RESUMO
The solid solutions of Yb14-xRExZnSb11 (RE = Sc, Y, La, Lu, and Gd; 0.2 ≤ x ≤ 0.7) were prepared to probe the intermediate valency of Yb in Yb14ZnSb11. The substitution of Yb with RE3+ elements should reduce or remove the intermediate valency of the remaining Yb ions. Large crystals are grown from Sn-flux, and the structure and magnetic susceptibility are presented. All compounds crystallize in the Ca14AlSb11 structure type and the RE3+ ions show Yb site substitution preferences that correlate with size. Two compositions of Yb14-xYxZnSb11 were investigated [x = 0.38(3), 0.45(3)] by temperature-dependent magnetic susceptibility and the broad feature in magnetic susceptibility measurements at 85 K in pristine Yb14ZnSb11 attributed to valence fluctuation decreases and is absent for x = 0.45(3). In compounds with nonmagnetic RE3+ substitutions (Sc, Y, La, and Lu), temperature-dependent magnetic susceptibility shows a transition from intermediate valency fluctuation toward temperature-independent (Y, La, and Lu) or Curie-Weiss behavior and possibly low temperature heavy Fermion behavior (Sc). In the example of the magnetic rare earth substitution, RE = Gd, the Curie-Weiss-dependent magnetic moment of Gd3+ is consistent with x. Hall resistivity of Yb14-xYxZnSb11 showed that the carrier concentration decreases with x and the signature of the low-T intermediate valence state seen for x = 0 is suppressed for x = 0.38 and gone for x = 0.45.
RESUMO
There is substantial evidence that impairment of peroxisome proliferator-activated receptor (PPAR)-γ-coactivator 1α (PGC-1α) levels and activity play an important role in Huntington's disease (HD) pathogenesis. We tested whether pharmacologic treatment with the pan-PPAR agonist bezafibrate would correct a deficiency of PGC-1α and exert beneficial effects in a transgenic mouse model of HD. We found that administration of bezafibrate in the diet restored levels of PGC-1α, PPARs and downstream genes to levels which occur in wild-type mice. There were significant improvements in phenotype and survival. In the striatum, astrogliosis and neuronal atrophy were attenuated and numbers of mitochondria were increased. Bezafibrate treatment prevented conversion of type I oxidative to type II glycolytic muscle fibers and increased the numbers of muscle mitochondria. Finally, bezafibrate rescued lipid accumulation and apparent vacuolization of brown adipose tissue in the HD mice. These findings provide strong evidence that treatment with bezafibrate exerts neuroprotective effects which may be beneficial in the treatment of HD.
Assuntos
Bezafibrato/farmacologia , Doença de Huntington/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transativadores/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/ultraestrutura , Animais , Bezafibrato/administração & dosagem , Corpo Estriado/patologia , Dieta , Modelos Animais de Doenças , Gliose/patologia , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/ultraestrutura , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/ultraestrutura , Neurônios/patologia , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo , PPAR gama/agonistas , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Taxa de Sobrevida , Fatores de Transcrição , Ativação Transcricional , Vacúolos/ultraestruturaRESUMO
In Alzheimer's disease (AD), oxidative stress is present early and contributes to disease pathogenesis. We previously reported that in Tg19959 transgenic AD mice, partial deficiency of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) exacerbated amyloid pathology. We therefore asked whether MnSOD overexpression would prove beneficial against AD pathogenesis, by studying the offspring of Tg19959 mice crossed with MnSOD-overexpressing mice. At 4 mo of age, there was a 2- to 3-fold increase in MnSOD protein levels in Tg19959-MnSOD mice compared to Tg19959 littermates. Tg19959-MnSOD mice also had a 50% increase in catalase protein levels, a 50% decrease in levels of oxidized protein, and a 33% reduction in cortical plaque burden compared to Tg19959 littermates. Spatial memory was impaired and synaptophysin levels were decreased in Tg19959 mice compared to wild-type littermates, but memory and synaptophysin levels were restored to wild-type levels in Tg19959-MnSOD littermates. These benefits occurred without changes in sodium dodecyl sulfate-soluble or formic acid-soluble Abeta pools or Abeta oligomers in Tg19959-MnSOD mice compared to Tg19959 littermates. These data demonstrate that facilitation of the mitochondrial antioxidant response improves resistance to Abeta, slows plaque formation or increases plaque degradation, and markedly attenuates the phenotype in a transgenic AD mouse model.
Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Transtornos da Memória/prevenção & controle , Superóxido Dismutase/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Catalase/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Estresse Oxidativo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Superóxido Dismutase/genética , Sinaptofisina/metabolismoRESUMO
Coenzyme Q(10) (CoQ(10)) and creatine are promising agents for neuroprotection in neurodegenerative diseases via their effects on improving mitochondrial function and cellular bioenergetics and their properties as antioxidants. We examined whether a combination of CoQ(10) with creatine can exert additive neuroprotective effects in a MPTP mouse model of Parkinson's disease, a 3-NP rat model of Huntington's disease (HD) and the R6/2 transgenic mouse model of HD. The combination of the two agents produced additive neuroprotective effects against dopamine depletion in the striatum and loss of tyrosine hydroxylase neurons in the substantia nigra pars compacta (SNpc) following chronic subcutaneous administration of MPTP. The combination treatment resulted in significant reduction in lipid peroxidation and pathologic alpha-synuclein accumulation in the SNpc neurons of the MPTP-treated mice. We also observed additive neuroprotective effects in reducing striatal lesion volumes produced by chronic subcutaneous administration of 3-NP to rats. The combination treatment showed significant effects on blocking 3-NP-induced impairment of glutathione homeostasis and reducing lipid peroxidation and DNA oxidative damage in the striatum. Lastly, the combination of CoQ(10) and creatine produced additive neuroprotective effects on improving motor performance and extending survival in the transgenic R6/2 HD mice. These findings suggest that combination therapy using CoQ(10) and creatine may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease and HD.
Assuntos
Creatina/uso terapêutico , Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Ubiquinona/análogos & derivados , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , 8-Hidroxi-2'-Desoxiguanosina , Análise de Variância , Animais , Cromatografia Líquida de Alta Pressão/métodos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Quimioterapia Combinada , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Doença de Huntington/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nitrocompostos , Doença de Parkinson/etiologia , Propionatos , Ratos , Ratos Endogâmicos Lew , Tirosina 3-Mono-Oxigenase/metabolismo , Ubiquinona/uso terapêutico , alfa-Sinucleína/metabolismoRESUMO
Oxidative stress is one of the earliest events in the pathogenesis of Alzheimer's disease (AD) and can markedly exacerbate amyloid pathology. Modulation of antioxidant and anti-inflammatory pathways represents an important approach for AD therapy. Synthetic triterpenoids have been found to facilitate antioxidant response and reduce inflammation in several models. We investigated the effect of the triterpenoid, 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic acid-MethylAmide (CDDO-MA) in Tg19959 mice, which carry the human amyloid precursor protein with two mutations. These mice develop memory impairments and amyloid plaques as early as 2-3 months of age. CDDO-MA was provided with chow (800 mg/kg) from 1 to 4 months of age. CDDO-MA significantly improved spatial memory retention and reduced plaque burden, Abeta42 levels, microgliosis, and oxidative stress in Tg19959 mice.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , Memória/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Placa Amiloide/efeitos dos fármacos , Triterpenos/uso terapêutico , Doença de Alzheimer/patologia , Animais , Cricetinae , Feminino , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Placa Amiloide/patologia , Triterpenos/farmacologiaRESUMO
The activity of a key mitochondrial tricarboxylic acid cycle enzyme, alpha-ketoglutarate dehydrogenase complex (KGDHC), declines in many neurodegenerative diseases. KGDHC consists of three subunits. The dihydrolipoyl succinyl transferase (DLST) component is unique to KGDHC. DLST(+/-) mice showed reduced mRNA and protein levels and decreased brain mitochondrial KGDHC activity. Neurotoxic effects of mitochondrial toxins were exacerbated in DLST(+/-) mice. MPTP produced a significantly greater reduction of striatal dopamine and tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta of DLST(+/-) mice. DLST deficiency enhanced the severity of lipid peroxidation in the substantia nigra after MPTP treatment. Striatal lesions induced by either malonate or 3-nitropropionic acid (3-NP) were significantly larger in DLST(+/-) mice than in wildtype controls. DLST deficiency enhanced the 3-NP inhibition of mitochondria enzymes, and 3-NP induced protein and DNA oxidations. These observations support the hypothesis that reductions in KGDHC may impair the adaptability of the brain and contribute to the pathogenesis of neurodegenerative diseases.
