Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson's Disease/Dementia with Lewy Bodies
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders of the aging population characterized by the accumulation of alpha-synuclein (alpha-syn). The mechanisms triggering alpha-syn toxicity are not completely understood, however, c-terminus truncation of alpha-syn by proteases such as calpain may have a role. Therefore, inhibition of calpain may be of value. The main objective of this study was to evaluate the effects of systemically administered novel low molecular weight calpain inhibitors on alpha-syn pathology in a transgenic mouse model. For this purpose, non-tg and alpha-syn tg mice received the calpain inhibitors - Gabadur, Neurodur or a vehicle, twice a day for 30 days. Immunocytochemical analysis showed a 60% reduction in alpha-syn deposition using Gabadur and a 40% reduction using Neurodur with a concomitant reduction in c-terminus alpha-syn and improvements in neurodegeneration. Western blot analysis showed a 77% decrease in alpha-spectrin breakdown products (SBDPs) SBDPs with Gabadur and 63% reduction using Neurodur. There was a 65% reduction in the active calpain form with Gabadur and a 45% reduction with Neurodur. Moreover, treatment with calpain inhibitors improved activity performance of the alpha-syn tg mice. Taken together, this study suggests that calpain inhibition might be considered in the treatment of synucleinopathies.
Hassen, G., Kesner, L., Stracher, A., Shulman, A., Rockenstein, E., Mante, M., Adame, A., Overk, C., Rissman, R., & Masliah, E. (2018). Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson's Disease/Dementia with Lewy Bodies. Scientific Reports, 8 (1), 18083. https://doi.org/10.1038/s41598-018-35729-1