Intranasal Delivery of miR-155-5p Antagomir Alleviates Acute Seizures Likely by Inhibiting Hippocampal Inflammation

Xu Zhou,1 Jun Chen,2 Hua Tao,1,2 Yujie Cai,1 Lidan Huang,1 Haihong Zhou,2 Yanyan Chen,1 Lili Cui,1 Wangtao Zhong,2 Keshen Li3 1Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People’s Republic of China; 2Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People’s Republic of China; 3Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001 China; Stroke Center, Neurology & Neurosurgery Division, Clinical Medicine Research Institute & The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, People’s Republic of ChinaCorrespondence: Hua Tao; Keshen LiAffiliated Hospital of Guangdong Medical University No. 57, Renmindadaonan Road, Xiashan District, Zhanjiang, Guangdong 524001, People’s Republic of ChinaTel/ Fax +86 759 2387 427; +86 759 2386 772 Email taohua1943@126.com; likeshen1971@126.comIntroduction: To confront the resistance to existing antiepileptic drugs, studies have gradually begun to investigate alternative pathologies distinct from the traditional treatments that overwhelmingly target ion channels. Microglia activation is the first inflammatory response in the brain, in which miR-155-5p plays a key proinflammatory role and thus represents a promising target for inflammatory modulation in epilepsy pathologies.Methods: In this study, a pentetrazol-induced acute seizure model was established, and the seizure degree was evaluated within 60 min after pentetrazol administration. Animals were then sacrificed for hippocampal tissue collection for biological experiments.Results: Intranasal delivery of miR-155-5p antagomir (30 min before pentetrazol administration) increased the percentage of animals with no induced seizures by 20%, extended the latency to generalized convulsions, and decreased seizure severity. In addition, miR-155-5p antagomir treatment alleviated hippocampal damage and decreased the expression of typical inflammatory modulators (TNF-α, IL-1β and IL-6). Further research revealed that intranasal delivery of miR-155-5p antagomir significantly decreased the relative level of miR-155-5p and increased the expression of its targets LXRα and SOCS1 in IBA1-labeled microglial cells in the hippocampus.Conclusion: These findings demonstrate that intranasal delivery of miR-155-5p antagomir alleviated acute seizures, likely by blocking hippocampal inflammation. However, other potential mechanisms of the effects of miR-155-5p antagomir and its long-term safety for epilepsy treatment remain to be investigated.Keywords: intranasal delivery, epilepsy, pentetrazol, inflammatory response, miR-155-5p