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11β-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice

癫痫发生 海马结构 基因敲除 莫里斯水上航行任务 海马体 癫痫 糖皮质激素 细胞凋亡 神经科学 神经保护 医学 内分泌学 内科学 生物 生物化学
作者
Xueying Li,Qiu Wan-hua,Lu Deng,Jingjing Lin,Wenting Huang,Yuchen Xu,Mulan Zhang,Nigel C. Jones,Runxuan Lin,Huiqin Xu,Li Lin,Peijun Li,Xinshi Wang
出处
期刊:Journal of Translational Medicine [BioMed Central]
卷期号:20 (1) 被引量:3
标识
DOI:10.1186/s12967-022-03618-x
摘要

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.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.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-3.11β-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.
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