Mitochondrial fission inhibitor Mdivi-1 alleviates lipopolysaccharide-induced parvalbumin interneurons dysregulation and cognitive impairments in a mouse model of sepsis-associated encephalopathy

Lei Dai; Shuxin Gu; Yibao Zhang; Siqi Ma; Peishan Wang; Jingyun Zhang; Cai Wang; Gaowei Su; Qun Fu; Wei Zhou; Yunxia Fan

doi:10.3389/fphar.2025.1525028

Mitochondrial fission inhibitor Mdivi-1 alleviates lipopolysaccharide-induced parvalbumin interneurons dysregulation and cognitive impairments in a mouse model of sepsis-associated encephalopathy

Front Pharmacol. 2025 Jun 12:16:1525028. doi: 10.3389/fphar.2025.1525028. eCollection 2025.

Authors

Lei Dai^#^{1

2}, Shuxin Gu^#^{1

2}, Yibao Zhang³, Siqi Ma³, Peishan Wang^{1

2}, Jingyun Zhang^{1

2}, Cai Wang^{1

2}, Gaowei Su^{1

2}, Qun Fu⁴, Wei Zhou⁵, Yunxia Fan^{1

2}

Affiliations

¹ Department of Anesthesiology, Jintan Affiliated Hospital of Jiangsu University, Changzhou, China.
² Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
³ Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
⁴ Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
⁵ Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

^# Contributed equally.

Abstract

Introduction: Dysregulation of parvalbumin (PV) interneurons has been implicated in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain poorly understood, and effective treatments are lacking. Given the high energy demands of PV interneurons and the emerging role of mitochondrial dynamics in SAE pathophysiology, this study aimed to investigate whether the mitochondrial fission inhibitor Mdivi-1 could alleviate PV interneuron dysfunction and cognitive impairments in a mouse model of SAE.

Methods: C57BL/6 male mice were injected with lipopolysaccharide (LPS) to establish an animal model of SAE. Mdivi-1 was administered intraperitoneally 1 h before LPS challenge. Hippocampal tissues were harvested 24 h after LPS challenge for biochemical and histochemical analyses, and mitochondrial morphology was evaluated using transmission electron microscopy. In vivo electrophysiology and behavioral tests were performed between 2 and 4 days after LPS challenge to measure neural oscillations in the hippocampus and assess cognitive function.

Results: Our results showed that LPS induced neuroinflammation, mitochondrial fission abnormalities, ATP depletion, and downregulation of PV interneurons in the hippocampus, collectively contributing to reduced gamma oscillations and cognitive impairments in mice. However, these effects were mitigated by Mdivi-1 treatment.

Conclusion: Our study suggests that Mdivi-1 may offer a promising therapeutic approach for attenuating PV interneurons dysfunction and cognitive impairments in SAE.

Keywords: Mdivi-1; cognitive impairment; neuroinflammation; parvalbumin interneurons; sepsis-associated encephalopathy.