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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2021-01-01
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| Series: | International Journal of Molecular Sciences |
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| author | Dian Yuan An Cheng Ichiro Kawahata Hisanao Izumi Jing Xu Kohji Fukunaga |
| author_facet | Dian Yuan An Cheng Ichiro Kawahata Hisanao Izumi Jing Xu Kohji Fukunaga |
| author_sort | Dian Yuan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T04:54:57Z |
| format | Article |
| id | doaj.art-3875595bbc354ff08106d7599fa036d7 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T04:54:57Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3875595bbc354ff08106d7599fa036d72023-12-03T13:06:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-0122274110.3390/ijms22020741Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized MiceDian Yuan0An Cheng1Ichiro Kawahata2Hisanao Izumi3Jing Xu4Kohji Fukunaga5Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, JapanAlzheimer’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.https://www.mdpi.com/1422-0067/22/2/741Alzheimer’s diseaseoxidative stressT-type calcium channelSAK3microglia |
| spellingShingle | Dian Yuan An Cheng Ichiro Kawahata Hisanao Izumi Jing Xu Kohji Fukunaga Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice International Journal of Molecular Sciences Alzheimer’s disease oxidative stress T-type calcium channel SAK3 microglia |
| 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 | Alzheimer’s disease oxidative stress T-type calcium channel SAK3 microglia |
| url | https://www.mdpi.com/1422-0067/22/2/741 |
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