Analysis of gene expression shows that long term levodopa treatment induces antioxidant and trophic molecules in the striatum of an animal model of Parkinson's disease (PD).

FERRARIO JE; TARAVINI IR; MOURLEVAT S; DELFINO MA; STEFANO A; RAISMAN-VOZARI R; MURER MG; RUBERG M; GERSHANIK O

Paris, Francia

Congreso; The Federation of European Neuroscience Societies, Forum 2002; 2002

The Federation of European Neuroscience Societies

Levodopa therapy is the most widely used treatment for PD. In addition to its potent therapeutic activity, several undesired effects may appear after several years of treatment, suspected to be related to a toxic effect of the drug. However, it has been reported that levodopa, under certain conditions, could promote neurite outgrowth (Mena et al., 1997) and plasticity (Murer et al, 1998). These properties may result from induction of gene expression. To approach this issue, we gave levodopa / carbidopa orally (170/70 mg/kg) for 6 months to female rats unilaterally lesioned with 6-hydroxy-dopamine and prepared a cDNA library enriched in transcripts differentially expressed in the ipsilateral striatum of levodopa-treated rats by subtraction with transcripts from vehicle-treated ones. Hybridization of the subtracted library with striatal cDNA of untreated animals showed that only 5% were common to both. The library has been estimated to contain approximately 200 different clones. As a fast and easy screening of the library the subtracted cDNA was hybridized to a rat gene microarray. Approximately 70 of the 1176 transcripts in the array were labeled. Among them we found several genes related to plasticity: i) neurotrophic factors or related molecules (HB-GAM, FGF2, rTGF), ii) markers of neurite outgrowth (MBP, PLP), iii) signal transduction molecules (ERK1, Ras-GRF, IP3-3K). In addition several molecules related to protection against oxidative stress were identified (SOD1, GPX4 and GST). A significant number of these genes were further confirmed by in situ hybridization analysis in an independent population of animals. These series of genes (among others) may give clues about changes occurring during levodopa treatment and support the putative antioxidant and plastic properties of long-term levodopa administration.