Objective: To evaluate whether an early treatment with the serotonin 5-HT1A/1B receptor agonist eltoprazine and the adenosine A2A receptor antagonist preladenant prevent the onset of L-dopa-induced dyskinesia, in the rat 6-hydroxydopamine  (6-OHDA) model of Parkinson’s Disease (PD).

Background: Previous reports by our research group, demonstrated that combination of eltoprazine and preladenat produced a reduction of L-dopa-induced dyskinesia, without impairing the efficacy of L-dopa in relieving motor symptoms1,2. Moreover, the combined administration of L-dopa plus eltoprazine and preladenant reduced the astroglial and microglial responses in the nigrostriatal system of dyskinetic 6-OHDA-lesioned rats. On this basis, we hypothesize that the early combined administration of eltoprazine and preladenant may produce prevention of the onset of L-dopa-induced-dyskinesia in a rodent model of PD.

Method: Unilateral 6-OHDA-lesioned rats, were treated for 2 weeks with eltoprazine and/or preladenant alone or in combination with L-dopa, and abnormal involuntary movements (AIMs) as index of dyskinesia, were evaluated. Moreover, induction of immediate-early gene zif-268 (as index of long-term changes correlated with dyskinesia), and microglial and astroglial markers (GFAP, IBA1, IL-1β, TNF-α, IL-10, etc) were evaluated.

Results: Behavioral evaluation of AIMs, demonstrated that association of L-dopa plus eltoprazine and preladenant significantly prevented the onset of dyskinetic-like behaviors induced by L-dopa, and this effect was maintained throughout treatment. Moreover, the pretreatment with L-dopa plus eltoprazine and preladenant significantly delayed the onset of dyskinetic-like behaviors induced by challenge with L-dopa. Zif-268 was increased in striatum of rats pretreated with L-dopa or L-dopa plus preladenant compared with vehicle pretreated rats; whereas, rats pretreated with eltoprazine (with or without preladenant) had lower zif-268 activation after challenge with L-dopa. Finally, association of L-dopa plus eltoprazine and preladenant reduced the neuroinflammatory response induced by L-dopa in the nigrostriatal system of 6-OHDA-lesioned rats.

Conclusion: The present findings suggest that combined administration of L-dopa with eltoprazine and preladenant may be a promising therapeutic strategy for treating motor symptoms, delaying the onset of dyskinesia and reducing the neuroinflammation response in PD.

References: 1. 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. 2. Kanda T, Uchida S. Clinical/pharmacological aspect of adenosine A2A receptor antagonist for dyskinesia. Int Rev Neurobiol 2014;119:127-50. 3. 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. 4. 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.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuroinflammation-and-activation-of-zif-268-in-dyskinetic-6-ohda-lesioned-rats-is-counteracted-by-association-of-a-5-ht1a-1b-receptor-agonist-and-an-a2a-receptor-antagonist/