Ultrasound stimulation of the vagal nerve improves acute septic encephalopathy in mice

Yukio Imamura; Hisatake Matsumoto; Jun Imamura; Naoya Matsumoto; Kazuma Yamakawa; Nao Yoshikawa; Yuki Murakami; Satoko Mitani; Junichiro Nakagawa; Tomoki Yamada; Hiroshi Ogura; Jun Oda; Takeshi Shimazu

doi:10.3389/fnins.2023.1211608

Ultrasound stimulation of the vagal nerve improves acute septic encephalopathy in mice

Front Neurosci. 2023 Jul 17:17:1211608. doi: 10.3389/fnins.2023.1211608. eCollection 2023.

Authors

Yukio Imamura^{1

2

3

4}, Hisatake Matsumoto¹, Jun Imamura⁵, Naoya Matsumoto¹, Kazuma Yamakawa^{1

6}, Nao Yoshikawa⁷, Yuki Murakami^{4

7}, Satoko Mitani^{7

8}, Junichiro Nakagawa¹, Tomoki Yamada¹, Hiroshi Ogura¹, Jun Oda¹, Takeshi Shimazu¹

Affiliations

¹ Department of Traumatology and Acute Critical Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
² Organization for Research Initiatives and Development, Doshisha University, Kyoto, Japan.
³ Department of Architectural and Environmental Planning, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
⁴ Department of Hygiene and Public Health, Kansai Medical University, Osaka, Japan.
⁵ Molex Corporation, Ltd., Yamato, Kanagawa, Japan.
⁶ Department of Emergency Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan.
⁷ Human Health Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁸ Faculty of Acupuncture and Moxibustion, Meiji University of Integrative Medicine, Kyoto, Japan.

Abstract

Septic encephalopathy (SE) is characterized by symptoms such as coma, delirium, and cognitive dysfunction, and effective therapeutic interventions for SE remain elusive. In this study, we aimed to investigate the potential alleviating effects of vagal nerve stimulation (VNS) on SE-associated signs. To evaluate our hypothesis, we utilized a mouse model of SE induced by intraperitoneal injection of lipopolysaccharide (0.3 mg per mouse) and administered noninvasive, high-frequency ultrasound VNS. To assess the efficacy of ultrasound VNS, we measured inflammation-related molecules, including the α7 nicotinic acetylcholine receptor (α7nAChR) expression in peritoneal macrophages and plasma interleukin 1β (IL-1β) levels. Consistent with our hypothesis, SE mice exhibited reduced α7nAChR expression in macrophages and elevated IL-1β levels in the blood. Remarkably, VNS in SE mice restored α7nAChR expression and IL-1β levels to those observed in control mice. Furthermore, we evaluated the effects of VNS on survival rate, body temperature, and locomotor activity. SE mice subjected to VNS demonstrated a modest, yet significant, improvement in survival rate, recovery from hypothermia, and increased locomotor activity. To investigate the impact on the brain, we examined the hippocampus of SE mice. In control mice, VNS increased the expression of c-fos, a marker of neuronal electrical excitability, in the hippocampus. In SE mice, VNS led to the restoration of aberrant firing patterns in hippocampal neurons. Additionally, proteomic analysis of hippocampal tissue in SE mice revealed abnormal increases in two proteins, tissue factor (TF) and acyl-CoA dehydrogenase family member 9 (ACAD9), which returned to control levels following VNS. Collectively, our findings support the value of exploring the beneficial effects of ultrasound VNS on SE.

Keywords: proteomics; septic encephalopathy; ultrasound; vagal nerve; α7 nicotinic acetyl choline receptor.

Associated data

figshare/10.6084/m9.figshare.21721433.v1