Assuntos
Predisposição Genética para Doença , Complexo Cetoglutarato Desidrogenase/deficiência , Complexo Cetoglutarato Desidrogenase/genética , Mitocôndrias/enzimologia , Mitocôndrias/genética , Neurotoxinas/toxicidade , Animais , Encéfalo/enzimologia , Coenzima A-Transferases/deficiência , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Metabolismo Energético/genética , Ativação Enzimática/genética , Feminino , Isoenzimas/deficiência , Isoenzimas/genética , Isoenzimas/metabolismo , Complexo Cetoglutarato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genéticaRESUMO
Yb14ZnSb11 has been of interest for its intermediate valency and possible Kondo designation. It is one of the few transition metal compounds of the Ca14AlSb11 structure type that show metallic behavior. While the solid solution of Yb14Mn1-xZnxSb11 shows an improvement in the high temperature figure of merit of about 10% over Yb14MnSb11, there has been no investigation of optimization of the Zn containing phase. In an effort to expand the possible high temperature p-type thermoelectric materials with this structure type, the rare earth (RE) containing solid solution Yb14-xRExZnSb11 (RE = Y, La) was investigated. The substitution of a small amount of 3+ rare earth (RE) for Yb2+ was employed as a means of optimizing Yb14MnSb11 for use as a thermoelectric material. Yb14ZnSb11 is considered an intermediate valence Kondo system where some percentage of the Yb is formally 3+ and undergoes a reduction to 2+ at ~85 K. The substitution of a 3+ RE element could either replace the Yb3+ or add to the total amount of 3+ RE and provides changes to the electronic states. RE = Y, La were chosen as they represent the two extremes in size as substitutions for Yb: a similar and much larger size RE, respectively, compared with Yb3+. The composition x = 0.5 was chosen as that is the typical amount of RE element that can be substituted into Yb14MnSb11. These two new RE containing compositions show a significant improvement in Seebeck while decreasing thermal conductivity. The addition of RE increases the melting point of Yb14ZnSb11 so that the transport data from 300 K to 1275 K can be collected. The figure of merit is increased five times over that of Yb14ZnSb11 and provides a zT ~0.7 at 1275 K.
RESUMO
Coenzyme Q10 (CoQ10) is a promising agent for neuroprotection in neurodegenerative diseases. We tested the effects of various doses of two formulations of CoQ10 in food and found that administration in the diet resulted in significant protection against loss of dopamine (DA), which was accompanied by a marked increase in plasma concentrations of CoQ10. We further investigated the neuroprotective effects of CoQ10, reduced CoQ10 (ubiquinol), and CoQ10 emulsions in the (MPTP) model of Parkinson's disease (PD). We found neuroprotection against MPTP induced loss of DA using both CoQ10, and reduced CoQ10, which produced the largest increases in plasma concentrations. Lastly, we administered CoQ10 in the diet to test its effects in a chronic MPTP model induced by administration of MPTP by Alzet pump for 1 month. We found neuroprotective effects against DA depletion, loss of tyrosine hydroxylase neurons and induction of alpha-synuclein inclusions in the substantia nigra pars compacta. The finding that CoQ10 is effective in a chronic dosing model of MPTP toxicity, is of particular interest, as this may be more relevant to PD. These results provide further evidence that administration of CoQ10 is a promising therapeutic strategy for the treatment of PD.
