RESUMO
3,4-Dihydroxyphenyl ethanol, known as hydroxytyrosol (HTy), is a phenylpropanoid found in diverse vegetable species. Several studies have demonstrated that HTy is a potent antioxidant. Thus, our study is aimed to evaluate the antioxidant effect of HTy and its derivatives, hydroxytyrosol acetate (HTyA) and nitrohydroxytyrosol (HTyN), in a model of oxidative stress induced by 1-methyl-4-phenylpyridinium (MPP+) in rats. Rats were administered intravenously (i.v.) in the tail with 1 mL saline solution or polyphenol compound (1.5 mg/kg) 5 min before intrastriatal infusion of 10 µg MPP+/8 µL. We found that rats injured with MPP+, pretreatment with HTy, HTyA or HTyN significantly decreased ipsilateral turns. This result was consistent with a significant preservation of striatal dopamine levels and decreased lipid fluorescence products (LFP), a marker of oxidative stress. Brain GSH/GSSG ratio, from rats pretreated with HTy or HTyN showed a significant preservation of that marker, decreased as a consequence of MPP+-induced oxidative damage. These results show an antioxidant effect of HTy, HTyA and HTyN in the MPP+ model of Parkinson's disease in the rat.
Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Acetatos/administração & dosagem , Antioxidantes/administração & dosagem , Catecóis/administração & dosagem , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Álcool Feniletílico/análogos & derivados , Administração Intravenosa , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Transtornos Parkinsonianos/prevenção & controle , Álcool Feniletílico/administração & dosagem , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
The involvement of dopaminergic (DAergic) receptor drugs in the neuroprotection against the neurotoxic action of 1-methyl-4-phenylpyridinium (MPP(+)) in the DAergic terminals in striatum was studied using an intracerebral microdialysis technique. Twenty-four hours after surgery (day 1), apomorphine and haloperidol, alone or with 1 mmol/l of MPP(+) perfusion through the microdialysis probe, were systemically administered. Forty-eight hours after surgery (day 2), 1 mmol/l of MPP(+) was perfused for 15 min in all groups of animals and the output of dopamine was measured. The amount of dopamine was directly proportional to the remaining striatal DAergic terminals. The results show that: (1) subcutaneous administration of apomorphine before MPP(+) perfusion prevented MPP(+)-induced neurotoxicity, and (2) intraperitoneal administration of haloperidol before MPP(+) perfusion did not prevent MPP(+)-induced neurotoxicity.
Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Apomorfina/farmacologia , Haloperidol/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Animais , Apomorfina/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Dopamina/metabolismo , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Haloperidol/administração & dosagem , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Microdiálise/métodos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/etiologia , Ratos , Ratos WistarRESUMO
Research indicates that inflammation and microglial activation are involved in the initiation and progression of Parkinson's disease (PD). Neuroinflammation contributes to the infiltration of peripheral immune cells and blood-brain barrier (BBB) leakage, linking peripheral and central inflammatory events in the pathogenesis of PD. Dopamine (DA) likely plays a role in this process. In the present study, the dopaminergic toxin 6-hydroxydopamine (6-OHDA) was used to damage dopaminergic neurons. Injection of 6-OHDA within the nigrostriatal pathway produced loss of astrocytes, disruption of the BBB, microglia activation and a reduction in osteopontin (OPN) immunoreactivity. Depletion of DA content by alpha-methylparatyrosine (α-MPT, a tyrosine hydroxylase inhibitor) reduced the infiltration of peripheral macrophages as well as the 6-OHDA-induced increase in microglial cells. DA could therefore be relevant in sustaining inflammation and lymphocyte recruitment induced by 6-OHDA, supporting DA implication in the degeneration of dopaminergic neurons induced by inflammatory processes.
Assuntos
Astrócitos/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Inflamação/imunologia , Linfócitos/fisiologia , Macrófagos/fisiologia , Substância Negra/metabolismo , Animais , Movimento Celular , Corpo Estriado/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inflamação/induzido quimicamente , Inflamação/patologia , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Osteopontina/metabolismo , Oxidopamina/farmacologia , Ratos , Ratos Wistar , Substância Negra/efeitos dos fármacos , Simpatolíticos/farmacologia , Fatores de Tempo , alfa-Metiltirosina/farmacologiaRESUMO
Evidence supports the role of inflammation in the development of neurodegenerative diseases. In this work, we are interested in inflammation as a risk factor by itself and not only as a factor contributing to neurodegeneration. We tested the influence of a mild to moderate peripheral inflammation (injection of carrageenan into the paws of rats) on the degeneration of dopaminergic neurons in an animal model based on the intranigral injection of lipopolysaccharide (LPS), a potent inflammatory agent. Overall, the treatment with carrageenan increased the effect of the intranigral injection of LPS on the loss of dopaminergic neurons in the SN along with all the other parameters studied, including: serum levels of the inflammatory markers TNF-α, IL-1ß, IL-6 and C-reactive protein; activation of microglia, expression of proinflammatory cytokines, the adhesion molecule ICAM and the enzyme iNOS, loss of astrocytes and damage to the blood brain barrier (BBB). The possible implication of BBB rupture in the increased loss of dopaminergic neurons has been studied using another Parkinson's disease animal model based on the intraperitoneal injection of rotenone. In this experiment, loss of dopaminergic neurons was also strengthened by carrageenan, without affecting the BBB. In conclusion, our data show that a mild to moderate peripheral inflammation can exacerbate the degeneration of dopaminergic neurons caused by a harmful stimulus.
Assuntos
Gânglios da Base/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Encefalite/complicações , Inflamação/complicações , Degeneração Estriatonigral/etiologia , Substância Negra/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Gânglios da Base/patologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Proteína C-Reativa/metabolismo , Carragenina , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Encefalite/induzido quimicamente , Encefalite/metabolismo , Encefalite/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/sangue , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/sangue , Interleucina-6/sangue , Lipopolissacarídeos , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Rotenona , Degeneração Estriatonigral/metabolismo , Degeneração Estriatonigral/patologia , Substância Negra/patologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangueRESUMO
Anti-inflammatory strategies have attracted much interest for their potential to prevent further deterioration of Parkinson's disease. Recent experimental and clinical evidence indicate that statins - extensively used in medical practice as effective lipid-lowering agents - have also anti-inflammatory effects. In this study, we investigated the influence of simvastatin on the degenerative process of the dopaminergic neurons of the rat following intranigral injection of lipopolysaccharide (LPS), a potent inductor of inflammation that we have previously used as an animal model of Parkinson's disease. We evaluated TH positive neurons, astroglial, and microglial populations and found that simvastatin prevented the inflammatory processes, as the induction of interleukin-1beta, tumor necrosis factor-alpha, and iNOS and the consequent dopaminergic degeneration induced by LPS. Moreover, simvastatin produced the activation of the neurotrophic factor BDNF, along with the prevention of the oxidative damage to proteins. Moreover, it also prevents the main changes produced by LPS on different mitogen-activated protein kinases, featured as increases of P-c-Jun N-terminal protein kinase, P-extracellular signal-regulated kinase, p-38, and P-glycogen synthase kinase and the decrease of the promotion of cell survival signals such as cAMP response element-binding protein and Akt. Our results suggest that statins could delay the progression of dopaminergic degeneration in disorders involving inflammatory processes.