Objective: To investigate whether in a model of Parkinson’s Disease (PD), an early treatment with the serotonin 5-HT1A/1B receptor agonist eltoprazine and the adenosine A2A receptor antagonist preladenant counteract neuroinflammation correlated to dyskinetic movements induced by L-dopa.

Background: Several evidence have implicated neuroinflammation in PD progression and L-dopa-induced dyskinesia 1. The serotonin 5-HT1A/1B receptor agonists suppressed L-dopa-induced dyskinetic movements in the unilateral 6-hydrossidopamine (6-OHDA)-lesioned rat model of PD, reducing, however, L-dopa efficacy 2. In contrast, the adenosine A2A receptor antagonists, which has neuroprotective effects, increased L-dopa efficacy without exacerbating dyskinetic-like behavior in animal models of PD 3. Our previous report demonstrated that combination of eltoprazine, with preladenat produced prevention and reduction of L-dopa-induced dyskinesia, without impairing the efficacy of L-dopa in relieving motor symptoms 4.

Methods: Unilateral 6-OHDA-lesioned rats, were sub-chronically treated with eltoprazine and/or preladenant, alone or in combination with L-dopa, and abnormal involuntary movements (AIMs) as index of dyskinesia, were evaluated. Four days after the last drugs administration all rats were treated with L-dopa or vehicle. The immunoreactivity (IR) for the glial fibrillary acidic protein (GFAP), and the co-localization of the ionized calcium binding adaptor molecule 1 (IBA1), with interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and IL-10, were evaluated in the denervated caudate-putamen (CPu) and substantia nigra pars compacta (SNc). Finally, the IR for tyrosine hydroxylase (TH) and the dopamine (DA) transporter (DAT) was quantified.

Results: Combined pre-treatment with L-dopa plus eltoprazine plus preladenant induced a reduction of basal GFAP and IBA1 IRs in CPu and SNc. Moreover, a reduction of IL-1β in IBA1-positive cells in CPu and SNc and of TNF-α in IBA1-positive cells in SNc was observed. Besides, a significant increase in IL-10 in IBA1-positive cells was also observed in SNc. Finally, a significant reduction of DAT and TH IRs was found in all the experimental groups.

Conclusions: The present findings indicate that the combined administration of L-dopa plus eltoprazine plus preladenant reduced the neuroinflammatory responses in the nigrostriatal system of 6-OHDA-lesioned rats.

References: 1. Tansey, M.G., Goldberg, M.S. (2010). Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis. 37, 510-518. 2. Bezard E, Tronci E, Pioli E, Björklund A, Carta M. Study of the antidyskinetic effect of eltoprazine in animal models of levodopa-induced dyskinesia. Mov Disord. 2013; 28 (8): 1088-96. 3. Kanda T, Uchida S. Clinical/pharmacological aspect of adenosine A2A receptor antagonist for dyskinesia. Int Rev Neurobiol 2014;119:127-50. 4. Pinna A, Ko WK, Costa G, Tronci E, Fidalgo C, Simola N, Li Q, Tabrizi MA, Bezard E, Carta M, Morelli M. Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson’s disease. Mov Disord. 2016; 31(4):501-11.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/combined-administration-of-a2a-receptor-antagonist-and-5-ht1a-1b-receptor-agonist-reverses-neuroinflammation-in-the-6-ohda-model-of-parkinsons-disease/