RESUMO
DJ-1 is an oxidative stress sensor that localizes to the mitochondria when the cell is exposed to oxidative stress. DJ-1 mutations that result in gene deficiency are linked to increased risk of Parkinson's disease (PD). Activation of microglial stress conditions that are linked to PD may result in neuronal death. We postulated that DJ-1 deficiency may increase microglial neurotoxicity. We found that down-regulation of DJ-1 in microglia using an shRNA approach increased cell sensitivity to dopamine as measured by secreted pro-inflammatory cytokines such as IL-1ß and IL-6. Furthermore, we discovered that DJ-1-deficient microglia had increased monoamine oxidase activity that resulted in elevation of intracellular reactive oxygen species and nitric oxide leading to increased dopaminergic neurotoxicity. Rasagaline, a monoamine oxidase inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and significantly reduced neurotoxicity. Moreover, we discovered that DJ-1-deficient microglia have reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), previously suggested as a risk factor for pro-inflammation in neurodegenerative diseases. Further studies of DJ-1-mediated cellular pathways in microglia may contribute useful insights into the development of PD providing future avenues for therapeutic intervention
Assuntos
Indanos/farmacologia , Microglia/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas Oncogênicas/deficiência , Animais , Western Blotting , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Dopamina/toxicidade , Ensaio de Imunoadsorção Enzimática , Inflamação/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Neurotransmissores/toxicidade , Peroxirredoxinas , Fagocitose/efeitos dos fármacos , Fenótipo , Proteína Desglicase DJ-1 , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies. Thus, we have recently synthesized multifunctional non-toxic, brain permeable iron chelating compounds, M30 and HLA20, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we examined the hepatic regulatory effects of these novel compounds using two experimental approaches: chelation activity and glucose metabolism parameters. The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells. In electron microscopy analysis, M30 was shown to reduce the electron-dense deposits of siderosomes by ~30 %, as well as down-regulate cytosolic ferritin particles observed in iron-overloaded cells. In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin(-/-)). The results clearly indicate that the novel multifunctional drugs, especially M30, display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters. Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism, including neurological diseases.
Assuntos
Glucose/metabolismo , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Benzofuranos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Compostos Férricos/farmacologia , Ferritinas/metabolismo , Teste de Tolerância a Glucose , Humanos , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Quelantes de Ferro/química , Leptina/deficiência , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/ultraestrutura , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Fármacos Neuroprotetores/química , Piperazinas/química , Piperazinas/farmacologia , Compostos de Amônio Quaternário/farmacologia , QuinolinasRESUMO
Microarray-derived transcriptomic studies in human substantia nigra pars compacta (SNpc) samples from sporadic Parkinson's disease (SPD) cases have opened an avenue to concentrate on potential gene intersections or cross-talks along the dopaminergic (DAergic) neurodegenerative cascade in SPD. One emerging gene candidate identified by our group was SKP1A (p19, S-phase kinase-associated protein 1A), found significantly decreased in the SNpc. It is part of the SCF (Skp1, Cullin 1, F-box protein) complex, the largest class of sophisticated ubiquitin-proteasome/E3 ligases, and can directly interact with Fbxo7, a gene defective in PARK15-linked PD. In vitro target validation by viral-mediated RNA interference revealed that the deficiency of Skp1 in a mouse SN-derived DAergic neuronal cell line potentiated the damage caused by exogenous insults implicated in PD pathology and caused the death of neurons undergoing differentiation, which developed Lewy body-like, α-synuclein-positive inclusions preceding cell death. Furthermore, recent animal studies show that site-directed intranigral stereotaxic injections of lentiviruses targeting SKP1A induce pathological and behavioral deficits in mice, supporting a significant role of Skp1 in SN DAergic neuronal survival in SPD. Thus, strategies aimed at increasing the activity or content of Skp1 may represent a novel therapeutic approach that has the potential to treat PD.
Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Doença de Parkinson , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Substância Negra/enzimologia , Animais , Neurônios Dopaminérgicos/fisiologia , Humanos , Doença de Parkinson/enzimologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA/fisiologia , Substância Negra/patologiaRESUMO
The aim of this study was to develop a new model of sporadic Parkinson disease (PD) based on silencing of the SKP1A gene, a component of the ubiquitin-proteasome/E3 ligase complex, Skp1, Cullin 1, F-box protein, which was found to be highly decreased in the substantia nigra of sporadic PD patients. Initially, an embryonic mouse substantia nigra-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses encoding the murine transcript of the SKP1A gene or with scrambled vector. SKP1A silencing resulted in increased susceptibility to neuronal damages induced by the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium ion and serum starvation, in parallel with a decline in the expression of the dopaminergic markers, dopamine transporter and vesicular monoamine transporter-2. SKP1A-deficient cells presented a delay in completion of the cell cycle and the inability to arrest at the G(0)/G(1) phase when induced to differentiate. Instead, the cells progressed through S phase, developing rounded aggregates with characteristics of aggresomes including immunoreactivity for gamma-tubulin, alpha-synuclein, ubiquitin, tyrosine hydroxylase, Hsc-70 (70-kDa heat shock cognate protein), and proteasome subunit, and culminating in a lethal phenotype. Conversely, stably enforced expression of wild type SKP1A duplicated the survival index of naïve SN4741 cells under proteasomal inhibition injury, suggesting a new structural role of SKP1 in dopaminergic neuronal function, besides its E3 ligase activity. These results link, for the first time, SKP1 to dopamine neuronal function and survival, suggesting an essential role in sporadic PD. In summary, this new model has reproduced to a significant extent the molecular alterations described in sporadic PD at the cellular level, implicating Skp1 as a potential modifier in sporadic PD neurodegeneration.
Assuntos
Inativação Gênica , Doença de Parkinson/genética , Complexo de Endopeptidases do Proteassoma/química , Proteínas Ligases SKP Culina F-Box/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/química , Animais , Linhagem Celular , Sobrevivência Celular , Proteínas de Choque Térmico HSC70/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Neurotoxinas/química , Doença de Parkinson/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Quinases Associadas a Fase S , Proteínas Ligases SKP Culina F-Box/fisiologiaRESUMO
Increasing evidence suggests that oxidative stress (OS)-induced pancreatic beta-cell impairments is involved in diabetes and diabetic complications. Our group has recently synthesized two multifunctional nontoxic, lipophilic, iron-chelating drugs, 5-{N-methyl-N-propargylaminomethyl}-8-hydroxyquinoline (M30) and 5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline (HLA20), for the treatment of various OS-mediated pathogeneses. These compounds contain the N-propargylamine cytoprotective moiety of the antiparkinsonian drug rasagiline (Azilect) and the iron-complexing component 8-hydroxyquinoline. The aim of this research was to evaluate the protective effect of the multifunctional iron-chelating drugs on rat insulin-producing pancreatic beta-cells (INS-1E and RINm) against OS-induced cytotoxicity. We found that M30 and HLA20 markedly and dose-dependently inhibited H(2)O(2)-induced cytotoxicity, associated with decreased intracellular reactive oxygen species formation and increased catalase activity. In accordance, the catalase inhibitor 3-amino-1,2,4-triazol blocked the protective action of M30 against H(2)O(2)-induced damage. Both compounds significantly increased the levels of the iron-responsive protein transferrin receptor indicating their iron-chelating effect. Further mechanistic studies showed that M30 and HLA20 attenuated H(2)O(2)-induced mitochondrial membrane potential loss, decreased the release of cytochrome c into the cytoplasm, and inhibited the activation of caspase-3, suggesting that these drugs may produce cytoprotective effects via the preservation of mitochondrial function. These results indicate that the novel drugs, M30 and HLA20 display significant cytoprotective activity against OS-induced cytotoxicity in insulin producing beta-cells, which might be of therapeutic use in the treatment of diabetes mellitus.
Assuntos
Antioxidantes , Hidroxiquinolinas/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 3/metabolismo , Catalase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Corantes , Citocromos c/metabolismo , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Peróxido de Hidrogênio/toxicidade , Células Secretoras de Insulina/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oxidantes/toxicidade , Ratos , Transdução de Sinais/efeitos dos fármacos , Sais de Tetrazólio , TiazóisRESUMO
BACKGROUND: High-throughput gene-based platform studies in human postmortem substantia nigra (SN) from sporadic Parkinson's disease (PD) cases have revealed significant dysregulation of genes involved in biological processes linked to previously established neurodegenerative mechanisms in both sporadic and hereditary PD. OBJECTIVE: Our study aimed to develop a new genetic model of PD by modulating the expression of single genes that were found to be most significantly affected in SN of sporadic PD. METHODS: SN-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses carrying different gene-specific sequences. RESULTS: Silencing of the E3 ligase ubiquitin SKP1A resulted in a decline in the expression of dopaminergic phenotypic markers together with progression into an aberrant cell cycle and death. Furthermore, added knockout of the dopamine-metabolizing enzyme aldehyde dehydrogenase, found almost absent in sporadic PD SN pars compacta, exacerbated the vulnerability of SKP1A-silenced neurons to MPP(+) and neurotrophin deprivation. CONCLUSION: Future studies should focus on a careful consideration of crucial dopaminergic gene network interactions as emerged from human sporadic PD, which will serve as a basis for the development of a slowly progressive genetic animal model of sporadic PD, with the potential of evaluating drugs with 'disease-modifying activity'.
