RESUMO
Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase occur in Alzheimer's disease (AD). Thiamine deficiency exacerbates amyloid beta (Aß) deposition, tau hyperphosphorylation and oxidative stress. Benfotiamine (BFT) rescued cognitive deficits and reduced Aß burden in amyloid precursor protein (APP)/PS1 mice. In this study, we examined whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) in the P301S mouse model of tauopathy. Chronic dietary treatment with BFT increased lifespan, improved behavior, reduced glycated tau, decreased NFTs and prevented death of motor neurons. BFT administration significantly ameliorated mitochondrial dysfunction and attenuated oxidative damage and inflammation. We found that BFT and its metabolites (but not thiamine) trigger the expression of Nrf2/antioxidant response element (ARE)-dependent genes in mouse brain as well as in wild-type but not Nrf2-deficient fibroblasts. Active metabolites were more potent in activating the Nrf2 target genes than the parent molecule BFT. Docking studies showed that BFT and its metabolites (but not thiamine) bind to Keap1 with high affinity. These findings demonstrate that BFT activates the Nrf2/ARE pathway and is a promising therapeutic agent for the treatment of diseases with tau pathology, such as AD, frontotemporal dementia and progressive supranuclear palsy.
Assuntos
Elementos de Resposta Antioxidante/genética , Fator 2 Relacionado a NF-E2/genética , Agregação Patológica de Proteínas/tratamento farmacológico , Tauopatias/tratamento farmacológico , Tiamina/análogos & derivados , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Camundongos , Camundongos Transgênicos , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Transdução de Sinais/efeitos dos fármacos , Tauopatias/genética , Tauopatias/fisiopatologia , Tiamina/administração & dosagem , Proteínas tau/genéticaRESUMO
Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function.
Assuntos
Desacetilase 6 de Histona/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Hidroxilaminas/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologiaRESUMO
6-Hydroxydopamine (6-OHDA)- and 1-methyl-4-phenylpyridinium (MPP(+))-induced hemi-parkinsonism was investigated in relation to the severity of the disorder in terms of behavioral disability and nigral neuronal loss and recovery regarding the number of stem cell-derived neurons transplanted in the striatum. Intra-median forebrain bundle infusion of the parkinsonian neurotoxins and intra-striatal transplantation of differentiated embryonic stem cells (ESCs) were carried out by rat brain stereotaxic surgery. The severity of the disease was determined using the number of amphetamine- or apomorphine-induced rotations, striatal dopamine levels as estimated by high-performance liquid chromatography (HPLC)-electrochemistry, and the number of surviving tyrosine hydroxylase immunoreactive dopaminergic neurons in the substantia nigra pars compacta. Rats that received unilateral infusion of 6-OHDA or MPP(+) responded with dose-dependent, unilateral bias in turning behavior when amphetamine or apomorphine was administered. Rotational asymmetry in both models correlated significantly well with the loss in the number of nigral dopaminergic neurons and striatal dopamine depletion. Transplantation of 2×10(5) differentiated murine ESCs revealed remarkably similar kinds of recovery in both animal models. The survival of the grafted dopaminergic cells in the striatum was better in animals with low-severity parkinsonism, but poor in the animals with severe parkinsonism. Amphetamine-induced rotational recovery correlated positively with an increasing number of cells transplanted in animals with uniform nigral neuronal lesion. These results suggest that disease severity is an important factor for determining the number of cells to be transplanted in parkinsonian rats for desirable recovery, which may be true in clinical conditions too.
