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In this study, we investigated the therapeutic potential of tabernanthalog (TBG), a non-hallucinogenic analog of psychedelic compounds, as a novel intervention for CRCI using a Lewis lung carcinoma (3LL) mouse model. Behavioral assessments revealed heightened anxiety-like behavior and memory impairment following 3LL cell transplantation. Biochemical analysis revealed reduced tryptophan levels in both blood and hippocampal tissue, accompanied by the downregulation of serotonergic receptor genes and upregulation of pro-inflammatory cytokine genes in the hippocampus of tumor-bearing mice. Additionally, microglial density and morphological activation were markedly elevated. TBG treatment reversed these behavioral deficits, improving both anxiety-related behavior and memory performance. These effects were associated with the normalization of microglial density and morphology, as well as the restoration of serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in BV-2 microglial cells exposed to conditioned medium from 3LL cells. Collectively, these findings suggest that TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation. This study highlights TBG as a promising therapeutic candidate for improving cognitive and emotional functioning in patients with cancer.<\/jats:p>","DOI":"10.3390\/ijms26157519","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:45:11Z","timestamp":1754466311000},"page":"7519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways"],"prefix":"10.3390","volume":"26","author":[{"given":"Masahide","family":"Arinaga","sequence":"first","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoichiro","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayumi","family":"Okamura","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuto","family":"Oshima","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiying","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko M.","family":"Iinuma","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shozo","family":"Jinno","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s40644-024-00797-2","article-title":"Seeing through \u201cbrain fog\u201d: Neuroimaging assessment and imaging biomarkers for cancer-related cognitive impairments","volume":"24","author":"Gu","year":"2024","journal-title":"Cancer Imaging"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12943-024-02219-0","article-title":"Neuroscience of cancer: Unraveling the complex interplay between the nervous system, the tumor and the tumor immune microenvironment","volume":"24","author":"Huang","year":"2025","journal-title":"Mol. 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