Inflammation as a target for the treatment of fever-associated epilepsy in zebrafish larvae

Abstract

Inflammation is considered to be involved in epileptogenesis. However, the relationship between fever and inflammation as well as the mechanisms of fever in the occurrence and development of childhood epilepsy need further investigation. Here, we described an in vivo model of hyperthermia-induced seizures in zebrafish larvae with pentylenetetrazole (PTZ) exposure. Hyperthermia increased the susceptibility to seizure and the production of pro-inflammatory factors in PTZ-induced zebrafish larvae. As mutations in GABRG2 have been associated with fever-associated epilepsy, we used a Tg(hGABRG2F343L) zebrafish model expressing mutant human GABRG2(F343L) to further investigate the involvement of inflammation in fever-induced seizures. Our data indicated that hyperthermia also increased the locomotor activity in Tg(hGABRG2F343L) zebrafish larvae. Although the production of pro-inflammatory factors was upregulated by GABRG2 mutation, hyperthermia did not change the production of pro-inflammatory factors significantly. Lipopolysaccharide (LPS) stimulation was sufficient to increase the locomotor activity in zebrafish larvae, suggesting that inflammation contributed to fever-associated epilepsy. The expression of GABRG2 was increased with PTZ induction, especially at a higher temperature. Moreover, inhibition of inflammation by dexamethasone (DEX) reduced the excitability of zebrafish larvae, especially at a higher temperature. Finally, in vitro experiments proved that LPS stimulation increased the production of IL-1β and IL-6 in GABRG2(F343L) transfected cells. Collectively, our study demonstrated that neuroinflammation was induced in febrile seizures, and the increased expression of IL-1β and IL-6 might be responsible for epileptogenesis. The vicious cycle between fever and inflammation might induce seizure onset, and anti-inflammatory strategies might be a potential treatment for fever-associated epilepsy.