RESUMO
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by deposition of amyloid plaques and disruption of neural circuitry, leading to cognitive decline. Animal models of AD deposit senile plaques and exhibit structural and functional deficits in neurons and neural networks. An effective treatment would prevent or restore these deficits, including calcium dyshomeostasis observed with in-vivo imaging. METHODS: We examined the effects of DA-9803, a multimodal botanical drug, in 5XFAD and APP/PS1 transgenic mice which underwent daily oral treatment with 30 or 100 mg/kg DA-9803 or vehicle alone. Behavioral testing and longitudinal imaging of amyloid deposits and intracellular calcium in neurons with multiphoton microscopy was performed. RESULTS: Chronic administration of DA-9803 restored behavioral deficits in 5XFAD mice and reduced amyloid-ß levels. DA-9803 also prevented progressive amyloid plaque deposition in APP/PS1 mice. Elevated calcium, detected in a subset of neurons before the treatment, was restored and served as a functional indicator of treatment efficacy in addition to the behavioral readout. In contrast, mice treated with vehicle alone continued to progressively accumulate amyloid plaques and calcium overload. CONCLUSIONS: In summary, treatment with DA-9803 prevented structural and functional outcome measures in mouse models of AD. Thus, DA-9803 shows promise as a novel therapeutic approach for Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Administração Oral , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cálcio/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Estudos Longitudinais , Masculino , Camundongos Transgênicos , Fitoterapia , Placa Amiloide/tratamento farmacológico , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , Distribuição AleatóriaRESUMO
Senile plaques are a major pathological hallmark of Alzheimer's disease (AD). Compelling evidence suggests that senile plaques lead to structural alterations of neuronal processes and that local toxicity may be mediated by increased oxidative stress. Anti-oxidant therapy can alleviate the neuronal abnormalities in APP mice, but the time-course of this beneficial effect is unknown. We used multiphoton microscopy to assess in vivo the characteristics of antioxidant treatment on senile plaques and neurites in AD model mice (APPswe/PS1dE9). We observed that α-phenyl-N-tert-butyl nitrone (PBN), Ginkgo biloba extract (EGb 761) and Trolox had no effect on the size of existing senile plaques. However, all anti-oxidants had a straightening effect on curved neurites. This effect was detected as soon as 4 days after commencing the treatment, and was maintained after 1 month of daily treatment, with no further increase in the effect. The straightening of neurites persisted 15 days after stopping the treatment. These data indicate that neuronal plasticity is fast and still active in adult animals, and suggest that amelioration of the neuritic distortions associated with senile plaques with antioxidants is both rapid and long lasting.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Presenilina-1/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Animais , Cromanos/farmacologia , Óxidos N-Cíclicos/farmacologia , Modelos Animais de Doenças , Sequestradores de Radicais Livres/antagonistas & inibidores , Sequestradores de Radicais Livres/farmacologia , Ginkgo biloba , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/genética , Extratos Vegetais/farmacologia , Placa Amiloide/genética , Presenilina-1/antagonistas & inibidores , Fatores de TempoRESUMO
Electroclinical uncoupling of neonatal seizures refers to electrographic seizure activity that is not clinically manifest. Uncoupling increases after treatment with Phenobarbital, which enhances the GABA(A) receptor (GABA(A)R) conductance. The effects of GABA(A)R activation depend on the intracellular Cl(-) concentration ([Cl(-)](i)) that is determined by the inward Cl(-) transporter NKCC1 and the outward Cl(-) transporter KCC2. Differential maturation of Cl(-) transport observed in cortical versus subcortical regions should alter the efficacy of GABA-mediated inhibition. In perinatal rat pups, most thalamic neurons maintained low [Cl(-)](i) and were inhibited by GABA. Phenobarbital suppressed thalamic seizure activity. Most neocortical neurons maintained higher [Cl(-)](i), and were excited by GABA(A)R activation. Phenobarbital had insignificant anticonvulsant responses in the neocortex until NKCC1 was blocked. Regional differences in the ontogeny of Cl(-) transport may thus explain why seizure activity in the cortex is not suppressed by anticonvulsants that block the transmission of seizure activity through subcortical networks.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Neocórtex/fisiopatologia , Neurônios/fisiologia , Convulsões/fisiopatologia , Tálamo/fisiopatologia , Ácido gama-Aminobutírico/metabolismo , Tonsila do Cerebelo/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Anticonvulsivantes/farmacologia , Bumetanida/farmacologia , Cloretos/metabolismo , Feminino , Técnicas In Vitro , Masculino , Neocórtex/efeitos dos fármacos , Neocórtex/crescimento & desenvolvimento , Fenobarbital/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Caracteres Sexuais , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Membro 2 da Família 12 de Carreador de Soluto , Transmissão Sináptica , Tálamo/efeitos dos fármacos , Tálamo/crescimento & desenvolvimentoRESUMO
Leukotrienes (LTs) are signaling molecules derived from arachidonic acid that initiate and amplify innate and adaptive immunity. In turn, how their synthesis is organized on the nuclear envelope of myeloid cells in response to extracellular signals is not understood. We define the supramolecular architecture of LT synthesis by identifying the activation-dependent assembly of novel multiprotein complexes on the outer and inner nuclear membranes of mast cells. These complexes are centered on the integral membrane protein 5-Lipoxygenase-Activating Protein, which we identify as a scaffold protein for 5-Lipoxygenase, the initial enzyme of LT synthesis. We also identify these complexes in mouse neutrophils isolated from inflamed joints. Our studies reveal the macromolecular organization of LT synthesis.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Proteínas de Transporte/metabolismo , Leucotrienos/biossíntese , Proteínas de Membrana/metabolismo , Complexos Multiproteicos/análise , Membrana Nuclear/metabolismo , Proteínas Ativadoras de 5-Lipoxigenase , Animais , Artrite/enzimologia , Artrite/metabolismo , Proteínas de Membrana/análise , Camundongos , Células Mieloides/química , Células Mieloides/metabolismo , Neutrófilos/química , Neutrófilos/metabolismo , Membrana Nuclear/químicaRESUMO
Alzheimer disease (AD) is characterized both by senile plaques and neurodegeneration, although the details of the relationship between the 2 are not well understood. We postulated that oxidative stress resulting from senile plaques may mediate plaques' effects on local neuronal processes. Using multiphoton microscopy, we directly demonstrate the generation of reactive oxygen species by senile plaques. After screening of several natural antioxidants ex vivo, we assessed in vivo the effect of 2 orally administered antioxidants in APPswe/PS1d9 transgenic mice. Both Ginkgo biloba extract and vitamin E reduced the oxidative stress resulting from senile plaques in vivo as monitored with intracranial imaging. Both treatments also lead to a progressive reversal of the structural changes in dystrophic neurites associated with senile plaques. These results suggest a causal relationship between plaque-associated oxidative stress and neuritic alterations and demonstrate for the first time that the focal neurotoxicity associated with the senile plaques of AD is partially reversible with antioxidant therapies. The quantitative ex vivo screen combined with in vivo monitoring of efficacy should lead to more effective clinical therapies for the prevention of oxidative stress and neurotoxicity in AD.