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Role of the protein Annexin A1 in the experimental model of Parkinsons Disease

Grant number: 21/00270-4
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): August 01, 2022
Effective date (End): January 31, 2027
Field of knowledge:Biological Sciences - Morphology - Histology
Principal researcher:Cristiane Damas Gil
Grantee:Luiz Philipe de Souza Ferreira
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Parkinson's Disease (PD) is a neurodegenerative disorder of high incidence in the global population, which affects men and women mainly between 45 - 54 years-old. Recent studies demonstrate that neuroinflammation is a crucial condition of PD, prompting the search for more effective treatments with a focus on inflammation. In this context, we highlight Annexin A1 (AnxA1), an anti-inflammatory protein able to regulate neuroinflammation and activation of the NLRP3 inflammasome, a cytoplasmic sensor that acts on the progression of PD. So far, these mechanisms have not been explored in a PD model. Thus, we will evaluate the role of AnxA1 in a PD murine model induced by the neurotoxin 6-hydroxidopamine (6-OHDA). Male and female C57Bl/6 wild-type (WT) mice and knockouts for AnxA1 protein (AnxA1-/-), will be distributed in three groups (n =12/group): Sham, 6-OHDA+Saline and 6-OHDA+Ac2-26 (mimetic peptide of the N-terminal region of AnxA1). The 6-OHDA+Saline and 6-OHDA+Ac2-26 groups will undergo stereotactic surgery for infusion of 6-OHDA into the striatum (CPu). Then, 1 ¼L of 6-OHDA (5¼g/¼L) in saline solution with 0.1% ascorbic acid will be administered through an infusion needle into the right CPu (ipsilateral). The left CPu (control; contralalteral) will receive 1 ¼L of vehicle solution (saline with 0.1% ascorbic acid). The Sham group will receive only saline in the ipsi and contralateral CPu. The 6-OHDA+Ac2-26 group will receive 1 dose of Ac2-26 (100 µg/animal, i.p.) immediately after the 6-OHDA infusion, followed by 6 more daily doses of peptide. The 6-OHDA+Saline group will receive only saline. The Naive group will be only manipulated. The effect of the absence of AnxA1 and pharmacological treatment with Ac2-26 will be observed by behavioral testing. We will histologically evaluate the CPu and the Substantia Nigra (SN) of the midbrain, especially neurons, microglia (Iba-1) and astrocytes (GFAP); the expression pattern and possible colocalization of AnxA1, Fpr2, and NLRP3 in astrocytes and microglia by immunohistochemistry and immunofluorescence; mRNA levels of AnxA1, Fpr2, ASC, caspase 1, NLRP3, and alpha-synuclein genes by RT-PCR; expression of ERK/MAPK kinase, caspase 1 and IL-1b by western blotting in CPu and SN; peripheral blood leukocyte profile by flow cytometry; levels of cytokines (TNF-alpha, IL-1b, IL-6, IL-10 and MCP-1), and beta-amyloid peptide by multiplex assay. The studies will contribute to a better understanding of the mechanisms of action of AnxA1 and its peptide, as well as their possible therapeutic applications in PD. (AU)

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