RESUMO
Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. Although PD has a relatively narrow clinical phenotype, it has become clear that its etiological basis is broad. Post-mortem brain analysis, despite its limitations, has provided invaluable insights into relevant pathogenic pathways including mitochondrial dysfunction, oxidative stress and protein homeostasis dysregulation. Identification of the genetic causes of PD followed the discovery of these abnormalities, and reinforced the importance of the biochemical defects identified post-mortem. Recent genetic studies have highlighted the mitochondrial and lysosomal areas of cell function as particularly significant in mediating the neurodegeneration of PD. Thus the careful analysis of post-mortem PD brain biochemistry remains a crucial component of research, and one that offers considerable opportunity to pursue etiological factors either by 'reverse biochemistry' i.e. from defective pathway to mutant gene, or by the complex interplay between pathways e.g. mitochondrial turnover by lysosomes. In this review we have documented the spectrum of biochemical defects identified in PD post-mortem brain and explored their relevance to metabolic pathways involved in neurodegeneration. We have highlighted the complex interactions between these pathways and the gene mutations causing or increasing risk for PD. These pathways are becoming a focus for the development of disease modifying therapies for PD. Parkinson's is accompanied by multiple changes in the brain that are responsible for the progression of the disease. We describe here the molecular alterations occurring in postmortem brains and classify them as: Neurotransmitters and neurotrophic factors; Lewy bodies and Parkinson's-linked genes; Transition metals, calcium and calcium-binding proteins; Inflammation; Mitochondrial abnormalities and oxidative stress; Abnormal protein removal and degradation; Apoptosis and transduction pathways. This article is part of a special issue on Parkinson disease.
Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Animais , Autopsia , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/fisiologia , Doença de Parkinson/genéticaRESUMO
Parkinson disease (PD) is a degenerative brain disorder characterized by motor symptoms that are unequivocally associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although our knowledge of the mechanisms that contribute to DA cell death in both hereditary and sporadic forms of the disease has advanced significantly, the nature of the pathogenic process remains poorly understood. In this review, we present evidence that neurodegeneration occurs when the electrical activity and excitability of these neurons is reduced. In particular, we will focus on the specific need these neurons may have for stimulation in order to survive and on the molecular and cellular mechanisms that may be compromised when this need is no longer met in PD.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Doença de Parkinson/metabolismo , Animais , Neurônios Dopaminérgicos/fisiologia , Humanos , Modelos BiológicosRESUMO
Epidemiological and experimental evidence indicates that nicotine is protective for Parkinson disease vulnerable dopamine neurons, but the underlying mechanism of this effect remains only partly characterized. To address this question, we established rat midbrain cultures maintained in experimental conditions that favor the selective and spontaneous loss of dopamine neurons. We report here that nicotine afforded neuroprotection to dopamine neurons (EC(50)=0.32 µM) but only in a situation where cytosolic Ca(2+) (Ca(2+)(cyt)) was slightly and chronically elevated above control levels by concurrent depolarizing treatments. By a pharmacological approach, we demonstrated that the rise in Ca(2+)(cyt) was necessary to sensitize dopamine neurons to the action of nicotine through a mechanism involving α-bungarotoxin-sensitive (presumably α7) nicotinic acetylcholine receptors (nAChRs) and secondarily T-type voltage-gated calcium channels. Confirming the role played by α7 nAChRs in this effect, nicotine had no protective action in midbrain cultures prepared from genetically engineered mice lacking this receptor subtype. Signaling studies revealed that Ca(2+)(cyt) elevations evoked by nicotine and concomitant depolarizing treatments served to activate a survival pathway involving the calcium effector protein calmodulin and phosphatidylinositol 3-kinase. Collectively, our data support the idea that the protective action of nicotine for dopamine neurons is activity-dependent and gated by Ca(2+)(cyt).
