title: Intranasal Delivery of miR-146a Mimics Delayed Seizure Onset in the Lithium-Pilocarpine Mouse Model.
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.
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Hua
authors.identifier: 0000-0002-9506-5987
authors.initials: H
authors.lastname: Tao
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Jianghao
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Huaijie
authors.initials: H
authors.lastname: Xing
authors.affiliation: Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Mingkang
authors.initials: M
authors.lastname: Yin
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Wangtao
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Keshen
authors.initials: K
authors.lastname: Li
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Bin
authors.identifier: 0000-0002-8943-0140
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Haihong
authors.identifier: 0000-0002-0060-6534
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Lili
authors.identifier: 0000-0003-0273-2531
authors.initials: L
authors.lastname: Cui
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000188:drug therapy*; D006624:Hippocampus / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy*; D008094:Lithium / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics; D010862:Pilocarpine / Q000008:administration & dosage*; D012640:Seizures; D013997:Time Factors
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D010862:Pilocarpine; D008094:Lithium