Dexmedetomidine improves sleep quality and alleviates emotional dysfunction by attenuating α-synuclein deposition in mice with sepsis-associated encephalopathy

Qi Jia; Lin Yang; Jiajia Wang; Jin Li; Lixia Du; Yongsheng Chen; Yi Li; Zongping Fang; Xijing Zhang

doi:10.1016/j.jare.2025.07.012

Dexmedetomidine improves sleep quality and alleviates emotional dysfunction by attenuating α-synuclein deposition in mice with sepsis-associated encephalopathy

J Adv Res. 2025 Jul 11:S2090-1232(25)00537-5. doi: 10.1016/j.jare.2025.07.012. Online ahead of print.

Authors

Qi Jia¹, Lin Yang¹, Jiajia Wang², Jin Li¹, Lixia Du¹, Yongsheng Chen³, Yi Li⁴, Zongping Fang⁵, Xijing Zhang⁶

Affiliations

¹ Department of Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032 Shaanxi Province, China; Key Laboratory of Anesthesiology (The Fourth Military Medical University), Ministry of Education of China, Xi'an, Shaanxi Province 710032, China.
² Key Laboratory of Anesthesiology (The Fourth Military Medical University), Ministry of Education of China, Xi'an, Shaanxi Province 710032, China.
³ Department of Critical Care Medicine, Yulin Hospital. The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Province 719000, China.
⁴ Department of Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032 Shaanxi Province, China.
⁵ Department of Critical Care Medicine, Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China. Electronic address: zongping03@163.com.
⁶ Department of Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032 Shaanxi Province, China. Electronic address: xjzhang0806@163.com.

PMID: 40653267
DOI: 10.1016/j.jare.2025.07.012

Abstract

Introduction: Most septic patients have severe sleep disorders that are closely related to poor prognoses, and some patients with sepsis-associated encephalopathy (SAE) experience severe cerebral inflammatory reactions similar to those in neurodegenerative disease. α-synuclein, a widely expressed synaptic protein whose abnormal deposition can lead to neurodegenerative diseases, was also observed to be deposited abnormally in an SAE mouse model.

Objectives: Sleep disorders are common in SAE patients and are strongly associated with prognoses. Our aim is to clarify sleep architecture changes, investigate the link between sleep and α-synuclein deposition, and identify new target for SAE treatment.

Methods: Injection of lipopolysaccharide i.cv and cecum ligation and puncture were used to establish SAE models. The telemetric implantation system was used to record electroencephalogram and electromyography signals of animals. Biological signal analysis, behavioral tests and molecular biology techniques were employed to investigate the relationship among sleep, α-synuclein, and emotional dysfunction of SAE mice. In addition, dexmedetomidine (50 ug kg^-1, i.p.) was used for treatment to investigate its effects on sleep quality and prognosis of SAE.

Results: SAE mice exhibited severe sleep fragmentation, including increased frequency of sleep and wakefulness, and decreased sleep quality. Fragmented sleep leading to α-synuclein deposition in the hippocampus, and developed anxiety and depression-like symptoms. Dexmedetomidine treatment not only improved sleep disorders but also reduced α-synuclein accumulation in the brain, thereby improving the mental symptoms associated with SAE.

Conclusion: We have identified details related to poor sleep quality in sepsis, and these changes promote α-synuclein deposition in the brain and have a negative impact on the prognosis of SAE. Furthermore, dexmedetomidine confers the novel effect of facilitating α-synuclein elimination beyond its sedative effect. These findings highlight the pivotal role of sleep quality in pathological process of SAE, while suggesting that α-synuclein may serve as a promising therapeutic target for SAE.

Keywords: Dexmedetomidine; Emotional dysfunction; Sepsis-associated encephalopathy; Sleep disorder; α-synuclein.