Estudo do efeito de moduladores do sistema renina angiotensina em sintomas não motores da Doença de Parkinson

Abstract

Parkinson's disease (PD) is characterized by the loss of 50-70% of dopaminergic neurons in the compact part of the substantia nigra. Although the pathological aspects are well described, the dopaminergic neuron death is still a subject of debate, and it is probably multifactorial. Among the several factors, some studies have shown the role of the Renin-Angiotensin System (RAS) in the death of dopaminergic neurons in PD. Herein, we aimed to investigate the mechanisms related to the development of cognitive and behavioural changes during a preclinical phase of PD as well as the effects of pharmacological strategies able to modulate RAS on those changes. Then, we used an experimental model of DP induced by intranasal infusion of the neurotoxin MPTP (1mg/nostril) in C57BL/6 mice aged 8-10 weeks. In this study, the animals were divided in 6 groups: SAL+SAL (control), SAL+MPTP (MPTP-mice received saline), Telmizartan (an antagonist of AT1 receptors)+MPTP and AVE099 ( an agonist of Mas receptors)+MPTP. Each treatments initiated 5 days before the MPTP infusion and remained until the 11th-day post-infusion. Standardized behavioural tests and immune assays were performed in key areas of PD, including substantia nigra, striatum and hippocampus. The treatment with AVE099 prevented olfactory memory loss at 5 days post-MPTP-infusion. Interestingly, AVE099 also prevented anxiety-like behaviour at 6 and 11 days post-MPTP- infusion. No significant differences were found in locomotor activity, work memory or in depressive-like behaviour. In addition, MPTP was not able to dramatically alter the components of RAS, such as Angiotensin II (AngII), Angiotensin (1-7) (Ang (1-7)), Angiotensinogen Converting Enzyme (ACE), Angiotensinogen Converting Enzyme 2 (ACE2) of DP in the 11th-day post infusion. On the other hand, the treatment with AVE0991 increased the levels of ACE2 in the striatum, and increased AngII and Ang (1-7) in the substantia nigra. However, decreased the levels of AngII and Ang (1-7) in the hippocampus and ACE in the substantia nigra. Therefore, our result suggests that the potentiation of the contra-regulatory axis of the renin-angiotensin system might play a crucial role in the neuroprotection of the pre-clinical signs of PD, including loss of olfactory memory and anxiety