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1.
Eur J Neurosci ; 45(1): 73-91, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27859864

RESUMO

In Parkinson's disease (PD), l-DOPA therapy leads to the emergence of motor complications including l-DOPA-induced dyskinesia (LID). LID relies on a sequence of pre- and postsynaptic neuronal events, leading to abnormal corticostriatal neurotransmission and maladaptive changes in striatal projection neurons. In recent years, additional non-neuronal mechanisms have been proposed to contribute to LID. Among these mechanisms, considerable attention has been focused on l-DOPA-induced inflammatory responses. Microglia and astrocytes are the main actors in neuroinflammatory responses, and their double role at the interface between immune and neurophysiological responses is starting to be elucidated. Both microglia and astrocytes express a multitude of neurotransmitter receptors and via the release of several soluble molecules modulate synaptic function in neuronal networks. Here we review preclinical and clinical evidence of glial overactivation by l-DOPA, supporting a role of microglia and astrocytes in the development of LID. We propose that in PD, chronically and abnormally activated microglia and astrocytes lead to an aberrant neuron-glia communication, which affect synaptic activity and neuroplasticity contributing to the development of LID.


Assuntos
Antiparkinsonianos/farmacologia , Astrócitos/efeitos dos fármacos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Microglia/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos
2.
Exp Neurol ; 286: 83-92, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27697481

RESUMO

Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. l-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any l-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic l-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Encefalite/induzido quimicamente , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/sangue , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/efeitos adversos , Lateralidade Funcional/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Levodopa/administração & dosagem , Levodopa/sangue , Lipopolissacarídeos/farmacologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Oxidopamina/toxicidade , Doença de Parkinson/sangue , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Simpatolíticos/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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