Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling
Stress-induced overactivation of glucocorticoid signaling may contribute to mental illness by inducing neuronal death and dysfunction. We previously reported that pretreatment with the plant flavonoid butein inhibits corticosterone (CORT)-induced apoptosis of Neuro2A (N2A) cells. In the current stud...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | IBRO Neuroscience Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667242123000404 |
| _version_ | 1797804539012710400 |
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| author | Masanori Ohmoto Masaya Takemoto Tohru Daikoku |
| author_facet | Masanori Ohmoto Masaya Takemoto Tohru Daikoku |
| author_sort | Masanori Ohmoto |
| collection | DOAJ |
| description | Stress-induced overactivation of glucocorticoid signaling may contribute to mental illness by inducing neuronal death and dysfunction. We previously reported that pretreatment with the plant flavonoid butein inhibits corticosterone (CORT)-induced apoptosis of Neuro2A (N2A) cells. In the current study, we examined whether MEK-ERK and PI3K-AKT signaling pathways are involved in neuroprotection by butein. N2A cells were pre-incubated with serum-free DMEM containing 0.5 μM butein for 30 min, and then incubated with serum-free DMEM containing 0.5 µM butein, 50 µM CORT, 50 µM LY294002, or 50 µM PD98059 as indicated for 24 h. We subsequently performed the MTT assay and the western blot analysis. As expected, CORT considerably reduced N2A cell viability and increased relative expression of the apoptosis effector cleaved caspase-3, whereas pretreatment with butein blocked these cytotoxic effects. Treatment with CORT alone also decreased both AKT and ERK protein phosphorylation. Butein pretreatment had no effect on AKT phosphorylation, and only partially reversed the reduction in phosphorylated ERK. However, cotreatment with butein and the PI3K inhibitor LY294002 during CORT exposure enhanced ERK phosphorylation, whereas cotreatment with butein and the ERK phosphorylation/activation inhibitor PD98059 enhanced AKT phosphorylation, suggesting that MEK-ERK negatively regulates AKT phosphorylation. Moreover, the protective efficacy of butein was blocked by PD98059 cotreatment but not LY294002 cotreatment. These findings suggest that butein protects neurons against glucocorticoid-induced apoptosis by sustaining ERK phosphorylation and downstream signaling. |
| first_indexed | 2024-03-13T05:38:42Z |
| format | Article |
| id | doaj.art-8a1d44e03d554f47b3ef60a40468210a |
| institution | Directory Open Access Journal |
| issn | 2667-2421 |
| language | English |
| last_indexed | 2024-03-13T05:38:42Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | IBRO Neuroscience Reports |
| spelling | doaj.art-8a1d44e03d554f47b3ef60a40468210a2023-06-14T04:34:44ZengElsevierIBRO Neuroscience Reports2667-24212023-06-0114447452Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signalingMasanori Ohmoto0Masaya Takemoto1Tohru Daikoku2Department of Pharmacy Practice and Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan; Correspondence to: Department of Pharmacy Practice and Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan.Department of Pharmaceutical Life Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, JapanDepartment of Pharmaceutical Life Sciences, Faculty of Pharmaceutical Sciences, Hokuriku University, JapanStress-induced overactivation of glucocorticoid signaling may contribute to mental illness by inducing neuronal death and dysfunction. We previously reported that pretreatment with the plant flavonoid butein inhibits corticosterone (CORT)-induced apoptosis of Neuro2A (N2A) cells. In the current study, we examined whether MEK-ERK and PI3K-AKT signaling pathways are involved in neuroprotection by butein. N2A cells were pre-incubated with serum-free DMEM containing 0.5 μM butein for 30 min, and then incubated with serum-free DMEM containing 0.5 µM butein, 50 µM CORT, 50 µM LY294002, or 50 µM PD98059 as indicated for 24 h. We subsequently performed the MTT assay and the western blot analysis. As expected, CORT considerably reduced N2A cell viability and increased relative expression of the apoptosis effector cleaved caspase-3, whereas pretreatment with butein blocked these cytotoxic effects. Treatment with CORT alone also decreased both AKT and ERK protein phosphorylation. Butein pretreatment had no effect on AKT phosphorylation, and only partially reversed the reduction in phosphorylated ERK. However, cotreatment with butein and the PI3K inhibitor LY294002 during CORT exposure enhanced ERK phosphorylation, whereas cotreatment with butein and the ERK phosphorylation/activation inhibitor PD98059 enhanced AKT phosphorylation, suggesting that MEK-ERK negatively regulates AKT phosphorylation. Moreover, the protective efficacy of butein was blocked by PD98059 cotreatment but not LY294002 cotreatment. These findings suggest that butein protects neurons against glucocorticoid-induced apoptosis by sustaining ERK phosphorylation and downstream signaling.http://www.sciencedirect.com/science/article/pii/S2667242123000404ButeinCorticosteroneApoptosisNeuro2A cellsMEKERK |
| spellingShingle | Masanori Ohmoto Masaya Takemoto Tohru Daikoku Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling IBRO Neuroscience Reports Butein Corticosterone Apoptosis Neuro2A cells MEK ERK |
| title | Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling |
| title_full | Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling |
| title_fullStr | Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling |
| title_full_unstemmed | Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling |
| title_short | Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling |
| title_sort | butein inhibits corticosterone induced apoptosis of neuro2a cells by maintaining mek erk signaling |
| topic | Butein Corticosterone Apoptosis Neuro2A cells MEK ERK |
| url | http://www.sciencedirect.com/science/article/pii/S2667242123000404 |
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