Regulation of Pleiotrophin and Fyn in the striatum of rats undergoing L-DOPA-induced dyskinesia.

L-DOPA is the gold standard pharmacological therapy for symptomatic treatment of Parkinson's disease (PD), however, its long-term use is associated with the emergence of L-DOPA-induced dyskinesia (LID). Understanding the underlying molecular mechanisms of LID is crucial for the development of newer and more effective therapeutic approaches. In previous publications, we have shown that Pleiotrophin (PTN), a developmentally regulated trophic factor, is up-regulated by L-DOPA in the striatum of dopamine denervated rats. We have also shown that both mRNA and protein levels of RPTPζ/ß, a PTN receptor, were upregulated in the same experimental condition and expressed in striatal medium spiny neurons. The PTN-RPTPζ/ß intracellular pathway has not been fully explored and it might be implicated in the striatal plastic changes triggered by L-DOPA treatment. RPTPζ/ß is part of the postsynaptic density zone and modulates Fyn, a Src tyrosine kinase that regulates the NR2A and NR2B subunits of the NMDA receptor and has been singled out as a key molecule in the development of LID. In this study, we evaluated the changes in PTN and Fyn protein levels and Fyn phosphorylation status in the 6-OHDA rat model of PD rendered dyskinetic with L-DOPA. We found an increase in the number of PTN immunoreactive neurons, no changes in the amount of total Fyn but a significant increase in Fyn phosphorylation in the dorsolateral striatum of dyskinetic rats. Our results support the idea that both PTN and Fyn may be involved in the development of LID, further contributing to the understanding of its molecular mechanisms.

Contrasting gene expression patterns induced by levodopa and pramipexole treatments in the rat model of Parkinson's disease.

Whether the treatment of Parkinson's disease has to be initiated with levodopa or a D2 agonist like pramipexole remains debatable. Levodopa is more potent against symptoms than D2 agonists, but D2 agonists are less prone to induce motor complications and may have neuroprotective effects. Although regulation of plastic changes in striatal circuits may be the key to their different therapeutic potential, the gene expression patterns induced by de novo treatments with levodopa or D2 agonists are currently unknown. By studying the whole striatal transcriptome in a rodent model of early stage Parkinson's disease, we have identified the gene expression patterns underlying therapeutically comparable chronic treatments with levodopa or pramipexole. Despite the overall relatively small size of mRNA expression changes at the level of individual transcripts, our data show a robust and complete segregation of the transcript expression patterns induced by both treatments. Moreover, transcripts related to oxidative metabolism and mitochondrial function were enriched in levodopa-treated compared to vehicle-treated and pramipexole-treated animals, whereas transcripts related to olfactory transduction pathways were enriched in both treatment groups compared to vehicle-treated animals. Thus, our data reveal the plasticity of genetic striatal networks possibly contributing to the therapeutic effects of the most common initial treatments for Parkinson's disease, suggesting a role for oxidative stress in the long term complications induced by levodopa and identifying previously overlooked signaling cascades as potentially new therapeutic targets.

Cabergoline and pramipexole fail to modify already established dyskinesias in an animal model of parkinsonism.

Levodopa-induced dyskinesias are one of the major limiting side effects encountered in the treatment of Parkinson's disease. Dopamine agonists of the D2 family are less prone to induce these abnormal involuntary movements (AIMs), and in some instances it has been proposed that they could counteract them once already established. As differences in the plasma half-life of a given DA agonist could be related with a greater or lesser propensity to induce or to counteract AIMs, we compared the effects of two D2 agonists (cabergoline and pramipexole) with different half-lives, and levodopa, at doses producing similar improvement in purposeful forelimb use, in rats with severe nigrostriatal lesion, previously sensitized to levodopa. The same therapeutic regime was subsequently used in pharmacologically naïve rats. We found that: (i) prior induction of AIMs by levodopa administration primes rats for the occurrence of AIMs during mono-therapy with pramipexole (but not with cabergoline); (ii) an intervening period of D2 agonist mono-therapy does not modify the severity of AIMs induced by subsequent mono-therapy with levodopa; iii. de novo treatment with D2 agonists is associated with a lower risk of AIMs (regardless of the severity of the lesion) and does not modify AIMs during subsequent mono-therapy with levodopa. An unexpected finding was that prior levodopa therapy sensitized rats to the therapeutic effects of D2 agonists given in mono-therapy. In summary, the use of the rat with nigrostriatal lesion to model relevant therapeutic conditions does not support that D2 agonists prevent the development of AIMs during subsequent levodopa mono-therapy or can revert the dysfunction underlying it.