Studie naar de neuroprotectieve effecten van candesartan in het striataal en het "medial forebrain bundle" diermodel voor de ziekte van parkinson

Abstract

Current Parkinson's disease (PD) research focuses on treatment strategies that can interfere with the dopaminergic (DA-ergic) neuronal cell death. The presence of a renin angiotensin system (RAS) in the brain has been shown and interactions with the dopaminergic system have been described. Furthermore, research has revealed that manipulation of the RAS with ACE-inhibitors and angiotensin II receptor type 1 (AT1) antagonists can cause neuroprotection in animal models of stroke and other neurodegenerative disorders such as PD. This neuroprotective effect has been attributed to a reduced stimulation of the AT1 receptor, which has been linked to the formation of reactive oxygen species, and an increased stimulation of the AT2 receptor which is involved in neuronal regeneration and differentiation. In this study, the striatal and the MFB 6-OHDA rat model were used to screen candesartan (CS), a selective and non-surmountable angiotensin II type 1 (AT1) receptor antagonist for its possible neuroprotective actions. Treatment with CS (3mg/kg/day s.c.) was started one day after lesioning and continued for 11 days. After a wash-out period of 48 hours, the rats were sacrificed and the brains were quickly removed. The neuroprotective effects were evaluated by determination of the striatal DA content and cell counts of the tyrosine hydroxylase immunopositive cells. In both models, treatment with candesartan was not able to protect DA-ergic neurons against the neurotoxicity of 6-OHDA, neither at the level of the SNpc, nor at the level of striatum. However, systemic administration of CS increased the DOPAC:DA ratio in the intact striatum of MFB lesioned rats and in the denervated striatum of the striatally lesioned rats. This increase may reflect an increase DA-ergic neurotransmission. In conclusion, treatment with candesartan could not protect DA-ergic neurons against 6-OHDA neurotoxicity. However, the effects of CS on the DOPAC:DA ratio support the hypothesis that there is an interaction between the DA-ergic system and the central RAS.

Date of Award	Jul 2008
Original language	Dutch
Supervisor	Sophie Sarre (Promotor), Birgit Mertens (Co-promotor) & Yvette Michotte (Co-promotor)