Possible neuroprotection strategies in Parkinson's Disease

• Grant number: 22/14820-9
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2023
• End date: May 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Roberto Giorgetti de Britto
• Grantee: Luiz Roberto Giorgetti de Britto
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant(s): 24/02166-8 - Involvement of the mTORC1 and mTORC2 complexes in the cognitive deficits in an animal model of Alzheimers Disease, AP.R

Abstract

Parkinson´s disease (PD) represents a major public health issue, since it is the second most prevalent neurodegenerative disease, behind Alzheimer´s disease. The number of cases of PD in Brazil is estimated to reach more than 600,000 in the next 5-8 years. Despite intense research on the physiopathological basis of PD, the mechanisms that trigger the disease are incompletely understood. The same applies to its progression after the initial diagnosis. Treatment is in general symptomatic, and presents several complications. In this regard, neuroprotection strategies have been suggested by several groups, but their efficiency in clinical studies have not produced consistent results yet. In the past few years, we approached this question by using animal models of PD and testing the TRPM2 calcium channel and irisin. TRPM2 is a channel that is overexpressed in PD (and other diseases), and irisin represents one the last steps of the well-known beneficial effects of physical exercise. The latter effects have already been demonstrated in PD and other diseases, and we have contributed to this literature. Our preliminary results with those two possible therapeutical targets were very encouraging, as both showed an important preventive effect on PD neurodegeneration. However, we have not yet tested those two targets in the context of a possible treatment after PD is installed. This is the central aim of this research project submitted to FAPESP, as it includes a possible translational component in a more direct way. We will use the PD model based on the neurotoxin 6-hydroxy-dopamine, which produces neurodegeneration of groups of neurons usually affected by PD. We will then evaluate the motor behavior of the rats and mice in which the neurotoxin will be injected, with a combination of behavioral procedures. Once the model is installed, we will start the treatment with a TRPM2 blocker (in mice) and with irisin (in rats) and will proceed with the analysis of the impact of the treatment on motor behavior, and on morphological, biochemical and gene expression parameters. The latter three parameters will be evaluated by immunohistochemistry, immunoblotting and real-time PCR, which are routinely used in our laboratory, and that will be conducted after euthanasia. During the two-year period suggested for the development of the project, we will also use TRPM2 knockout mice. We are currently establishing the colony in our labs. In these mice, we will evaluate the impact of the neurotoxin used to generate a model of PD, with the same techniques mentioned above. We then anticipate that this research project will generate relevant data on neuroprotection in a PD model, with a possible impact on the future development of therapeutical strategies for PD. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BIANCHETTI, MARIA E.; FERREIRA, ANA FLAVIA F.; BRITTO, LUIZ R. G.. Inhibition of neuroinflammation by GIBH-130 (AD-16) reduces neurodegeneration, motor deficits, and proinflammatory cytokines in a hemiparkinsonian model. FRONTIERS IN NEUROANATOMY, v. 18, p. 12-pg., 2024-12-16. (18/07366-4, 22/14846-8, 22/14820-9, 23/05618-4, 20/02109-3)

FERREIRA, ANA FLAVIA F.; ULRICH, HENNING; FENG, ZHONG-PING; SUN, HONG-SHUO; BRITTO, LUIZ ROBERTO. Neurodegeneration and glial morphological changes are both prevented by TRPM2 inhibition during the progression of a Parkinson's disease mouse model. Experimental Neurology, v. 377, p. 15-pg., 2024-04-25. (20/02109-3, 18/07366-4, 22/14820-9)