4.7 Article

Regulation of Inflammation-Related Genes through Fosl1 Suppression in a Levetiracetam-Treated Pilocarpine-Induced Status Epilepticus Mouse Model

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出版社

MDPI
DOI: 10.3390/ijms23147608

关键词

levetiracetam; Fosl1; inflammation; epileptogenesis; epilepsy after brain injury

资金

  1. KAKENHI from the Japan Society for the Promotion of Science [15K18947, 17K15533, 17H04714, 20H04341, 17K08356, 21K06702]

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Levetiracetam suppresses neuroinflammation and prevents epilepsy onset by inhibiting the expression of Fosl1, which regulates astrocyte reactivity during epileptogenesis.
Levetiracetam (LEV) suppresses the upregulation of proinflammatory molecules that occurs during epileptogenesis after status epilepticus (SE). Based on previous studies, LEV likely helps prevent the onset of epilepsy after insults to the brain, unlike other conventional anti-epileptic drugs. Recently, we discovered that the increase in Fosl1 expression that occurs after lipopolysaccharide (LPS) stimulation is suppressed by LEV and that Fosl1 inhibition suppresses inflammation in BV-2 microglial cells. These data indicate that Fosl1 is an important target of LEV and a key factor in preventing epilepsy onset. In this study, we examined the effects of LEV on Fosl1 expression and neuroinflammation in vivo. During epileptogenesis, the post-SE upregulation of hippocampal levels of Fosl1 and many inflammatory factors were suppressed by LEV. Fosl1 expression showed a characteristic pattern different from that of the expression of Fos, an immediate-early gene belonging to the same Fos family. At 2 days after SE, Fosl1 was predominantly expressed in astrocytes but was rarely detected in microglia, whereas Fos expression was distributed in various brain cell types. The expression of A2 astrocyte markers was similar to that of Fosl1 and was significantly suppressed by LEV. These results suggest that LEV may regulate astrocyte reactivity through regulation of Fosl1.

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