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Ghrelin prevents lethality in a rat endotoxemic model through central effects on the vagal pathway and adenosine A2B signaling

Brain ghrelin and anti-septic action

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Abstract

Accumulating evidence suggest that ghrelin plays a role as an antiseptic peptide. The present study aimed to clarify whether the brain may be implicated ghrelin’s antiseptic action. We examined the effect of brain ghrelin on survival in a novel endotoxemic model achieved by treating rats with lipopolysaccharide (LPS) and colchicine. The observation of survival stopped three days after chemicals’ injection or at death. Intracisternal ghrelin dose-dependently reduced lethality in the endotoxemic model; meanwhile, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin injection affected the mortality rate. The brain ghrelin-induced lethality reduction was significantly blocked by surgical vagotomy. Moreover, intracisternal injection of a ghrelin receptor antagonist blocked the improved survival achieved by intracisternal ghrelin injection or intravenous 2-deoxy-d-glucose administration. Intracisternal injection of an adenosine A2B receptor agonist reduced the lethality and the ghrelin-induced improvement of survival was blocked by adenosine A2B receptor antagonist. I addition, intracisternal ghrelin significantly blocked the colonic hyperpermeability produced by LPS and colchicine. These results suggest that ghrelin acts centrally to reduce endotoxemic lethality. Accordingly, activation of the vagal pathway and adenosine A2B receptors in the brain may be implicated in the ghrelin-induced increased survival. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the decreased septic lethality caused by brain ghrelin.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.

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Funding

This work was supported in part by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan [19K08410 (TO) and 18K07896 (TN)].

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Authors and Affiliations

  1. Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan

    Sho Igarashi, Masatomo Ishioh, Takuya Funayama, Chihiro Sumi, Takeshi Saito, Yasumichi Toki, Mayumi Hatayama, Masayo Yamamoto, Motohiro Shindo, Hiroki Tanabe & Toshikatsu Okumura

  2. Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan

    Tsukasa Nozu

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  1. Sho Igarashi
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  2. Tsukasa Nozu
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Contributions

SI: Conceptualization, Formal analysis, Investigation, Methodology, Writing-original draft, TN: Conceptualization, Formal analysis, Investigation, Methodology, Writing-original draft, MI: Formal analysis, Investigation, Methodology, TF: Formal analysis, Investigation, CS: Formal analysis, Investigation, TS: Formal analysis, Investigation, MH: Formal analysis, Investigation, YT: Formal analysis, Investigation, MY: Formal analysis, Investigation, MS: Formal analysis, Investigation, HT: Formal analysis, Investigation, Methodology, TO: Conceptualization, Formal analysis, Investigation, Methodology, Writing-original draft. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Toshikatsu Okumura.

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The authors declare no competing financial interests.

Ethical considerations

Approval was obtained from the Research and Development and Animal Care committees at Asahikawa Medical University (No. 13030) for all of the experiments conducted in this study.

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Key Points

• Ghrelin acts centrally to improve survival in a rat endotoxemic lethality model.

• Improvement of survival by ghrelin was not observed in vagotomized rats.

• Ghrelin-induced improvement was blocked by adenosine A2B receptor antagonist.

• Ghrelin improves survival via the vagal pathway and adenosine signal in sepsis.

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Igarashi, S., Nozu, T., Ishioh, M. et al. Ghrelin prevents lethality in a rat endotoxemic model through central effects on the vagal pathway and adenosine A2B signaling. J Physiol Biochem 79, 625–634 (2023). https://doi.org/10.1007/s13105-023-00962-4

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