Assuntos
Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Ubiquinona/análogos & derivados , Vitaminas/farmacologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Ração Animal , Animais , Coenzimas/metabolismo , Coenzimas/farmacologia , Modelos Animais de Doenças , Dopamina/fisiologia , Interações Medicamentosas , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/farmacologia , Oxirredução , Transtornos Parkinsonianos/patologia , Ubiquinona/metabolismo , Ubiquinona/farmacologia , Vitaminas/metabolismoRESUMO
Large crystals of Yb14MgSb11 were grown through a Sn flux method. Magnetic susceptibility measurements yield an effective magnetic moment of 3.4(1) µB, revealing the presence of both divalent and trivalent Yb in Yb14MgSb11. Previously assumed to only contain Yb2+ as in Yb14MnSb11, the mixed valency demonstrates that Yb14MgSb11 is a Zintl phase.
RESUMO
ALS is a devastating neurodegenerative disorder for which no effective treatment exists. The precise molecular mechanisms underlying the selective degeneration of motor neurons are still unknown. A motor neuron specific apoptotic pathway involving Fas and NO has been discovered. Motor neurons from ALS-mice have an increased sensitivity to Fas-induced cell death via this pathway. In this study we therefore crossed G93A-SOD1 overexpressing ALS mice with Fas ligand (FasL) mutant (gld) mice to investigate whether the reduced Fas signaling could have beneficial effects on motor neuron death. G93A-SOD1 mutant mice with a homozygous FasL mutant showed a modest but statistically significant extension of survival, and reduced loss of motor neurons. These results indicate that motor neuron apoptosis triggered by Fas is relevant in ALS pathogenesis.
Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/fisiopatologia , Proteína Ligante Fas/metabolismo , Superóxido Dismutase/genética , Fatores Etários , Esclerose Lateral Amiotrófica/mortalidade , Animais , Comportamento Animal , Contagem de Células/métodos , Modelos Animais de Doenças , Proteína Ligante Fas/fisiologia , Imuno-Histoquímica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Neurônios Motores/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Probabilidade , Medula Espinal/patologia , Superóxido Dismutase/metabolismo , Análise de Sobrevida , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMO
AIMS: Mitochondrial damage due to Ca(2+) overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca(2+) threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. RESULTS: We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms. INNOVATION: Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. CONCLUSION: Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity.
Assuntos
Ciclofilinas/genética , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , 1-Metil-4-fenilpiridínio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Astrócitos/efeitos dos fármacos , Gânglios da Base/metabolismo , Cálcio/metabolismo , Morte Celular/genética , Peptidil-Prolil Isomerase F , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Intoxicação por MPTP/genética , Intoxicação por MPTP/patologia , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Mitocôndrias/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismoRESUMO
In addition to mitochondria, NADPH oxidase (NOX) is a source of oxidative stress, which can induce oxidative damage in Alzheimer's disease (AD). For this reason, several groups have investigated the effect of its inhibition. In AD mice, NADPH oxidase 2 (NOX2) deficiency improved behavior and cerebrovascular function, and reduced oxidative stress. In our study, we administered the NOX inhibitor apocynin to Tg19959 mice, and found that it did not improve cognitive and synaptic deficits, and did not decrease amyloid deposition, microgliosis and hyperphosphorylated tau. However, apocynin reduced carbonyl levels in the cerebral cortex but not the hippocampus, which may have not been sufficient to ameliorate symptoms. Also, the reduction of NOX-mediated oxidative stress may not be sufficient to prevent AD, since other sources of reactive oxygen species such as mitochondria may be more important.
