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Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice

Alzheimer’s disease (AD), characterized by cognitive impairments, is considered to be one of the most widespread chronic neurodegenerative diseases worldwide. We recently introduced a novel therapeutic agent for AD treatment, the T-type calcium channel enhancer ethyl-8-methyl-2,4-dioxo-2-(piperidin-...

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Autores principales: Yuan, Dian, Cheng, An, Kawahata, Ichiro, Izumi, Hisanao, Xu, Jing, Fukunaga, Kohji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828528/
https://www.ncbi.nlm.nih.gov/pubmed/33451040
http://dx.doi.org/10.3390/ijms22020741
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author Yuan, Dian
Cheng, An
Kawahata, Ichiro
Izumi, Hisanao
Xu, Jing
Fukunaga, Kohji
author_facet Yuan, Dian
Cheng, An
Kawahata, Ichiro
Izumi, Hisanao
Xu, Jing
Fukunaga, Kohji
author_sort Yuan, Dian
collection PubMed
description Alzheimer’s disease (AD), characterized by cognitive impairments, is considered to be one of the most widespread chronic neurodegenerative diseases worldwide. We recently introduced a novel therapeutic agent for AD treatment, the T-type calcium channel enhancer ethyl-8-methyl-2,4-dioxo-2-(piperidin-1-yl)-2H-spiro[cyclopentane-1,3-imidazo[1,2-a]pyridin]-2-ene-3-carboxylate (SAK3). SAK3 enhances calcium/calmodulin-dependent protein kinase II and proteasome activity, thereby promoting amyloid beta degradation in mice with AD. However, the antioxidative effects of SAK3 remain unclear. We investigated the antioxidative effects of SAK3 in olfactory bulbectomized mice (OBX mice), compared with the effects of donepezil as a positive control. As previously reported, single oral administration of both SAK3 (0.5 mg/kg, p.o.) and donepezil (1.0 mg/kg, p.o.) significantly improved cognitive and depressive behaviors in OBX mice. Single oral SAK3 administration markedly reduced 4-hydroxy-2-nonenal and nitrotyrosine protein levels in the hippocampus of OBX mice, which persisted until 1 week after administration. These effects are similar to those observed with donepezil therapy. Increased protein levels of oxidative stress markers were observed in the microglial cells, which were significantly rescued by SAK3 and donepezil. SAK3 could ameliorate oxidative stress in OBX mice, like donepezil, suggesting that the antioxidative effects of SAK3 and donepezil are among the neuroprotective mechanisms in AD pathogenesis.
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spelling pubmed-78285282021-01-25 Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice Yuan, Dian Cheng, An Kawahata, Ichiro Izumi, Hisanao Xu, Jing Fukunaga, Kohji Int J Mol Sci Article Alzheimer’s disease (AD), characterized by cognitive impairments, is considered to be one of the most widespread chronic neurodegenerative diseases worldwide. We recently introduced a novel therapeutic agent for AD treatment, the T-type calcium channel enhancer ethyl-8-methyl-2,4-dioxo-2-(piperidin-1-yl)-2H-spiro[cyclopentane-1,3-imidazo[1,2-a]pyridin]-2-ene-3-carboxylate (SAK3). SAK3 enhances calcium/calmodulin-dependent protein kinase II and proteasome activity, thereby promoting amyloid beta degradation in mice with AD. However, the antioxidative effects of SAK3 remain unclear. We investigated the antioxidative effects of SAK3 in olfactory bulbectomized mice (OBX mice), compared with the effects of donepezil as a positive control. As previously reported, single oral administration of both SAK3 (0.5 mg/kg, p.o.) and donepezil (1.0 mg/kg, p.o.) significantly improved cognitive and depressive behaviors in OBX mice. Single oral SAK3 administration markedly reduced 4-hydroxy-2-nonenal and nitrotyrosine protein levels in the hippocampus of OBX mice, which persisted until 1 week after administration. These effects are similar to those observed with donepezil therapy. Increased protein levels of oxidative stress markers were observed in the microglial cells, which were significantly rescued by SAK3 and donepezil. SAK3 could ameliorate oxidative stress in OBX mice, like donepezil, suggesting that the antioxidative effects of SAK3 and donepezil are among the neuroprotective mechanisms in AD pathogenesis. MDPI 2021-01-13 /pmc/articles/PMC7828528/ /pubmed/33451040 http://dx.doi.org/10.3390/ijms22020741 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yuan, Dian
Cheng, An
Kawahata, Ichiro
Izumi, Hisanao
Xu, Jing
Fukunaga, Kohji
Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice
title Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice
title_full Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice
title_fullStr Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice
title_full_unstemmed Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice
title_short Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice
title_sort single administration of the t-type calcium channel enhancer sak3 reduces oxidative stress and improves cognition in olfactory bulbectomized mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828528/
https://www.ncbi.nlm.nih.gov/pubmed/33451040
http://dx.doi.org/10.3390/ijms22020741
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