terapêutico , Envelhecimento , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Autofagia/efeitos dos fármacos , Biomarcadores , Encéfalo/metabolismo , Ciclo Celular/efeitos dos fármacos , Comportamento Cooperativo , Diabetes Mellitus Tipo 2/complicações , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação , Resistência à Insulina , Lisossomos/efeitos dos fármacos , Lisossomos/fisiologia , Camundongos , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Modelos Neurológicos , Neuroimagem , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Nootrópicos/farmacologia , Parcerias Público-Privadas , Alocação de Recursos , Proteínas tau/efeitos dos fármacos , Proteínas tau/fisiologiaRESUMO
Davunetide (NAP) is a leading drug candidate being tested against tauopathy. Davunetide is an eight-amino-acid peptide fragment derived by structure-activity studies from activity-dependent neuroprotective protein, activity-dependent neuroprotective protein (ADNP). ADNP is essential for brain formation. ADNP haploinsufficiency in mice results in tauopathy and cognitive deficits ameliorated by davunetide treatment. This article summarizes in brief recent reviews about NAP protection against tauopathy including the all D-amino acid analogue-D-NAP (AL-408). D-NAP was discovered to have similar neuroprotective functions to NAP in vitro. Here, D-NAP was tested as prophylactic as well as therapeutic treatment for amytrophic lateral sclerosis (ALS) in the widely used TgN(SOD1-G93A)1Gur transgenic mouse model. Results showed D-NAP-associated prophylactic protection, thus daily treatment starting from day 2 of age resulted in a prolonged life course in the D-NAP-treated mice, which was coupled to a significant decrease in tau hyperphosphorylation. These studies correlate protection against tau hyperphosphorylation and longevity in a severe model of ALS-like motor impairment and early mortality. NAP is a first-in-class drug candidate/investigation compound providing neuroprotection coupled to inhibition of tau pathology. D-NAP (AL-408) is a pipeline product.
Assuntos
Esclerose Lateral Amiotrófica/prevenção & controle , Oligopeptídeos/uso terapêutico , Tauopatias/tratamento farmacológico , Proteínas tau/metabolismo , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Mutação Puntual , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Recombinantes de Fusão/genética , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Tauopatias/classificação , Tauopatias/genética , Proteínas tau/fisiologiaRESUMO
Tau is a microtubule (MT)-stabilizing protein that is altered in Alzheimer's disease (AD) and other tauopathies. It is hypothesized that the hyperphosphorylated, conformationally altered, and multimeric forms of tau lead to a disruption of MT stability; however, direct evidence is lacking in vivo. In this study, an in vivo stable isotope-mass spectrometric technique was used to measure the turnover, or dynamicity, of MTs in brains of living animals. We demonstrated an age-dependent increase in MT dynamics in two different tau transgenic mouse models, 3xTg and rTg4510. MT hyperdynamicity was dependent on tau expression, since a reduction of transgene expression with doxycycline reversed the MT changes. Treatment of rTg4510 mice with the epothilone, BMS-241027, also restored MT dynamics to baseline levels. In addition, MT stabilization with BMS-241027 had beneficial effects on Morris water maze deficits, tau pathology, and neurodegeneration. Interestingly, pathological and functional benefits of BMS-241027 were observed at doses that only partially reversed MT hyperdynamicity. Together, these data suggest that tau-mediated loss of MT stability may contribute to disease progression and that very low doses of BMS-241027 may be useful in the treatment of AD and other tauopathies.