Upregulation of Receptor Protein Tyrosine Phosphatase z/beta in the nigrostriatal system of hemiparkinsonian rats treated with levodopa: possible mediator of neuroplasticity ?

FERRARIO, JUAN ESTEBAN; GOMES, MARGARETE ZANARDO; SALDAÑA-ORTEGA, MARISA; HERRERO, TRINIDAD; HUNOT, STEPHANE; RAISMAN-VOZARI, RITA

San Diego, USA

Congreso; Society for Neuroscience Meeting; 2007

Society for Neuroscience

Parkinson’s disease (PD) is characterized by the selective damage to dopaminergic neurons in the nigrostriatal pathway. However, surviving neurons undergo both spontaneous and levodopa-induced plastic changes. We have recently identified pleiotrophin (PTN) mRNA as being increased in the lesioned striatum of hemiparkinsonian rats after a long-term treatment with levodopa. PTN is a secreted heparin-binding growth factor that is highly expressed during early postnatal brain development where it mediates axon growth and guidance. In addition, it has been shown that PTN enhances the maturation of dopaminergic neurons in vitro. This data, among others, suggest that PTN may be a new modulatory factor of dopaminergic neurons, and consequently, may contribute to the plastic adaptations aimed at restoring dopaminergic neurotransmission in the damaged striatum. Thus, the PTN receptors involved in this function might represent a crucial pharmacological target in the treatment of PD. The intracellular effects of PTN are mediated by three known membrane receptors: N-syndecan (an heparan sulfate proteoglycan), RPTP z/beta (a tyrosine phosphatase) and ALK (a tyrosine kinase). Abundant evidence suggests that RPTPz/beta mediates the differentiation and axonal growth attributed to PTN. To go beyond our previous observations in vivo, we analyzed the changes in expression of PTN and its receptors in the dopaminergic system, by quantitative real time RT-PCR on total RNA purified from striatal and ventral mesencephalon of rats lesioned intrastriatally with 6-OHDA, which were treated either with vehicle or levodopa for 21 days. We found that the mRNAs of PTN and two of its receptors, RPTPz/beta and N-Syndecan, are upregulated in the striatum of 6-OHDA rats; and RPTP z/beta is even more expressed in animals treated with levodopa. We did not detect changes in the expression of any of these genes in the dopaminergic neuronal bodies at the ventral mesencephalon. Finally, we investigated the mechanisms involved in the PTN-RPTPz/beta signal in the dopaminergic system by immnuhistochemical detection of these molecules and by pharmacological manipulation of primary cultures of dopaminergic neurons. It is, therefore, tempting to speculate that RPTPz/beta has an active role in the recovery of dopaminergic neurons observed spontaneously and after levodopa treatment.