Efeito antidiscinético do MRS2500, antagonista dos receptores P2Y1, em ratos com parkinsonismo experimental induzido por 6-OHDA e tratados com L-DOPA

Abstract

Dyskinesia is the major adverse effect of L-DOPA chronic treatment in Parkinson's disease patients, characterized by peaks of abnormal involuntary movements coinciding with L-DOPA peak of action. Since ATP plays an important role in the control of striatum dopamine release by purine receptors activation, the aim of this study was the evaluation of the possible anti-dyskinetic effect of the MRS2500, a P2Y1 receptor antagonist, in the pathophysiology of L-DOPA-induced dyskinesia (LID). 70 male Wistar rats (250-300g) were used, divided into five groups: 1. False-operated, 2. False-operated treated with MRS2500, 3. Operated animals that received 6-OHDA (18 µg/3 µL) intrastriatally, called Parkinsonian; 4. Parkinsonian treated with L-DOPA (30mg/kg) orally, called dyskinetic, and 5. Dyskinetic treated with MRS2500 (2 nmol/μl). The experimental model was induced by 6-OHDA injection in the animals' striatum through stereotaxic surgery. The treatment with L-DOPA and/or MRS2500 were initiated on the 15th day after surgery, followed for 22 days. L-DOPA was administered daily orally and MRS2500 was administered in the striatum by continuous infusion through mini infusion pumps. The evaluation of abnormal involuntary movements (AIMs) was performed on the 21st, 28th and 35th days after surgery, followed by motor coordination evaluation on the 36th day. In order to understand the mechanistic underlying the MRS2500 anti-dyskinetic effect we evaluated neuronal degeneration, by tyrosine hydroxylase (TH) immunostaining, dopamine transporters (DAT) alterations, and neuroinflammation (astrogliosis, microgliosis and COX-2). MRS2500 decreased AIMs on dyskinetic animals and improved motor coordination performance. In addition, MRS2500 prevented significantly decreased astrogliosis, microgliosis and COX-2 immunostaining, enhanced by L-DOPA treatment. Thus, our results suggests that P2Y1 purinergic receptors play an important role in the development of L-DOPA-induced dyskinesia. Moreover, the anti-dyskinetic effect of P2Y1 receptors blockade by MRS2500 is probably due to its activity against neuroinflammation.