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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Contributive Role of TNF-alpha to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson's Disease

Texto completo
Autor(es):
dos Santos Pereira, Mauricio [1, 2, 3, 4] ; Abreu, Gabriel Henrique Dias [1, 3] ; Rocca, Jeremy [2] ; Hamadat, Sabah [2] ; Raisman-Vozari, Rita [2] ; Michel, Patrick Pierre [2] ; Del Bel, Elaine [1, 3, 4]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo - Brazil
[2] Sorbonne Univ UM75, Paris Brain Inst, Inserm U 1127, CNRS UMR 7225, Paris - France
[3] Univ Sao Paulo, FORP, Dept Basic & Oral Biol, Campus USP, Ribeirao Preto - Brazil
[4] Univ Sao Paulo, FMRP, Dept Physiol, Campus USP, Ribeirao Preto - Brazil
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN PHARMACOLOGY; v. 11, JAN 11 2021.
Citações Web of Science: 0
Resumo

Our present objective was to better characterize the mechanisms that regulate striatal neuroinflammation in mice developing L-DOPA-induced dyskinesia (LID). For that, we used 6-hydroxydopamine (6-OHDA)-lesioned mice rendered dyskinetic by repeated intraperitoneal injections of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) and quantified ensuing neuroinflammatory changes in the dopamine-denervated dorsal striatum. LID development was associated with a prominent astrocytic response, and a more moderate microglial cell reaction restricted to this striatal area. The glial response was associated with elevations in two pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta. Treatment with the phytocannabinoid cannabidiol and the transient receptor potential vanilloid-1 (TRPV-1) channel antagonist capsazepine diminished LID intensity and decreased TNF-alpha levels without impacting other inflammation markers. To possibly reproduce the neuroinflammatory component of LID, we exposed astrocyte and microglial cells in culture to candidate molecules that might operate as inflammatory cues during LID development, i.e., L-DOPA, dopamine, or glutamate. Neither L-DOPA nor dopamine produced an inflammatory response in glial cell cultures. However, glutamate enhanced TNF-alpha secretion and GFAP expression in astrocyte cultures and promoted Iba-1 expression in microglial cultures. Of interest, the antidyskinetic treatment with cannabidiol + capsazepine reduced TNF-alpha release in glutamate-activated astrocytes. TNF-alpha, on its own, promoted the synaptic release of glutamate in cortical neuronal cultures, whereas cannabidiol + capsazepine prevented this effect. Therefore, we may assume that the release of TNF-alpha by glutamate-activated astrocytes may contribute to LID by exacerbating corticostriatal glutamatergic inputs excitability and maintaining astrocytes in an activated state through a self-reinforcing mechanism. (AU)

Processo FAPESP: 14/25029-4 - Estudo da contribuição do processo inflamatório na discinesia induzida por L-DOPA na Doença de Parkinson
Beneficiário:Elaine Aparecida Del Bel Belluz Guimarães
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 18/03482-0 - A ação de fármacos canabinóides no processo de neuroinflamação dependente de glia: um link com a discinesia induzida por l-dopa
Beneficiário:Maurício dos Santos Pereira
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
Processo FAPESP: 17/24304-0 - Novas perspectivas no emprego de fármacos que modificam neurotransmissores atípicos no tratamento de transtornos neuropsiquiátricos
Beneficiário:Francisco Silveira Guimaraes
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 17/14207-7 - A ação de fármacos canabinóides na discinesia induzida por l-dopa: análise da neuroinflamação e liberação de glutamato em células gliais
Beneficiário:Maurício dos Santos Pereira
Linha de fomento: Bolsas no Brasil - Pós-Doutorado