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

Kavya Prasad, Erik F J de Vries*, Esther van der Meiden, Rodrigo Moraga-Amaro, Daniel Aaron Vazquez-Matias, Lara Barazzuol, Rudi A J O Dierckx, Aren van Waarde

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Adenosine A 2A-receptors (A 2AR) and dopamine D 2-receptors (D 2R) are known to work together in a synergistic manner. Inhibiting A 2ARs 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 A 2AR antagonist KW6002 on D 2R 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.

Original languageEnglish
Article number109862
Number of pages11
JournalNeuropharmacology
Volume247
DOIs
Publication statusPublished - 1-Apr-2024

Keywords

  • A2A receptor
  • D2 receptor
  • Animal model
  • Parkinson's disease
  • Positron emission tomography
  • A2A receptor antagonist

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