Effects of the selective adenosine A2A receptor antagonist, SCH 412348, on the parkinsonian phenotype of MitoPark mice.
Adenosine A2A 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 A2A 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 A2A receptor antagonists in genetic models of hypodopaminergic states. SCH 412348 is a potent and selective adenosine A2A 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 (0.3-10mg/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 A2A receptor antagonists and predict that they will retain their efficacy in both mild and severe forms of motor impairment.
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Karen M
KM
Smith
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Susan E
SE
Browne
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Srinivasan
S
Jayaraman
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Carina J
CJ
Bleickardt
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Lisa M
LM
Hodge
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Edward
E
Lis
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Leon
L
Yao
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Sunday L
SL
Rittle
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Nathalie
N
Innocent
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Deborra E
DE
Mullins
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
George
G
Boykow
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Ian J
IJ
Reynolds
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
David
D
Hill
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
Eric M
EM
Parker
Department of In Vivo Pharmacology-Neuroscience, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: Robert.Hodgson@Merck.com.
Robert A
RA
Hodgson
D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005917:Globus Pallidus / Q000378:metabolism; D018476:Hypokinesia / Q000139:chemically induced; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D045442:Rotarod Performance Test; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C534887:(7-(2-(4-difluorophenyl)-1-piperazinyl)ethyl)-2-(2-furanyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D005680:gamma-Aminobutyric Acid
A(2A) receptor antagonist; Locomotor activity; MitoPark mouse; Movement disorder; Parkinson׳s disease