Assuntos
Acetofenonas/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Antioxidantes/farmacologia , Doença de Alzheimer/psicologia , Animais , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genéticaRESUMO
Increased oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD). A large body of evidence suggests that mitochondrial dysfunction and increased reactive oxygen species occur prior to amyloid-ß (Aß) deposition. Coenzyme Q10 (CoQ10), a component of the mitochondrial electron transport chain, is well characterized as a neuroprotective antioxidant in animal models and human trials of Huntington's disease and Parkinson's disease, and reduces plaque burden in AßPP/PS1 mice. We now show that CoQ10 reduces oxidative stress and amyloid pathology and improves behavioral performance in the Tg19959 mouse model of AD. CoQ10 treatment decreased brain levels of protein carbonyls, a marker of oxidative stress. CoQ10 treatment resulted in decreased plaque area and number in hippocampus and in overlying cortex immunostained with an Aß42-specific antibody. Brain Aß42 levels were also decreased by CoQ10 supplementation. Levels of amyloid-ß protein precursor (AßPP) ß-carboxyterminal fragments were decreased. Importantly, CoQ10-treated mice showed improved cognitive performance during Morris water maze testing. Our results show decreased pathology and improved behavior in transgenic AD mice treated with the naturally occurring antioxidant compound CoQ10. CoQ10 is well tolerated in humans and may be promising for therapeutic trials in AD.
Assuntos
Doença de Alzheimer/dietoterapia , Peptídeos beta-Amiloides/metabolismo , Sintomas Comportamentais/tratamento farmacológico , Ubiquinona/análogos & derivados , Vitaminas/uso terapêutico , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Amiloide/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sintomas Comportamentais/etiologia , Transtornos Cognitivos/dietoterapia , Transtornos Cognitivos/etiologia , Ensaio de Imunoadsorção Enzimática , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Destreza Motora/efeitos dos fármacos , Destreza Motora/fisiologia , Mutação/genética , Neuroblastoma/patologia , Fragmentos de Peptídeos/metabolismo , Carbonilação Proteica/efeitos dos fármacos , Carbonilação Proteica/genética , Fatores de Tempo , Ubiquinona/uso terapêuticoRESUMO
Oxidative damage, neuroinflammation, and mitochondrial dysfunction contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), and these pathologic processes are tightly regulated by the Nrf2/ARE (NF-E2-related factor 2/antioxidant response element) signaling program. Therefore, modulation of the Nrf2/ARE pathway is an attractive therapeutic target for neurodegenerative diseases such as ALS. We examined two triterpenoids, CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) ethylamide and CDDO trifluoroethylamide (CDDO-TFEA), that potently activate Nrf2/ARE in a cell culture model of ALS and in the G93A SOD1 mouse model of ALS. Treatment of NSC-34 cells stably expressing mutant G93A SOD1 with CDDO-TFEA upregulated Nrf2 expression and resulted in translocation of Nrf2 into the nucleus. Western blot analysis showed an increase in the expression of Nrf2/ARE-regulated proteins. When treatment started at a "presymptomatic age" of 30days, both of these compounds significantly attenuated weight loss, enhanced motor performance, and extended the survival of G93A SOD1 mice. Treatment started at a "symptomatic age," as assessed by impaired motor performance, was neuroprotective and slowed disease progression. These findings provide further evidence that compounds that activate the Nrf2/ARE signaling pathway may be useful in the treatment of ALS.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/análogos & derivados , Proteínas/metabolismo , Animais , Linhagem Celular , Núcleo Celular/enzimologia , Modelos Animais de Doenças , Inflamação/metabolismo , Complexo Principal de Histocompatibilidade/genética , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Doenças Neurodegenerativas/genética , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Estresse Oxidativo , Proteínas/genética , RNA Mensageiro/biossíntese , Transdução de Sinais , Superóxido Dismutase/biossíntese , Superóxido Dismutase/genética , Proteínas de Transporte VesicularRESUMO
Oxidative stress is a prominent feature of Huntington's disease (HD) due to mitochondrial dysfunction and the ensuing overproduction of reactive oxygen species (ROS). This phenomenon ultimately contributes to cognitive and motor impairment, as well as brain pathology, especially in the striatum. Targeting the transcription of the endogenous antioxidant machinery could be a promising therapeutic approach. The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an important pathway involved in antioxidant and anti-inflammatory responses. Synthetic triterpenoids, which are derived from 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic acid (CDDO) activate the Nrf2/ARE pathway and reduce oxidative stress in animal models of neurodegenerative diseases. We investigated the effects of CDDO-ethyl amide (CDDO-EA) and CDDO-trifluoroethyl amide (CDDO-TFEA) in N171-82Q mice, a transgenic mouse model of HD. CDDO-EA or CDDO-TFEA were administered in the diet at various concentrations, starting at 30days of age. CDDO-EA and CDDO-TFEA upregulated Nrf2/ARE induced genes in the brain and peripheral tissues, reduced oxidative stress, improved motor impairment and increased longevity. They also rescued striatal atrophy in the brain and vacuolation in the brown adipose tissue. Therefore compounds targeting the Nrf2/ARE pathway show great promise for the treatment of HD.
