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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 α-synuclein (α-syn). The mechanisms triggering α-syn toxicity are not completely understood, however, c-terminus truncation of α-syn by proteases...

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Autores principales: Hassen, Getaw Worku, Kesner, Leo, Stracher, Alfred, Shulman, Abraham, Rockenstein, Edward, Mante, Michael, Adame, Anthony, Overk, Cassia, Rissman, Robert A., Masliah, Eliezer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308237/
https://www.ncbi.nlm.nih.gov/pubmed/30591714
http://dx.doi.org/10.1038/s41598-018-35729-1
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author Hassen, Getaw Worku
Kesner, Leo
Stracher, Alfred
Shulman, Abraham
Rockenstein, Edward
Mante, Michael
Adame, Anthony
Overk, Cassia
Rissman, Robert A.
Masliah, Eliezer
author_facet Hassen, Getaw Worku
Kesner, Leo
Stracher, Alfred
Shulman, Abraham
Rockenstein, Edward
Mante, Michael
Adame, Anthony
Overk, Cassia
Rissman, Robert A.
Masliah, Eliezer
author_sort Hassen, Getaw Worku
collection PubMed
description Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders of the aging population characterized by the accumulation of α-synuclein (α-syn). The mechanisms triggering α-syn toxicity are not completely understood, however, c-terminus truncation of α-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 α-syn pathology in a transgenic mouse model. For this purpose, non-tg and α-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 α-syn deposition using Gabadur and a 40% reduction using Neurodur with a concomitant reduction in c-terminus α-syn and improvements in neurodegeneration. Western blot analysis showed a 77% decrease in α-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 α-syn tg mice. Taken together, this study suggests that calpain inhibition might be considered in the treatment of synucleinopathies.
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spelling pubmed-63082372019-01-04 Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies Hassen, Getaw Worku Kesner, Leo Stracher, Alfred Shulman, Abraham Rockenstein, Edward Mante, Michael Adame, Anthony Overk, Cassia Rissman, Robert A. Masliah, Eliezer Sci Rep Article Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders of the aging population characterized by the accumulation of α-synuclein (α-syn). The mechanisms triggering α-syn toxicity are not completely understood, however, c-terminus truncation of α-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 α-syn pathology in a transgenic mouse model. For this purpose, non-tg and α-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 α-syn deposition using Gabadur and a 40% reduction using Neurodur with a concomitant reduction in c-terminus α-syn and improvements in neurodegeneration. Western blot analysis showed a 77% decrease in α-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 α-syn tg mice. Taken together, this study suggests that calpain inhibition might be considered in the treatment of synucleinopathies. Nature Publishing Group UK 2018-12-27 /pmc/articles/PMC6308237/ /pubmed/30591714 http://dx.doi.org/10.1038/s41598-018-35729-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hassen, Getaw Worku
Kesner, Leo
Stracher, Alfred
Shulman, Abraham
Rockenstein, Edward
Mante, Michael
Adame, Anthony
Overk, Cassia
Rissman, Robert A.
Masliah, Eliezer
Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies
title Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies
title_full Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies
title_fullStr Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies
title_full_unstemmed Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies
title_short Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies
title_sort effects of novel calpain inhibitors in transgenic animal model of parkinson’s disease/dementia with lewy bodies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308237/
https://www.ncbi.nlm.nih.gov/pubmed/30591714
http://dx.doi.org/10.1038/s41598-018-35729-1
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