Abstract
Unveiling the key mechanism of temporal lobe epilepsy (TLE) for the development of novel treatments is of increasing interest, and anti-inflammatory miR-146a is now considered a promising molecular target for TLE. In the current study, a C57BL/6 TLE mouse model was established using the lithium-pilocarpine protocol. The seizure degree was evaluated according to the Racine scale, and level 5 was considered the threshold for generalized convulsions. Animals were sacrificed to analyze the hippocampus at three time points (2 h and 4 and 8 weeks after pilocarpine administration to evaluate the acute, latent, and chronic phases, resp.). After intranasal delivery of miR-146a mimics (30 min before pilocarpine injection), the percent of animals with no induced seizures increased by 6.7%, the latency to generalized convulsions was extended, and seizure severity was reduced. Additionally, hippocampal damage was alleviated. While the relative miR-146a levels significantly increased, the expression of its target mRNAs (IRAK-1 and TRAF-6) and typical inflammatory modulators (NF-κB, TNF-α, IL-1β, and IL-6) decreased, supporting an anti-inflammatory role of miR-146a via the TLR pathway. This study is the first to demonstrate that intranasal delivery of miR-146a mimics can improve seizure onset and hippocampal damage in the acute phase of lithium-pilocarpine-induced seizures, which provides inflammation-based clues for the development of novel TLE treatments.
Highlights
Many antiepileptic drugs (AEDs) have been developed for seizure treatment in past decades, almost onethird of epileptic patients are resistant to these AEDs [1,2,3,4]
The percentage of no induced seizures increased by 6.7% (a), the latency to generalized convulsion after pilocarpine administration was extended (b), and the seizure severity was reduced (c) in the APT group compared with the APE group. All these behavioral observations within 2 h after pilocarpine administration indicate that intranasal delivery of miR-146a mimics could improve seizure onset in the acute phase of the temporal lobe epilepsy (TLE) model
Our team found that expression of the functional rs57095329 A allele elevated the levels of anti-inflammatory miR-146a and was associated with a reduced risk of seizure frequency in drug-resistant patients containing 95% TLE cases [26], which further urged us to evaluate the potential of miR-146a as a molecular target for seizure treatment in the lithium-pilocarpine model
Summary
Many antiepileptic drugs (AEDs) have been developed for seizure treatment in past decades, almost onethird of epileptic patients are resistant to these AEDs [1,2,3,4]. Increasing interest has focused on unveiling the precise mechanism of TLE in order to develop novel therapies for seizure treatment. Increasing clinical and experimental studies have indicated that neuroinflammation is one of the key mechanisms responsible for TLE. Inflammatory mediators, such as tumor necrosis factors alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and toll-like receptor 4 (TLR4), have been reported to be abnormally expressed in the hippocampus of TLE rodents and TLE patients [8,9,10]. In a series of in vivo studies, anti-inflammatory treatments, such as aspirin, minocycline and rapamycin, significantly reduced epileptic
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