Current Parkinson's disease (PD) research focusses on evaluating treatment strategies that combine antiparkinsonian and neuroprotective effects. The presence of a renin angiotensin system (RAS) in the brain has been shown and interactions of this system with the dopaminergic (DA-ergic) system have been described. Furthermore, manipulation of this RAS with angiotensin II (Ang II) type 1 (AT1) receptor antagonists resulted in neuroprotection in animal models of stroke and the MPTP model of PD. The neuroprotective effect has been attributed to an inhibition of the AT1 receptor and increased stimulation of the AT2 receptor. In this study, candesartan (CS), a highly potent and non-surmountable AT1 receptor antagonist was screened for its neuroprotective effects in two 6-hydroxydopamine (6-OHDA) rat models of PD. In addition, the neurochemical effects of CS were studied in order to further elucidate the interactions between the RAS and the DA-ergic system. Treatment with CS (3mg/kg/day s.c.) of rats with unilateral 6-OHDA lesion of the medial forebrain bundle (MFB) or striatum, was started 24 hours after the lesion and continued for 11 days. After a wash-out period of 48 hours, the rats were sacrificed and the brains quickly removed. Neuroprotection was evaluated by determination of the striatal DA and DOPAC content and cell counts in the substantia nigra pars compacta (SNpc) after tyrosine hydroxylase immunostaining. The neurochemical effects of acute administration of CS (3mg/kg s.c.) were investigated with in vivo microdialysis. In both models, treatment with CS, started after lesioning, could not protect DA-ergic neurons, neither at the level of the cell bodies in the SNpc, nor at the level of the DA-ergic terminals in the striatum. After acute administration of CS, the extracellular DOPAC:DA ratio as determined by microdialysis was decreased in the striatum of intact rats. Our data suggest that CS is not neuroprotective when treatment is started after lesioning. Furthermore, the neurochemical effects imply a relationship of the AT1 and/or AT2 receptor with the synthesis of DA, possibly via interaction with tyrosine hydroxylase.
Original languageEnglish
Title of host publicationVicore Pharma Meeting
Publication statusPublished - Jun 2008
EventFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet - Stockholm, Sweden
Duration: 21 Sep 200925 Sep 2009

Publication series

NameVicore Pharma Meeting


ConferenceFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet

    Research areas

  • neuroprotection, candesartan, Parkinson's disease

ID: 1752304