Assuntos
Modelos Animais de Doenças , Predisposição Genética para Doença , Doença de Parkinson/genética , Interferência de RNA/fisiologia , Animais , Humanos , Modelos Biológicos , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Elementos Silenciadores Transcricionais/genética , Elementos Silenciadores Transcricionais/fisiologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson's disease (PD). OBJECTIVE: Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (-)-epigallocatechin-3-gallate (EGCG), the main antioxidant/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged in animal parkinsonism. METHODS/RESULTS: We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. A detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C alpha-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail. CONCLUSION: These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG.
Assuntos
Catequina/análogos & derivados , Corpo Estriado/efeitos dos fármacos , Indanos/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Substância Negra/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Catequina/farmacologia , Catequina/uso terapêutico , Linhagem Celular , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Indanos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Resultado do TratamentoRESUMO
Although much progress has been made in understanding the pathogenesis of Alzheimer's disease (AD), the current therapeutic approaches are merely symptomatic, intended for the treatment of cognitive symptoms, such as disturbances in memory and perception. Novel promising strategies suggest the use of anti-inflammatory drugs, antioxidants including natural occurring plant flavonoids, iron-complexing molecules, neurotrophic factor delivery, inhibitors of the amyloid-beta protein precursor processing secretases, gamma and beta, that generate amyloid-beta peptides and the interference with lipid and cholesterol metabolism. Human epidemiological and new animal data suggest that tea drinking may decrease the incidence of dementia, AD and Parkinson's disease. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. This review provides a detailed overview on the multimodal activities of green tea polyphenols with emphasis on their iron chelating, neurorescue/neuroregenerative and mitochondrial stabilization action.
Assuntos
Catequina/análogos & derivados , Flavonoides/farmacologia , Quelantes de Ferro , Nootrópicos/farmacologia , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Chá , Doença de Alzheimer/patologia , Catequina/farmacologia , Humanos , Doenças Neurodegenerativas/patologia , PolifenóisRESUMO
Green tea is currently considered a source of dietary constituents endowed with biological and pharmacological activities relevant to human health. Human epidemiological and new animal data suggest that the pharmacological benefits of tea drinking may help to protect the brain as we age. Indeed, tea consumption is inversely correlated with the incidence of dementia and Alzheimer's and Parkinson's diseases. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. The intense efforts dedicated in recent years to shed light on the molecular mechanisms participating in the brain protective action of green tea indicate that in addition to the known antioxidant activity of catechins, the modulation of signal transduction pathways, cell survival/death genes, and mitochondrial function all contribute significantly to the induction of neuron viability. Because of the multietiological character of neurodegenerative disease pathology, these natural compounds are receiving significant attention as therapeutic cytoprotective agents that simultaneously manipulate multiple desired targets in the central nervous system. This article elaborates on the multimodal activities of green tea polyphenols with emphasis on their recently described neurorescue/neuroregenerative and mitochondrial stabilization actions.
