The novel substituted pyrimidine, KP544, reduces motor deficits in the R6/2 transgenic mouse model of Huntington's disease

Article type: Research Article

Authors: Dey, Nicholas D.^; | Boersen, Angela J.^; | Myers, Rebecca A.^; | York, Lynae R.^; | Bombard, Matthew C.^; | Lu, Ming^; | Sandstrom, Michael I. | Hulce, Verne D. | Lescaudron, Laurent^{; ; ;} | Dunbar, Gary L.^;

Affiliations: Field Neurosciences Laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48858, USA | Department of Psychology and Program in Neuroscience, Central Michigan University, Mt. Pleasant, MI 48858, USA | Field Neurosciences Institute, 4677 Towne Center, Saginaw, MI 48604, USA | INSERM U643, Nantes, F44093 France | CHU Nantes, Institut de Transplantation et de Recherche en Transplantation, ITERT, Nantes, F44093 France | Université de Nantes, Faculté de Médecine, Nantes, F44000 France | Université de Nantes, Faculté des Sciences et des Techniques, Service de Physiologie Animale et Humaine, Nantes, F44322 France

Note: [] Corresponding author: Gary L. Dunbar, Ph.D., Director, Program in Neuroscience, Health Professions Building, Room 2182, Central Michigan University, Mt. Pleasant, MI 48859, USA. E-mail: dunba1g@cmich.edu

Abstract: Purpose: The purpose of this study was to test the potential therapeutic effects of the substituted pyrimidine, KP544, which has been shown to amplify the effects of nerve growth factor in vitro, on motor deficits in the R6/2 transgenic mouse model of Huntington's disease (HD). Methods: Young, female R6/2 mice were given daily oral intubation of either 10 mg/kg KP544 or vehicle (0.5% methylcellulose) at 6 weeks of age and tested from postnatal weeks 8 through 12 on a battery of motor tasks, including assessments of clasping (drawing of the limbs to the torso when suspended by the tail), motor coordination on the rotarod, and spontaneous motor activity in the open-field. Following testing, the mice were sacrificed and the brains were sectioned and stained with cresyl violet for histological examination. Results: KP544 treatment decreased balance deficits on the rotarod task, reduced clasping, delayed the onset of hypoactivity, and reduced enlargement of the lateral ventricles in R6/2 mice. Conclusion: These results suggest that KP544 can reduce motor deficits and anatomical alterations in R6/2 mice. Further research into the use of KP544 as a potential pharmacotherapy HD is warranted.

Keywords: Rotarod, clasping, spontaneous motor activity, nerve growth factor amplifier

Journal: Restorative Neurology and Neuroscience, vol. 25, no. 5-6, pp. 485-492, 2007