{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T22:09:12Z","timestamp":1782166152562,"version":"3.54.5"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>We have previously demonstrated that intratracheal lipopolysaccharide (LPS) injection induces significant pulmonary inflammation accompanied by hippocampal microglial activation, indicative of neuroinflammation. Hochuekkito (HET) is a traditional Japanese herbal medicine used to treat various conditions, including mental disorders and physical weakness. We have previously reported that HET ameliorates anxiety-like behaviors induced by intraperitoneal LPS injections in mice. However, its anxiolytic effects on anxiety-like behaviors due to pulmonary inflammation remain poorly understood. Therefore, in the present study, we aimed to investigate the effects of HET on anxiety-like behaviors induced by intratracheal LPS injection in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Mice received HET (1.0\u00a0g\/kg) once daily for 2 weeks through oral gavage prior to LPS treatment. The light-dark box test was conducted 24\u00a0h following LPS injection to assess anxiety-like behaviors. Diazepam, a clinically used anxiolytic, served as a positive control. The lung wet-to-dry weight ratio was determined, and the concentrations of interleukin-6 (IL-6) in the lungs and serum were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Repeated administration of HET prevented the development of anxiety-like behaviors and reduced serum IL-6 concentrations and hippocampal\n                      <jats:italic>Il6<\/jats:italic>\n                      mRNA expression levels in LPS-treated mice. Diazepam failed to exert significant effects in LPS-treated mice, whereas HET remained effective under inflammatory conditions. Moreover, LPS injections significantly increased the number of Iba-1-immunoreactive microglial cells in the CA1 region of the hippocampus, whereas this effect was suppressed by treatment with HET. In the bronchoalveolar lavage fluid (BALF), the LPS-induced increase in white blood cell count was significantly reduced by treatment with HET. Furthermore, HET alleviated LPS-induced pulmonary inflammation, as evidenced by decreased lung wet-to-dry weight ratios.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study suggests that inflammation induced by intratracheal LPS injection contributes to anxiety-like behaviors in mice and that IL-6 may play a key role in linking peripheral inflammation to neuroinflammatory responses. The anxiolytic effects of HET appear to be associated, at least in part, with the suppression of IL-6 elevation in both the periphery and the hippocampus, along with attenuation of microglial activation. Our findings suggest that HET may serve as a potential therapeutic agent for anxiety-like behaviors associated with pulmonary inflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1774957","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:39:24Z","timestamp":1777527564000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hochuekkito attenuates anxiety-like behavior associated with pulmonary inflammation induced by intratracheal lipopolysaccharides in mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Yasuhisa","family":"Izushi","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy, Graduate School of Pharmacy, Shujitsu University","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichiro","family":"Ushio","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences for Health Crisis Management, Faculty of Pharmaceutical Sciences, Fukuoka University","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teppei","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy, Graduate School of Pharmacy, Shujitsu University","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Tasaka","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacy, School of Pharmacy, Shujitsu University","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuko","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Medical Neurobiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Asanuma","sequence":"additional","affiliation":[{"name":"Department of Medical Neurobiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihisa","family":"Kitamura","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy, Graduate School of Pharmacy, Shujitsu University","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.jad.2021.10.039","article-title":"Intersections between pneumonia, lowered oxygen saturation percentage and immune activation mediate depression, anxiety, and chronic fatigue syndrome-like symptoms due to COVID-19: a nomothetic network approach","volume":"297","author":"Al-Jassas","year":"2022","journal-title":"J. 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