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Microglia and neuroprotection in gp91phox knockout mice

Grant number: 12/13895-3
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): October 01, 2012
Effective date (End): September 30, 2014
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Marina Sorrentino Hernandes
Grantee:Graziella D Agostino Ribeiro dos Santos
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Parkinson's disease (PD) is characterized by the progressive loss of dopamine containing neurons of the substantia nigra pars compacta. Although a single causative factor has not yet been identified, a restricted number of converging pathogenic mechanisms have been suggested, including oxidative stress and mitochondrial dysfunction. However, the molecular mechanisms involved in PD remain largely unknown. Our laboratory has focused over the last year in studying the involvement of NADPH oxidase, a membrane-associated multiunit enzyme that catalyzes the reduction of oxygen using NADPH as an electron donor, in PD. The classical retrograde degeneration of the nigrostriatal dopaminergic system induced by 6-hydroxy dopamine (6-OHDA) was not observed in gp91phox knockout mice (gp91phox-/-). However, these mice presented changes in the microglia phenotype in basal conditions, demonstrating that NADPH oxidase plays a critical role in the modulation of microglia phenotype. Our main objective here is to investigate the possible neuroprotective role played by microglia in gp91phox-/- mice. In order to lesion the nigrostriatal system, 6-OHDA will be unilaterally injected into the right striatum of both gp91phox-/- and wild type (Wt) mice. Groups of Wt mice and gp91phox-/- will be treated with minocycline (40mg/kg/day i.p.), a microglia inhibitor, for 7 days after PD induction. To further investigate the protective role of microglia in gp91phox-/-, apomorphine-induced rotational tests will be conducted to evaluate the extent of the lesion induced by 6-OHDA. Furthermore immunoreactivity for tyrosine hydroxylase and a microglia marker will also be evaluated after minocycline treatment.

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