Assuntos
Encéfalo/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/análogos & derivados , Animais , Antioxidantes/metabolismo , Sintomas Comportamentais/prevenção & controle , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Humanos , Doença de Huntington/complicações , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Camundongos , Camundongos Transgênicos , Atividade Motora , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/química , Transdução de Sinais/imunologia , Ativação Transcricional/efeitos dos fármacosRESUMO
Sirtuins are NAD-dependent deacetylases that regulate important biologic processes including transcription, cell survival and metabolism. Activation of SIRT1, a mammalian sirtuin, extends longevity and increases neuronal survival. An important substrate of SIRT1 is peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha), a principal regulator of energy metabolism, whose function is significantly impaired in Huntington's disease (HD). We studied the effects of a pharmacological preparation of the SIRT1 activator resveratrol (SRT501-M), in the N171-82Q transgenic mouse model of HD. We analyzed motor performance, survival, central and peripheral pathology and levels of PGC-1alpha expression. Administration of SRT501-M increased expression of PGC-1alpha, as well as its downstream targets, nuclear respiratory factor-1 (NRF-1) and uncoupling protein-1 (UCP-1) in brown adipose tissue (BAT), but there was no effect on PGC-1alpha, NRF-1 or the mitochondrial transcription factor (Tfam) in the striatum. SRT501-M administration also reduced BAT vacuolation and decreased elevated blood glucose levels. However, there was no significant improvement in weight loss, motor performance, survival and striatal atrophy. Activation of the PGC-1alpha signaling pathway via resveratrol-induced activation of SIRT1, therefore, is an effective therapy in BAT, but not in the central nervous system of HD transgenic mice.
Assuntos
Modelos Animais de Doenças , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Doença de Huntington/genética , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Resveratrol , Sirtuína 1/biossíntese , Sirtuína 1/deficiência , Sirtuína 1/fisiologia , Transativadores/biossíntese , Transativadores/deficiência , Transativadores/fisiologia , Fatores de Transcrição , Resultado do TratamentoRESUMO
A large body of evidence suggests the importance of inflammation and oxidative or nitrosative stress in Alzheimer's disease (AD) pathogenesis. Inflammatory stimuli upregulate transcription of inducible nitric oxide synthase (iNOS), which can lead to the production of nitric oxide and other reactive nitrogen species. We previously found that genetic deletion of iNOS in mice overexpressing the amyloid precursor protein (APP) and presenilin-1 (PS1) reduced mortality, nitrosative stress, amyloid plaque burden, microgliosis, astrocytosis, and peri-plaque tau phosphorylation. We therefore examined the effects of N6-(1-iminoethyl)-L-lysine (L-NIL), a pharmacological iNOS inhibitor, or d-NIL, its enantiomeric control, in a transgenic mouse model of amyloid deposition. Tg19959 mice carry human APP with two mutations and develop amyloid plaques and memory impairment starting at 3-4 months of age. Mice were given L-NIL or D-NIL in the drinking water from 1 month of age and assessed behaviorally and histopathologically at 8 months of age. We found that L-NIL administration reduced disinhibition in the elevated plus maze, improved spatial memory performance in the Morris water maze, and decreased cortical amyloid deposition as well as microglial activation in 8-month-old Tg19959 mice. These findings are consistent with previous reports demonstrating that iNOS inhibition ameliorates AD pathogenesis.