Assuntos
Catequina/uso terapêutico , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Chá/química , Catequina/farmacologia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fenômenos Fisiológicos da NutriçãoRESUMO
Parkinson's disease is the most common neurodegenerative disorder after Alzheimer's disease, with the majority of cases being sporadic or "idiopathic". The aetiology of the sporadic form is still unknown, but there is a broad consensus that Parkinson's disease involves multiple pathways. In previous human post-mortem studies investigating substantia nigra of parkinsonian subjects, gene expression alterations in various metabolic pathways including protein folding, trafficking, aggregation, ubiquitination and oxidative stress were found. These studies revealed transcriptomic dysregulation of various genes, amongst others Skp1A and PSMC4 (part of ubiquitin-proteasome system), HSC70 (belonging to the chaperone family) and ALDH1A1 (an enzyme involved in the catabolism of dopamine). To investigate whether these alterations are manifested at the protein level, we performed immunohistochemical analysis in the substantia nigra of Parkinson's disease and compared them to Alzheimer's disease and non-neurological post-mortem controls. We were able to confirm cell-specific reductions in the protein content of ALHD1A1 and Skp1A in the dopaminergic neurons of the substantia nigra of Parkinsonian patients compared to Alzheimer's and control subjects. Furthermore, we observed particular distribution for HSC70 and PSMC4 in the cytoplasm and accumulation within Lewy body in the dopaminergic neurons of the substantia nigra in Parkinson patients. These findings, together with previous evidence, suggest a malfunction of the ubiquitin-proteasome and possible autophagy systems as major players in protein misfolding and aggregation in Parkinson's disease. Nevertheless, this needs further proof, possibly with trajectory time line.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Aldeído Desidrogenase/metabolismo , Proteínas de Choque Térmico HSC70/metabolismo , Doença de Parkinson/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Substância Negra/metabolismo , Idoso , Idoso de 80 Anos ou mais , Família Aldeído Desidrogenase 1 , Doença de Alzheimer/patologia , Dopamina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteólise , Retinal Desidrogenase , Estatísticas não ParamétricasRESUMO
High-throughput gene-based platform studies in human post-mortem substantia nigra from sporadic Parkinson's disease (PD) cases have revealed significant dysregulation of genes involved in biological processes linked to previously established neurodegenerative mechanisms both in sporadic and hereditary PD. These include protein aggregation, mitochondrial dysfunction, oxidative stress, cell cycle, vesicle trafficking, synaptic transmission, dopamine metabolism and cell adhesion/cytoskeleton maintenance. These observations have extended our current view on the molecular pathways underlying the etio-pathology of the disease and provided a basis for the development of a novel genetic model of sporadic PD, centered on gradual silencing/over-expression of the candidate genes. The uncovered signatures may serve as future predictive biomarkers for early PD diagnosis, disease progression and drug development.
Assuntos
Regulação da Expressão Gênica , Doença de Parkinson/patologia , Animais , Modelos Animais de Doenças , Predisposição Genética para Doença/genética , Humanos , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Proteínas/genética , Proteínas/metabolismoRESUMO
It is evident that brain aging engages changes in biological systems linked to synaptic function and cell metabolism and in the capacity to cope with different stresses that are either idiopathic in nature, or subject to environmental insults. In a substantial segment of the aging population there is a pathological transition to cognitive and behavioral dysfunction and thus, age constitutes the primary risk factor for Alzheimer's disease and other neurodegenerative disorders. To address the etiological complexity of aging and age-associated conditions, a new paradigm gaining increasing acceptance considers the use of multi-targeted ligands or combination of drugs to modulate several targets at once. During the past years intensive efforts are dedicated to the implementation of life style habits such as exercise and dietary compounds/supplements in combination with symptomatic treatment drugs to improve age-related cognitive decline and to attenuate motor and neurological dysfunction in neurodegenerative diseases. The catechin polyphenols constituents of green tea, which were for long time regarded merely as dietary antioxidants, have caught our and other scientist's attention because of their diverse pharmacological activities, which have been allied to a possible beneficial action on brain health. This review will elaborate on the impact of nutritional supplementation on brain function in general, and provide a compilation of the most updated literature on epidemiology, clinical and animal studies with green tea polyphenols in age-associated cognitive decline and in fighting neurodegenerative diseases. To conclude, a future perspective on the utility and assigned patents with green tea constituents will be presented.
Assuntos
Envelhecimento , Encéfalo/metabolismo , Suplementos Nutricionais , Doenças Neurodegenerativas/prevenção & controle , Neurônios/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Chá/química , Animais , Encéfalo/crescimento & desenvolvimento , Catequina/uso terapêutico , Manipulação de Alimentos , Humanos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/dietoterapia , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Patentes como AssuntoRESUMO
AIMS: To assess whether reduction of Skp1 will increase the vulnerability of dopaminergic neurons to genetic/environmental factors known to play a role in the pathological process of PD. METHODS: Short hairpin RNA lentiviruses infection of substantia nigra (SN)-derived cell-line (SN4741) and mice intranigral injection. RESULTS: We have knocked down the expression of SKP1A, an E3 ubiquitin ligase element, found significantly decreased in human SN in patients with PD. The deficiency of SKP1A in SN4741 cells closely recapitulated cardinal features of the dopamine (DA) neuron pathology of human PD, such as decreased expression of DA phenotypic markers and cell cycle aberrations. Moreover, the knocked down cells displayed a lethal phenotype in differentiated cells exhibiting proteinaceous round inclusions, which were almost identical in composition to human Lewy bodies. Knock down of SKP1A rendered SN4741 cells especially sensitive to genetic reduction of the DA metabolizing enzyme, aldehyde dehydrogenase 1 and exposure to external Stressors implicated in PD pathology. CONCLUSION: Future studies should contemplate intrinsic and environmental manipulations in Skp1-deficient animals to emulate the motor and non-motor disabilities, the progressive nature of PD, and striatal-nigral and adjacent areas pathology. This model may provide a reliable "platform" to develop new therapeutic interventions for PD.