Assuntos
Cálcio/metabolismo , Dopamina/metabolismo , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Fármacos Neuroprotetores/farmacologia , Nicotina/farmacologia , Animais , Canais de Cálcio Tipo T/metabolismo , Calmodulina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Mesencéfalo/citologia , Camundongos , Modelos Neurológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptores Nicotínicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tetraetilamônio/farmacologia , Técnicas de Cultura de Tecidos , Receptor Nicotínico de Acetilcolina alfa7RESUMO
While K(ATP) channels serve primarily as metabolic gatekeepers in excitable cells, they might also participate in other important cellular functions. Here, we demonstrate that K(ATP) channel blockade with the sulfonylurea derivative glibenclamide provided robust protection to dopamine neurons undergoing spontaneous and selective degeneration in midbrain cultures. Unexpectedly, glibenclamide operated not by a direct effect on dopamine neurons but instead by halting the proliferation of a population of immature glial cells lacking astrocytic and microglial markers. The antimitotic effect of glibenclamide appeared essential to unmask a prosurvival phosphoinositide 3-kinase (PI3K)/Akt-dependent signaling pathway that controlled shuttling of calcium from endoplasmic reticulum to mitochondria in dopamine neurons. Preventing integrin-ligand interactions with a decoy ligand, the Arg-Gly-Asp-Ser sequence peptide, reproduced survival promotion by glibenclamide via a mechanism that also required PI3K/Akt-dependent regulation of mitochondrial calcium. Noticeably, Arg-Gly-Asp-Ser did not cause a reduction in glial cell numbers indicating that it prevented the death process downstream of the level at which glibenclamide intervenes. Based on these results, we propose that K(ATP) channel blockade protected dopamine neurons by inhibiting a glia-to-neuron signaling pathway that propagates through integrin/ligand interactions and ultimately disrupts PI3K/Akt-dependent signaling and mitochondrial calcium homeostasis.
Assuntos
Cálcio/fisiologia , Dopamina/metabolismo , Glibureto/farmacologia , Canais KATP/antagonistas & inibidores , Mesencéfalo/efeitos dos fármacos , Mitocôndrias/fisiologia , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Sobrevivência Celular , Células Cultivadas , Homeostase , Integrinas/fisiologia , Mesencéfalo/citologia , Mesencéfalo/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
Neurodegenerative diseases are characterized by neuronal degeneration as well as neuroinflammation. While CD38 is strongly expressed in brain cells including neurons, astrocytes as well as microglial cells, the role played by CD38 in neurodegeneration and neuroinflammation remains elusive. Yet, CD38 expression increases as a consequence of aging which is otherwise the primary risk associated with neurodegenerative diseases, and several experimental data demonstrated that CD38 knockout mice are protected from neurodegenerative and neuroinflammatory insults. Moreover, nicotinamide adenine dinucleotide, whose levels are tightly controlled by CD38, is a recognized and potent neuroprotective agent, and NAD supplementation was found to be beneficial against neurodegenerative diseases. The aims of this review are to summarize the physiological role played by CD38 in the brain, present the arguments indicating the involvement of CD38 in neurodegeneration and neuroinflammation, and to discuss these observations in light of CD38 complex biology.
Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Glicoproteínas de Membrana/metabolismo , Degeneração Neural/enzimologia , Doenças Neurodegenerativas/enzimologia , ADP-Ribosil Ciclase 1/genética , Envelhecimento/metabolismo , Animais , Astrócitos/enzimologia , Encéfalo/enzimologia , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Microglia/enzimologia , NAD/metabolismo , NAD/farmacologia , Degeneração Neural/patologia , Doenças Neurodegenerativas/patologia , Neurônios/enzimologia , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologiaRESUMO
High plasma levels of the end product of purine metabolism uric acid (UA) predict a reduced risk of developing Parkinson's disease suggesting that UA may operate as a protective factor for midbrain dopaminergic neurons. Consistent with this view, UA exerted partial but long-term protection in a culture model in which these neurons die spontaneously. The rescued neurons were functional as they accumulated dopamine, efficiently. The use of the fluorescent probe dihydrorhodamine-123 revealed that UA operated by an antioxidant mechanism. The iron chelating agent desferrioxamine, the H(2)O(2) scavenger enzyme catalase and the inhibitor of lipid peroxidation Trolox mimicked the effects of UA, suggesting that UA neutralized reactive oxygen species produced via a Fenton-type chemical reaction. UA was, however, not significantly accumulated into neurons, which indicates that the antioxidant effect occurred probably extracellularly. Structure - activity relationships among purine derivatives revealed that the antioxidant properties of UA resulted from the presence of a 8-one substituent in its chemical structure. Of interest, the stimulation of L-type Ca(2+) channels by high K(+)-induced depolarization and the ensuing activation of extracellular signal-regulated kinases 1/2 strongly improved the neuroprotective effect of UA whereas the depolarizing signal alone had no effect. In summary, our data indicate that UA may interfere directly with the disease's pathomechanism.
