11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice
Abstract Background Glucocorticoid signalling is closely related to both epilepsy and associated cognitive impairment, possibly through mechanisms involving neuronal apoptosis. As a critical enzyme for glucocorticoid action, the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in epileptogenesi...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03618-x |
| _version_ | 1798002946529558528 |
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| author | Xueying Li Wanhua Qiu Lu Deng Jingjing Lin Wenting Huang Yuchen Xu Mulan Zhang Nigel C. Jones Runxuan Lin Huiqin Xu Li Lin Peijun Li Xinshi Wang |
| author_facet | Xueying Li Wanhua Qiu Lu Deng Jingjing Lin Wenting Huang Yuchen Xu Mulan Zhang Nigel C. Jones Runxuan Lin Huiqin Xu Li Lin Peijun Li Xinshi Wang |
| author_sort | Xueying Li |
| collection | DOAJ |
| description | Abstract Background Glucocorticoid signalling is closely related to both epilepsy and associated cognitive impairment, possibly through mechanisms involving neuronal apoptosis. As a critical enzyme for glucocorticoid action, the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in epileptogenesis and associated cognitive impairment has not previously been studied. Methods We first investigated the expression of 11β-HSD1 in the pentylenetetrazole (PTZ) kindling mouse model of epilepsy. We then observed the effect of overexpressing 11β-HSD1 on the excitability of primary cultured neurons in vitro using whole-cell patch clamp recordings. Further, we assessed the effects of adeno-associated virus (AAV)-induced hippocampal 11β-HSD1 knockdown in the PTZ model, conducting behavioural observations of seizures, assessment of spatial learning and memory using the Morris water maze, and biochemical and histopathological analyses. Results We found that 11β-HSD1 was primarily expressed in neurons but not astrocytes, and its expression was significantly (p < 0.05) increased in the hippocampus of PTZ epilepsy mice compared to sham controls. Whole-cell patch clamp recordings showed that overexpression of 11β-HSD1 significantly decreased the threshold voltage while increasing the frequency of action potential firing in cultured hippocampal neurons. Hippocampal knockdown of 11β-HSD1 significantly reduced the severity score of PTZ seizures and increased the latent period required to reach the fully kindled state compared to control knockdown. Knockdown of 11β-HSD1 also significantly mitigated the impairment of spatial learning and memory, attenuated hippocampal neuronal damage and increased the ratio of Bcl-2/Bax, while decreasing the expression of cleaved caspase-3. Conclusions 11β-HSD1 participates in the pathogenesis of both epilepsy and the associated cognitive impairment by elevating neuronal excitability and contributing to apoptosis and subsequent hippocampal neuronal damage. Inhibition of 11β-HSD1, therefore, represents a promising strategy to treat epilepsy and cognitive comorbidity. |
| first_indexed | 2024-04-11T12:00:22Z |
| format | Article |
| id | doaj.art-0b136d42cbb548fca16bcbf087fa8ab5 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-11T12:00:22Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-0b136d42cbb548fca16bcbf087fa8ab52022-12-22T04:24:51ZengBMCJournal of Translational Medicine1479-58762022-09-0120111310.1186/s12967-022-03618-x11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in miceXueying Li0Wanhua Qiu1Lu Deng2Jingjing Lin3Wenting Huang4Yuchen Xu5Mulan Zhang6Nigel C. Jones7Runxuan Lin8Huiqin Xu9Li Lin10Peijun Li11Xinshi Wang12Department of Neurology, The First Affiliated Hospital of Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversityDepartment of Neurology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Neurology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Neuroscience, Central Clinical School, Monash UniversityDepartment of Neuroscience, Central Clinical School, Monash UniversityDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversityDepartment of Neurology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical UniversityAbstract Background Glucocorticoid signalling is closely related to both epilepsy and associated cognitive impairment, possibly through mechanisms involving neuronal apoptosis. As a critical enzyme for glucocorticoid action, the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in epileptogenesis and associated cognitive impairment has not previously been studied. Methods We first investigated the expression of 11β-HSD1 in the pentylenetetrazole (PTZ) kindling mouse model of epilepsy. We then observed the effect of overexpressing 11β-HSD1 on the excitability of primary cultured neurons in vitro using whole-cell patch clamp recordings. Further, we assessed the effects of adeno-associated virus (AAV)-induced hippocampal 11β-HSD1 knockdown in the PTZ model, conducting behavioural observations of seizures, assessment of spatial learning and memory using the Morris water maze, and biochemical and histopathological analyses. Results We found that 11β-HSD1 was primarily expressed in neurons but not astrocytes, and its expression was significantly (p < 0.05) increased in the hippocampus of PTZ epilepsy mice compared to sham controls. Whole-cell patch clamp recordings showed that overexpression of 11β-HSD1 significantly decreased the threshold voltage while increasing the frequency of action potential firing in cultured hippocampal neurons. Hippocampal knockdown of 11β-HSD1 significantly reduced the severity score of PTZ seizures and increased the latent period required to reach the fully kindled state compared to control knockdown. Knockdown of 11β-HSD1 also significantly mitigated the impairment of spatial learning and memory, attenuated hippocampal neuronal damage and increased the ratio of Bcl-2/Bax, while decreasing the expression of cleaved caspase-3. Conclusions 11β-HSD1 participates in the pathogenesis of both epilepsy and the associated cognitive impairment by elevating neuronal excitability and contributing to apoptosis and subsequent hippocampal neuronal damage. Inhibition of 11β-HSD1, therefore, represents a promising strategy to treat epilepsy and cognitive comorbidity.https://doi.org/10.1186/s12967-022-03618-x11β-hydroxysteroid dehydrogenase 1 (11β-HSD1)EpilepsyCognitive impairmentPatch clampApoptosis |
| spellingShingle | Xueying Li Wanhua Qiu Lu Deng Jingjing Lin Wenting Huang Yuchen Xu Mulan Zhang Nigel C. Jones Runxuan Lin Huiqin Xu Li Lin Peijun Li Xinshi Wang 11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice Journal of Translational Medicine 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) Epilepsy Cognitive impairment Patch clamp Apoptosis |
| title | 11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice |
| title_full | 11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice |
| title_fullStr | 11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice |
| title_full_unstemmed | 11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice |
| title_short | 11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice |
| title_sort | 11β hsd1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice |
| topic | 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) Epilepsy Cognitive impairment Patch clamp Apoptosis |
| url | https://doi.org/10.1186/s12967-022-03618-x |
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