Assuntos
Meio Ambiente , Técnicas de Silenciamento de Genes , Doença de Parkinson/genética , Proteínas Quinases Associadas a Fase S/genética , Ubiquitina-Proteína Ligases/deficiência , Animais , Ciclo Celular/genética , Linhagem Celular , Técnicas de Silenciamento de Genes/métodos , Marcadores Genéticos/genética , Humanos , Camundongos , Doença de Parkinson/enzimologia , Doença de Parkinson/patologia , Fenótipo , Substância Negra/patologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
Mounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseases like Alzheimer's and Parkinson's (AD and PD, respectively) are becoming an increasing burden, as aging is their main risk factor. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multi-pharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach.
Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Polifenóis/farmacologia , Chá/química , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Suplementos Nutricionais , Humanos , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/uso terapêutico , Polifenóis/uso terapêuticoRESUMO
Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-ß and amyloid-ß protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Indanos/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Quelantes/uso terapêutico , Inibidores da Colinesterase/farmacologia , Humanos , Hidroxiquinolinas/uso terapêutico , Indanos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/uso terapêutico , Piperazinas/uso terapêuticoRESUMO
BACKGROUND: The search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD. RESULTS: The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75-0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n = 29). CONCLUSIONS: The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.
Assuntos
Doença de Parkinson/sangue , Doença de Parkinson/genética , Idoso , Doença de Alzheimer/sangue , Biomarcadores/sangue , Feminino , Expressão Gênica , Marcadores Genéticos , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
Monoamine oxidase (MAO) inhibitors were reported to have therapeutic value in several common neurodegenerative conditions owed to their diverse pharmacological functions in neuron survival. Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible MAO-B inhibitor in the treatment of Parkinson's disease (PD). It has been demonstrated to be neuroprotective in PD model systems by preventing the formation of reactive oxygen species derived from prevention of derived from oxidation of dopamine by MAO-B and via an antiapoptotic action, which appears to be independent of MAO-B inhibition and related to its embedded N-propargyl moiety. This review reflects on earlier and present evidence supporting a role for rasagiline as a neuroprotective molecule in the treatment of PD.
Assuntos
Indanos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/fisiologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Humanos , Indanos/química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/química , Doença de Parkinson/enzimologia , Relação Estrutura-AtividadeRESUMO
During the last century, the world population has shown a staggering increase in its proportion of elderly members and thus, neurodegenerative diseases like Alzheimer's and Parkinson's diseases (AD and PD, respectively) are becoming an increasing burden. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation, supporting a therapeutic use of antioxidants. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black tea drinking (enriched in a class of flavonoids named catechins) may help protecting the aging brain and reduce the incidence of dementia, AD, and PD. Mechanistic studies on the neuroprotective/neuroregenerative effects of green tea catechins revealed that they act not only as antioxidants metal chelators, but also as modulators of intracellular neuronal signaling and metabolism, cell survival/death genes, and mitochondrial function. Thus, these dietary compounds are receiving significant attention as therapeutic multifunctional cytoprotective agents that simultaneously manipulate various brain targets. The scope of this review is to assess and put into perspective salient features of the beneficial brain action of natural, non-toxic green tea catechins in aging-impaired cognition and neurodegenerative diseases and to discuss a scenario concerning their potential, in drug combination, to target distinct pathologies, in the quest for a disease modifying therapy.
Assuntos
Envelhecimento , Flavonoides/uso terapêutico , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Fenóis/uso terapêutico , Chá/química , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Humanos , Modelos Biológicos , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/epidemiologia , Polifenóis , Chá/classificaçãoRESUMO
Neurodegenerative diseases like Parkinson's disease (PD) and Alzheimer's disease (AD) are considered disorders of multifactorial origin, inevitably progressive and having a long preclinical period. Therefore, the availability of biological markers or biomarkers (BMs) for early disease diagnosis will impact the management of AD and PD in several dimensions; it will 1) help to capture high-risk individuals before symptoms develop, a stage where prevention efforts might be expected to have their greatest impact; 2) provide a measure of disease progression that can be evaluated objectively, while clinical measures are much less accurate; 3) help to discriminate between true AD or PD and other causes of a similar clinical syndrome; 4) delineate pathophysiological processes responsible for the disease; 5) determine the clinical efficacy of novel, disease-modifying (neuroprotective) strategies. In the long run the availability of reliable BMs will significantly advance the research and therapeutics of AD and PD.
RESUMO
Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson's disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson's disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1α as a potential therapeutic target for early intervention.