Involvement of interferon-γ on Parkinsonism, L-DOPA-induced dyskinesia and expression of neuroinflammatory elements

Author(s)

Daniele Pereira Ferrari

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2020-06-18

Examining board members

Elaine Aparecida Del Bel Belluz Guimaraes; Fernando Eduardo Padovan Neto

• Advisor: Elaine Aparecida Del Bel Belluz Guimaraes

Abstract

Parkinson\'s disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons, which cause is still unknown. The most effective treatment for PD motor symptoms is through the administration of L-DOPA. The chronicity of this treatment leads to the development of L-DOPA-induced dyskinesia (LID) characterized by abnormal involuntary movements (AIMs). In the lesioned striatum of parkinsonian and dyskinetic animals, the presence of activated glial cells and increased expression of inducible nitric oxide synthase (iNOS) suggested the involvement of neuroinflammation in the pathophysiology of PD and dyskinesia. iNOS transcription is dependent on proinflammatory cytokines, including interferon-γ (IFN-γ). IFN-γ is a potent activator of both microglia and astrocytes, and it was observed increased levels of this cytokine on the plasma and brain of PD patients, suggesting its potential role in PD. The influence of IFN-γ on LID has not been studied yet. This study aimed to analyze the participation of IFN-γ on 6-OHDA-induced parkinsonism, on LID development and expression of neuroinflammatory mediators. In the first experiment, WT and IFN-γ/KO received unilateral injections of 6-OHDA into the striatum and were sacrificed after 1, 3, 7, or 21 days. The analysis of immunoreactivity for tyrosine hydroxylase (TH) in the striatum and SNc indicated the starting of dopaminergic lesion since the first day after microinjection in both structures with rapid progression until the 21st day, reaching about 85% in the striatum and 83% in SNc. There was no difference in the development of the lesion between the animal groups. In the second experiment, hemiparkinsonian WT and IFN- γ/KO mice were treated with L-DOPA for 21 days. The analysis of AIMs indicated high levels of dyskinesia from the first day of the treatment, which was stable until the 21st treatment day, being similar between WT and IFN-γ/KO groups. The nigrostriatal pathway lesion was confirmed by the cylinder test and immunohistochemistry for TH and indicated no difference between the groups. Higher expression of TH+ neurons was observed in the lesioned striatum of IFN-γ/KO animals treated with L-DOPA, compared to the WT group. The FosB expression analysis in the striatum did not indicate differences between dyskinetic animals. The L-DOPA treated IFN-γ/KO animals showed increased expression of iNOS, Iba- 1 (microglia marker), and GFAP (astrocyte marker) in the lesioned striatum, compared to LDOPA treated WT animals. Morphology analysis indicated glial cell reactivity in the lesioned striatum. A positive correlation was found between the intensity of dyskinesia and the expression of microglia in WT and IFN-γ/KO striatum. IFN-γ does not appear to interfere with dopaminergic degeneration induced by 6-OHDA or in LID development. However, its deficit contributes to alterations in neuroinflammatory reactions in the lesioned striatum after treatment with L-DOPA. (AU)

• FAPESP's process: 17/14419-4 - Effect of interferon-³ on parkinsonism and on l-DOPA-induced dyskinesia
• Grantee: Daniele Pereira Ferrari
• Support Opportunities: Scholarships in Brazil - Master