Journal
JOURNAL OF TRANSLATIONAL MEDICINE
Volume 20, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12967-022-03618-x
Keywords
11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1); Epilepsy; Cognitive impairment; Patch clamp; Apoptosis
Categories
Funding
- Zhejiang Medical Health Science and Technology Project [2019RC202]
- Wenzhou Science and Technology Project [Y2020060]
- National Natural Science Foundation of China [81871035, 82071378]
- Zhejiang Provincial Natural Science Foundation [LY22H090016, LZ19H090001]
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11 beta-HSD1 participates in the pathogenesis of epilepsy and associated cognitive impairment by elevating neuronal excitability and contributing to apoptosis and hippocampal neuronal damage. Inhibition of 11 beta-HSD1 represents a promising strategy to treat epilepsy and cognitive comorbidity.
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 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1) in epileptogenesis and associated cognitive impairment has not previously been studied. Methods: We first investigated the expression of 11 beta-HSD1 in the pentylenetetrazole (PTZ) kindling mouse model of epilepsy. We then observed the effect of overexpressing 11 beta-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 11 beta-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 11 beta-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 11 beta-HSD1 significantly decreased the threshold voltage while increasing the frequency of action potential firing in cultured hippocampal neurons. Hippocampal knockdown of 11 beta-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 11 beta-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: 11 beta-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 11 beta-HSD1, therefore, represents a promising strategy to treat epilepsy and cognitive comorbidity.
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