Resolving neuroinflammatory and social deficits in ASD model mice: Dexmedetomidine downregulates NF-κB/IL-6 pathway via α2AR

Zheng-Kai Liang; Wei Xiong; Chen Wang; Li Chen; Xin Zou; Jing-Wen Mai; Bo Dong; Chongqi Guo; Wen-Jun Xin; De-Xing Luo; Ting Xu; Xia Feng

doi:10.1016/j.bbi.2024.03.040

Resolving neuroinflammatory and social deficits in ASD model mice: Dexmedetomidine downregulates NF-κB/IL-6 pathway via α2AR

Brain Behav Immun. 2024 Mar 27:119:84-95. doi: 10.1016/j.bbi.2024.03.040. Online ahead of print.

Authors

Zheng-Kai Liang¹, Wei Xiong¹, Chen Wang¹, Li Chen², Xin Zou², Jing-Wen Mai³, Bo Dong², Chongqi Guo², Wen-Jun Xin², De-Xing Luo⁴, Ting Xu⁵, Xia Feng⁶

Affiliations

¹ Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China.
² Neuroscience Program, Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, PR China.
³ Department of Anesthesiology, Huizhou Central People's Hospital, Huizhou 516000, PR China.
⁴ Department of Anesthesiology, Huizhou Central People's Hospital, Huizhou 516000, PR China. Electronic address: kw888kw@163.com.
⁵ Neuroscience Program, Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, PR China. Electronic address: xuting8@mail.sysu.edu.cn.
⁶ Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China. Electronic address: fengxia@mail.sysu.edu.cn.

PMID: 38552922
DOI: 10.1016/j.bbi.2024.03.040

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals' daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T⁺ Itpr3^tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.

Keywords: Autism spectrum disorder; Dexmedetomidine; Interleukin-6; Nuclear factor kappa B; Prelimbic cortex; Social deficits; α2 adrenergic receptor.