Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms

✍ Scribed by Liqun Yu; Hai-Ying Shen; Joana E. Coelho; Inês M. Araújo; Qing-Yuan Huang; Yuan-Ji Day; Nelson Rebola; Paula M. Canas; Erica Kirsten Rapp; Jarrod Ferrara; Darcie Taylor; Christa E. Müller; Joel Linden; Rodrigo A. Cunha; Jiang-Fan Chen

• Book ID: 102705410
• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 629 KB
• Volume: 63
• Category: Article
• ISSN: 0364-5134
• DOI: 10.1002/ana.21313

✦ Synopsis

Abstract

Objective

To investigate whether the motor and neuroprotective effects of adenosine A~2A~ receptor (A~2A~R) antagonists are mediated by distinct cell types in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) model of Parkinson's disease.

Methods

We used the forebrain A~2A~R knock‐out mice coupled with flow cytometric analyses and intracerebroventricular injection to determine the contribution of A~2A~Rs in forebrain neurons and glial cells to A~2A~R antagonist‐mediated motor and neuroprotective effects.

Results

The selective deletion of A~2A~Rs in forebrain neurons abolished the motor stimulant effects of the A~2A~R antagonist KW‐6002 but did not affect acute MPTP neurotoxicity. Intracerebroventricular administration of KW‐6002 into forebrain A~2A~R knock‐out mice reinstated protection against acute MPTP‐induced dopaminergic neurotoxicity and attenuated MPTP‐induced striatal microglial and astroglial activation.

Interpretation

A~2A~R activity in forebrain neurons is critical to the control of motor activity, whereas brain cells other than forebrain neurons (likely glial cells) are important components for protection against acute MPTP toxicity. Ann Neurol 2008