Role of the SK3 channel in neuroinflammatory mechanisms of L-DOPA induced-dyskinesia and Parkinson's disease

• Grant number: 18/18354-7
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: November 19, 2018
• End date: May 18, 2019
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Elaine Aparecida Del Bel Belluz Guimarães
• Grantee: Daniele Pereira Ferrari
• Supervisor: Walter Stuehmer
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Max Planck Society, Gottingen, Germany
• Associated to the scholarship: 17/14419-4 - Effect of interferon-³ on parkinsonism and on l-DOPA-induced dyskinesia, BP.MS

Abstract

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons whose cause is still unknown. The most effective treatment for PD motor symptoms is through administration of L-DOPA. However, the chronicity of this treatment leads to the development L-DOPA-induced dyskinesia (LID). Our group demonstrated the presence of activated astrocytes, microglia and increased expression of inducible nitric oxide-synthase (iNOS) in the lesioned striatum of parkinsonian/dyskinetic rats. It suggests the presence of inflammatory reaction in the pathophysiology of LID. Microglia responds to CNS damage by up-regulating functions that involve Ca2+ signaling, such as production of cytokines and nitric oxide. Small-conductance Ca2+ activated K+ channels (SK3) are expressed in microglia at the striatum and contributes to microglia-mediated neurotoxicity. Our aim is to determine the impact of SK3 channels in neurodegenerative and inflammatory responses in mice model of PD and LID. Thus, SK3 overexpressing (SK3-T/T), knockout (SK3/KO) and wild type (WT) mice will receive infusion of 6-OHDA in the striatum and will be tested for spontaneous forelimb use in the cylinder test and dyskinesia development by L-DOPA treatment. WT group will be evaluated for the SK3 channel expression on microglia during the development of nigroestriatal DA degeneration and in LID in the striatum and SNc by immunohistochemistry and confocal image analyses. SK3-T/T and SK3/KO will be evaluated for the development of LID, DA degeneration, microglia activation and expression of iNOS. The immunohistochemistry analyses will be performed in the striatum and substantia nigra.