Caracterização de um modelo prodrômico da Doença de Parkinson e estudo do efeito de moduladores do sistema Renina-Angiotensina

Abstract

Parkinson's disease (PD) is classically conceived as a motor condition characterized resting tremor, bradykinesia, rigidity and postural instability, related to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The decrease in dopamine also affects non-dopaminergic nuclei, leading to non-motor symptoms related to PD (NMS-PD), which can appear up to 25 years before the motor symptoms. Although NMS-PD reduce the quality of life of PD patients, the mechanisms underlying the development of these symptoms remain poorly understood. Previous research has identified the presence of the Renin-Angiotensin System (RAS) in the brain, raising the hypothesis that RAS molecules may play a role in neurodegenerative diseases, including PD. The main goal of this study was to investigate the potential involvement of the RAS in NMS-PD. First, with the aim of standardizing a prodromal model of PD, we administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or a saline solution intranasally to male C57BL/6 mice. Subsequently, we conducted a comprehensive behavioral assessment and analyzed neuroinflammatory and dopaminergic markers in key areas of PD, such as the SNpc and the Striatum. After this characterization, we conducted new experiments to investigate the role of RAS components in NMS-PD. We divided male C57BL/6 mice into five groups, including a MPTP group that received 0.9% saline. The other groups received specific treatments: Perindopril (5mg/Kg, an angiotensin-converting enzyme (ACE) inhibitor), Telmisartan (10mg/Kg, an AT1 receptor antagonist), and AVE099 (10mg/Kg, a Mas receptor agonist), administered by gavage. These treatments began five days before MPTP infusion and continued until the 11th day after infusion. Our results revealed a significant improvement in behavioral, inflammatory, and neurochemical parameters in animals treated with AVE0991, indicating a potential neuroprotective role of RAS alternative axis in experimental PD.