Objective
Current Parkinson's disease research focusses on treatment strategies that can interfere with the dopaminergic neuronal cell death. In this study, the striatal and the medial forebrain bundle (MFB) 6-hydroxydopamine rat model are used to screen drugs for their neuroprotective actions. These are evaluated through behavioral tests, tyrosine hydroxylase immunostaining and the dihydroxyphenylacetic acid (DOPAC) - dopamine (DA) ratio. During the screening, special attention is paid to drugs that mediate their neuroprotective effect by increasing the striatal expression of neurotrophic factors such as glial cell-line-derived neurotrophic factor (GDNF). Candesartan, a highly potent and non-surmountable antagonist of the angiotensin II type 1 receptor, has been suggested to possess neuroprotective properties and is the first compound tested in our model. However, before the start of the screening, the methodological approach was adapted in order to retrieve maximal data from one animal.

Methods
After determining motor behaviour, the rat is sacrificed, the striata are removed and the caudal part of the brain post-fixated for tyrosine hydroxylase immunostaining. The striata are homogenized in a sucrose-solution with a protease inhibitor which makes the sample compatible with the HPLC technique for analysis of the DA- and DOPAC content and with the Western blotting protocol for the determination of striatal GDNF.

Results
The optimized protocol can now be applied in routine in unilateral striatal and MFB 6-hydroxydopamine lesioned rats. Preliminary experiments indicate that systemic administration of candesartan (3mg/kg during 11 days) increases the DOPAC-DA ratio in the striatum of control animals and in the intact striatum of MFB lesioned rats.

Discussion
The developed protocol allows an efficient and reproducible screening of potential neuroprotective drugs in a 6-hydroxydopamine rat model. The observed increase in DOPAC-DA ratio suggests an antiparkinsonian effect and a possible neuroprotective action of candesartan. However, additional experiments (behavioral and immunohistological tests, Western blotting for GDNF,...) are required to unravel its potential role in the treatment of Parkinson's disease.
Original languageEnglish
Title of host publicationParkinsonism & Related Disorders
Volume13
Publication statusPublished - Dec 2007
EventFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet - Stockholm, Sweden
Duration: 21 Sep 200925 Sep 2009

Publication series

NameParkinsonism & Related Disorders
NumberS131

Conference

ConferenceFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet
CountrySweden
CityStockholm
Period21/09/0925/09/09

    Research areas

  • Parkinson's disease, neuroprotection

ID: 1750830