Assuntos
Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Dopamina/fisiologia , Mesencéfalo/citologia , Mesencéfalo/fisiologia , Neurônios/fisiologia , Fármacos Neuroprotetores , Purinas/metabolismo , Ácido Úrico/farmacologia , Animais , Western Blotting , Cálcio/metabolismo , Células Cultivadas , Citosol/fisiologia , Dopamina/metabolismo , Eletrofisiologia , Imunofluorescência , Mesencéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Potássio/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Timidina/análogos & derivados , Timidina/metabolismo , Ácido Úrico/análogos & derivadosRESUMO
Epidemiological evidence suggests that caffeine or its metabolites reduce the risk of developing Parkinson's disease, possibly by protecting dopaminergic neurons, but the underlying mechanism is not clearly understood. Here, we show that the primary metabolite of caffeine, paraxanthine (PX; 1, 7-dimethylxanthine), was strongly protective against neurodegeneration and loss of synaptic function in a culture system of selective dopaminergic cell death. In contrast, caffeine itself afforded only marginal protection. The survival effect of PX was highly specific to dopaminergic neurons and independent of glial cell line-derived neurotrophic factor (GDNF). Nevertheless, PX had the potential to rescue dopaminergic neurons that had matured initially with and were then deprived of GDNF. The protective effect of PX was not mediated by blockade of adenosine receptors or by elevation of intracellular cAMP levels, two pharmacological effects typical of methylxanthine derivatives. Instead, it was attributable to a moderate increase in free cytosolic calcium via the activation of reticulum endoplasmic ryanodine receptor (RyR) channels. Consistent with these observations, PX and also ryanodine, the preferential agonist of RyRs, were protective in an unrelated paradigm of mitochondrial toxin-induced dopaminergic cell death. In conclusion, our data suggest that PX has a neuroprotective potential for diseased dopaminergic neurons.
Assuntos
Cafeína/metabolismo , Fármacos Neuroprotetores/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Teofilina/farmacologia , Animais , Apoptose/fisiologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dopamina/fisiologia , Embrião de Mamíferos/citologia , Técnica Indireta de Fluorescência para Anticorpo , Concentração de Íons de Hidrogênio , Mesencéfalo/citologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/agonistas , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Ratos , Ratos Wistar , Rianodina/farmacologia , Solubilidade , Teofilina/agonistas , Teofilina/síntese química , Teofilina/química , Teofilina/isolamento & purificaçãoRESUMO
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic nigrostriatal neurons but which involves the loss of additional neurotransmitter pathways. Mono- or polytherapeutic interventions in PD patients have declining efficacy long-term and no influence on disease progression. The systematic analysis of available genetic and functional data as well as the substantial overlap between Alzheimer's disease (AD) and PD features led us to repurpose and explore the effectiveness of a combination therapy (ABC) with two drugs - acamprosate and baclofen - that was already effective in AD animal models, for the treatment of PD. We showed in vitro that ABC strongly and synergistically protected neuronal cells from oxidative stress in the oxygen and glucose deprivation model, as well as dopaminergic neurons from cell death in the 6-hydroxydopamine (6-OHDA) rat model. Furthermore, we showed that ABC normalised altered motor symptoms in vivo in 6-OHDA-treated rats, acting by protecting dopaminergic cell bodies and their striatal terminals. Interestingly, ABC also restored a normal behaviour pattern in lesioned rats suggesting a symptomatic effect, and did not negatively interact with L-dopa. Our results demonstrate the potential value of combining repurposed drugs as a promising new strategy to treat this debilitating disease.
Assuntos
Baclofeno/farmacologia , Doença de Parkinson/tratamento farmacológico , Taurina/análogos & derivados , Acamprosato , Animais , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Quimioterapia Combinada/métodos , Feminino , Masculino , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/metabolismo , Doença de Parkinson/metabolismo , Ratos , Ratos Wistar , Taurina/farmacologiaRESUMO
Alzheimer disease (AD) represents a major medical problem where mono-therapeutic interventions demonstrated only a limited efficacy so far. We explored the possibility of developing a combinational therapy that might prevent the degradation of neuronal and endothelial structures in this disease. We argued that the distorted balance between excitatory (glutamate) and inhibitory (GABA/glycine) systems constitutes a therapeutic target for such intervention. We found that a combination of two approved drugs - acamprosate and baclofen - synergistically protected neurons and endothelial structures in vitro against amyloid-beta (Aß) oligomers. The neuroprotective effects of these drugs were mediated by modulation of targets in GABA/glycinergic and glutamatergic pathways. In vivo, the combination alleviated cognitive deficits in the acute Aß25-35 peptide injection model and in the mouse mutant APP transgenic model. Several patterns altered in AD were also synergistically normalised. Our results open up the possibility for a promising therapeutic approach for AD by combining repurposed drugs.