Details

Autor(en) / Beteiligte

• Smith, Karen M
• Browne, Susan E
• Jayaraman, Srinivasan
• Bleickardt, Carina J
• Hodge, Lisa M
• Lis, Edward
• Yao, Leon
• Rittle, Sunday L
• Innocent, Nathalie
• Mullins, Deborra E
• Boykow, George
• Reynolds, Ian J
• Hill, David
• Parker, Eric M
• Hodgson, Robert A

Titel

Effects of the selective adenosine A sub(2A) receptor antagonist, SCH 412348, on the parkinsonian phenotype of MitoPark mice

Ist Teil von

• European journal of pharmacology, 2014-04, Vol.728, p.31-38

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• Adenosine A sub(2A) receptors are predominantly localized on striatopallidal gamma-aminobutyric acid (GABA) neurons, where they are colocalized with dopamine D sub(2) receptors and are involved in the regulation of movement. Adenosine A sub(2A) receptor antagonists have been evaluated as a novel treatment for Parkinson'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 sub(2A) receptor antagonists in genetic models of hypodopaminergic states. SCH 412348 is a potent and selective adenosine A sub(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'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 sub(2A) receptor antagonists and predict that they will retain their efficacy in both mild and severe forms of motor impairment.