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A_2A adenosine receptor overexpression and functionality, as well as TNF- levels, correlate with motor symptoms in Parkinson’s disease

Katia Varani^*, Fabrizio Vincenzi^*, Alice Tosi^*, Stefania Gessi^*, Ilaria Casetta, Gino Granieri, Patrik Fazio, Edward Leung, Stephen MacLennan, Enrico Granieri and Pier Andrea Borea^*,1

^* Department of Clinical and Experimental Medicine, Pharmacology Section, and

Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy;

Neurological Clinic, University Hospital of Ferrara, Ferrara, Italy; and

King Pharmaceuticals Inc, Research and Development, Cary, North Carolina, USA

¹ Correspondence: Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, via Fossato di Mortara 17-19 44100 Ferrara, Italy. E-mail: bpa{at}unife.it

The antagonistic interaction between adenosine and dopamine receptors could have important pathophysiological and therapeutic implications in Parkinson’s disease (PD). The primary aim of this study was to investigate the expression, affinity, and density of A₁, A_2A, A_2B, and A₃ adenosine receptors (ARs) and D₂ dopamine receptors (D₂Rs) in PD. An increase in A_2AAR density in putamen was found. The presence and functionality of ARs in human lymphocyte and neutrophil membranes from patients with PD revealed a specific A_2AAR alteration compared with healthy subjects. A statistically significant linear correlation among the A_2AAR density, functionality, or tumor necrosis factor- (TNF-) levels and Unified Parkinson’s Disease Rating Scale (UPDRS) motor score was reported. Adenosine concentration and TNF- levels were increased in plasma of patients with PD. In rat adrenal pheochromocytoma (PC12) cells, a widely useful model, adenosine antagonists decreased dopamine uptake, and an opposite effect was mediated by A_2A agonists. This is the first report showing the presence of an A_2AAR alteration in putamen in PD that mirrors a similar up-regulation in human peripheral blood cells. Moreover, the correlation found between A_2AAR density or A_2A agonist potency and UPDRS motor score highlights the central role of A_2AARs in the pharmacological treatment of PD.—Varani, K., Vincenzi, F., Tosi, A., Gessi, S., Casetta, I., Granieri, G., Fazio, P., Leung, E., MacLennan, S., Granieri, E., Borea, P. A. A_2A adenosine receptor overexpression and functionality, as well as TNF- levels, correlate with motor symptoms in Parkinson’s disease.

Key Words: D₂ dopamine receptors • human putamen • human lymphocytes and neutrophils

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