Assuntos
Amiloide/metabolismo , Lisina/análogos & derivados , Memória/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Imuno-Histoquímica , Lisina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Fosforilação , Proteínas tau/metabolismoRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which is currently untreatable. Inflammation plays a major role in the pathogenesis of motor neuron death in ALS. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL) are amongst the most important mediators of neuro-inflammation. We have previously demonstrated that elevation of these pro-inflammatory cytokines occurs in both ALS transgenic mice and in human ALS postmortem spinal cord tissues. Lenalidomide is a potent immunomodulatory agent, with the ability to down-regulate pro-inflammatory cytokines and up-regulate anti-inflammatory cytokines. We previously reported the neuroprotective effects of lenalidomide, when treatment was started 2 months prior to onset of disease in the G93A SOD1 transgenic mouse model of ALS. Since in ALS patients, treatment can only begin after the appearance of symptoms, we sought to determine the efficacy of lenalidomide administration starting at symptom onset in the G93A SOD1 mice. We found that lenalidomide treatment extended the survival interval from the age of onset by 18.3 days ( approximately 45%). Additionally, lenalidomide treatment improved rotarod performance, reduced weight loss, and attenuated neuronal cell death in the lumbar spinal cord. Qualitative histological analysis showed that lenalidomide treatment modestly reduced the expression of the proinflammatory cytokines Fas Ligand, IL-1beta, TNF-alpha and CD40 ligand. RNA protection Assay (RPA) on a pre-selected panel of cytokines showed that proinflammatory cytokines were reduced and anti-inflammatory cytokines were up-regulated. These data encourage further clinical evaluation of lenalidomide as therapeutic strategy to block or slow disease progression in human ALS patients.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Talidomida/análogos & derivados , Esclerose Lateral Amiotrófica/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Peso Corporal/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Coxeadura Animal/tratamento farmacológico , Coxeadura Animal/fisiopatologia , Coxeadura Animal/prevenção & controle , Lenalidomida , Camundongos , Camundongos Transgênicos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/imunologia , Neurônios Motores/patologia , Degeneração Neural/tratamento farmacológico , Degeneração Neural/imunologia , Degeneração Neural/prevenção & controle , Medula Espinal/fisiopatologia , Taxa de Sobrevida , Talidomida/farmacologia , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes. CDDO-MA blocked t-butylhydroperoxide-induced production of reactive oxygen species (ROS) by activation of ARE genes only in wild type, but not Nrf2 knockout mouse embryonic fibroblasts. Oral administration of CDDO-MA resulted in significant protection against MPTP-induced nigrostriatal dopaminergic neurodegeneration, pathological alpha-synuclein accumulation and oxidative damage in mice. Additionally, CDDO-MA treatment in rats produced significant rescue against striatal lesions caused by the neurotoxin 3-NP, and associated increases in the oxidative damage markers malondialdehyde, F(2)-Isoprostanes, 8-hydroxy-2-deoxyguanosine, 3-nitrotyrosine, and impaired glutathione homeostasis. Our results indicate that the CDDO-MA renders its neuroprotective effects through its potent activation of the Nrf2/ARE pathway, and suggest that triterpenoids may be beneficial for the treatment of neurodegenerative diseases like Parkinson's disease and Huntington's disease.
Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/análogos & derivados , Transcrição Gênica , Animais , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Doenças Neurodegenerativas/patologia , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/farmacologia , Ratos , Ratos Endogâmicos Lew , Terpenos/metabolismoRESUMO
Whether increased levels of matrix metalloproteinases (MMPs) correspond to a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) needs to be determined and it is actively being pursued. Here we present evidence suggesting that MMP-9 contributes to the motor neuron cell death in ALS. We examined the role of MMP-9 in a mouse model of familial ALS and found that lack of MMP-9 increased survival (31%) in G93A SOD1 mice. Also, MMP-9 deficiency in G93A mice significantly attenuated neuronal loss, and reduced neuronal TNF-alpha and FasL immunoreactivities in the lumbar spinal cord. These findings suggest that MMP-9 is an important player in the pathogenesis of ALS. Our data suggest that the mechanism for MMP-9 neurotoxicity in ALS may be by upregulating neuronal TNF-alpha and FasL expression and activation. This study provides new mechanism and suggests that MMP inhibitors may offer a new therapeutic strategy for ALS.