Effects of the selective adenosine A_2A receptor antagonist, SCH 412348, on the parkinsonian phenotype of MitoPark mice

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• 作者：Karen M. Smith ; Susan E. Browne ; Srinivasan Jayaraman ; Carina J. Bleickardt ; Lisa M. Hodge ; Edward Lis ; Leon Yao ; Sunday L. Rittle ; Nathalie Innocent ; Deborra E. Mullins ; George Boykow ; Ian J. Reynolds ; David Hill ; Eric M. Parker ; Robert A. Hodgson ; ^{Robert.Hodgson@Merck.com" class="auth_mail}
• 关键词：A2A receptor antagonist ; Movement disorder ; MitoPark mouse ; Locomotor activity ; Parkinson壮s disease
• 刊名：European Journal of Pharmacology
• 出版年：5 April, 2014
• 年：2014
• 卷：728
• 期：Complete
• 页码：31-38
• 全文大小：498 K

文摘

Adenosine A_2A receptors are predominantly localized on striatopallidal gamma-aminobutyric acid (GABA) neurons, where they are colocalized with dopamine D₂ receptors and are involved in the regulation of movement. Adenosine A_2A receptor antagonists have been evaluated as a novel treatment for Parkinson壮s disease and have demonstrated efficacy in a broad spectrum of pharmacological and toxicological rodent and primate models. Fewer studies have been performed to evaluate the efficacy of adenosine A_2A receptor antagonists in genetic models of hypodopaminergic states. SCH 412348 is a potent and selective adenosine A_2A receptor antagonist that shows efficacy in rodent and primate models of movement disorders. Here we evaluated the effects of SCH 412348 in the MitoPark mouse, a genetic model that displays a progressive loss of dopamine neurons. The dopamine cell loss is associated with a profound akinetic phenotype that is sensitive to levodopa (l-dopa). SCH 412348 (0.3-10 mg/kg administered orally) dose dependently increased locomotor activity in the mice. Moreover, SCH 412348 retained its efficacy in the mice as motor impairment progressed (12-22 weeks of age), demonstrating that the compound was efficacious in mild to severe Parkinson壮s disease-like impairment in the mice. Additionally, SCH 412348 fully restored lost functionality in a measure of hind limb bradykinesia and partially restored functionality in a rotarod test. These findings provide further evidence of the anti-Parkinsonian effects of selective adenosine A_2A receptor antagonists and predict that they will retain their efficacy in both mild and severe forms of motor impairment.