Effects of the adenosine A2A receptor antagonist KW6002 on the dopaminergic system, motor performance, and neuroinflammation in a rat model of Parkinson's disease

• Published in: Neuropharmacology Vol. 247; p. 109862
• Main Authors: Prasad, Kavya, de Vries, Erik F.J., van der Meiden, Esther, Moraga-Amaro, Rodrigo, Vazquez-Matias, Daniel Aaron, Barazzuol, Lara, Dierckx, Rudi A.J.O., van Waarde, Aren
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-04-2024
• Subjects: A2A receptor; A2A receptor antagonist; Animal model; D2 receptor; Parkinson's disease; Positron emission tomography; Animal model; D2 receptor; Parkinson's disease; A2A receptor; Positron emission tomography; A2A receptor antagonist
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2024.109862

Adenosine A2A-receptors (A2AR) and dopamine D2-receptors (D2R) are known to work together in a synergistic manner. Inhibiting A2ARs by genetic or pharmacological means can relief symptoms and have neuroprotective effects in certain conditions. We applied PET imaging to evaluate the impact of the A2AR antagonist KW6002 on D2R availability and neuroinflammation in an animal model of Parkinson's disease. Male Wistar rats with 6-hydroxydopamine-induced damage to the right striatum were given 3 mg/kg of KW6002 daily for 20 days. Motor function was assessed using the rotarod and cylinder tests, and neuroinflammation and dopamine receptor availability were measured using PET scans with the tracers [11C]PBR28 and [11C]raclopride, respectively. On day 7 and 22 following 6-OHDA injection, rats were sacrificed for postmortem analysis. PET scans revealed a peak in neuroinflammation on day 7. Chronic treatment with KW6002 significantly reduced [11C]PBR28 uptake in the ipsilateral striatum [normalized to contralateral striatum] and [11C]raclopride binding in both striata when compared to the vehicle group. These imaging findings were accompanied by an improvement in motor function. Postmortem analysis showed an 84% decrease in the number of Iba-1+ cells in the ipsilateral striatum [normalized to contralateral striatum] of KW6002-treated rats compared to vehicle rats on day 22 (p = 0.007), corroborating the PET findings. Analysis of tyrosine hydroxylase levels showed less dopaminergic neuron loss in the ipsilateral striatum of KW6002-treated rats compared to controls on day 7. These findings suggest that KW6002 reduces inflammation and dopaminergic neuron loss, leading to less motor symptoms in this animal model of Parkinson's disease.
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•KW6002 treatment reduces [11C]PBR28 uptake in ipsilateral striatum and substantia nigra.•D2 availability in both striata, NAc and SNc decreases after chronic KW6002 administration.•Treatment with KW6002 reduced microglial reactivity in the 6-OHDA-induced lesion.•Treatment with KW6002 increased tyrosine hydroxylase expression in ipsilateral striatum.•KW6002 improves motor performance of rats.