D2R Agonist Bromocriptine Improves Neurodegeneration in Spinocerebellar Ataxia Type 1 Mouse Model (P05.021)

Abstract

Objective: To explore the use of dopamine D2 receptor (D2R) agonist Bromocriptine (BRC) as a potential Spinocerebellar Ataxia Type 1 (SCA1) therapeutic. Background SCA1, a dominantly inherited neurodegenerative disease, results from an expanded CAG repeat mutation in the ataxin-1 gene which causes progressive ataxia, loss of cerebellar Purkinje cells (PCs) and neurons in the brainstem. The prominent pathological features both in SCA1 patients and mouse model are remarkable PC dendritic atrophy and the development of S100B positive PC vacuoles. Mutant ataxin-1 aggregation and neurotoxicity is dependent on its phosphorylation status at S776. Previously, we have shown that D2R agonist BRC can reduce S776 phosphorylation and aggregation of the mutant ataxin-1 in cell culture models. Design/Methods: In this study, we treated SCA1 mice with 20mg/kg BRC every other day for 3 weeks. We explored the therapeutic potential of BRC at two age intervals corresponding to differential degenerative state of disease. After treatment, animals were analyzed for improvements in ataxic behavior on rotarod and bar tests and their brains processed for morphological and Western blot analysis. Results: A significant improvement was demonstrated on the bar test in SCA1 mice treated with BRC compared to vehicle treated mice. However, no significant changes were observed on the rotarod test. Immunohistochemical analysis showed improved PC morphology by increasing PC dendritic branch area and reducing S100B vacuole formation in SCA1 mice treated with BRC as compared to the vehicle treated animals. Furthermore, Western blot analysis revealed that BRC treated animals have increased levels of the calcium binding protein, CaB, a PC marker protein down regulated in SCA1, as compared to vehicle. Conclusions: Currently there is no treatment available for SCA1 patients. Our findings that BRC suppresses SCA1 phenotype suggest that BRC treatment may help reduce SCA1 pathology in human patients. Supported by: The Currier Spinocerebellar Degenerative Grant from the University of Mississippi Medical Center, Jackson, MS. Disclosure: Dr. Hearst has nothing to disclose. Dr. Lopez has nothing to disclose. Dr. Shao has nothing to disclose. Dr. Vig has nothing to disclose.