{"title":"慢性应激通过犬尿氨酸-3-单加氧酶下调犬尿氨酸-3-单加氧酶增加犬尿氨酸，引起小胶质细胞衰退，从而诱导行为改变。","authors":"Masaya Hasegawa, Kazuo Kunisawa, Bolati Wulaer, Hisayoshi Kubota, Hitomi Kurahashi, Takatoshi Sakata, Honomi Ando, Suwako Fujigaki, Hidetsugu Fujigaki, Yasuko Yamamoto, Taku Nagai, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri","doi":"10.1111/bph.17407","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Background and Purpose</h3>\n \n <p>Alterations in tryptophan-kynurenine (TRP-KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3-monooxygenase (KMO) induces depression-like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP-KYN pathway in stress-induced behavioural changes and the regulation of the HPA axis.</p>\n </section>\n \n <section>\n \n <h3> Experimental Approach</h3>\n \n <p>Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP-KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS-induced behavioural changes and an increase in serum corticosterone (CORT) concentration.</p>\n </section>\n \n <section>\n \n <h3> Key Results</h3>\n \n <p>CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. <i>Kmo</i><sup>+/−</sup> mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short-term CUMS. Nicotine attenuated CUMS-induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin-releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine.</p>\n </section>\n \n <section>\n \n <h3> Conclusions and Implications</h3>\n \n <p>CUMS-induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.</p>\n </section>\n </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 7","pages":"1466-1486"},"PeriodicalIF":6.8000,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17407","citationCount":"0","resultStr":"{\"title\":\"Chronic stress induces behavioural changes through increased kynurenic acid by downregulation of kynurenine-3-monooxygenase with microglial decline\",\"authors\":\"Masaya Hasegawa, Kazuo Kunisawa, Bolati Wulaer, Hisayoshi Kubota, Hitomi Kurahashi, Takatoshi Sakata, Honomi Ando, Suwako Fujigaki, Hidetsugu Fujigaki, Yasuko Yamamoto, Taku Nagai, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri\",\"doi\":\"10.1111/bph.17407\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Background and Purpose</h3>\\n \\n <p>Alterations in tryptophan-kynurenine (TRP-KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3-monooxygenase (KMO) induces depression-like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP-KYN pathway in stress-induced behavioural changes and the regulation of the HPA axis.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Experimental Approach</h3>\\n \\n <p>Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP-KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS-induced behavioural changes and an increase in serum corticosterone (CORT) concentration.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Key Results</h3>\\n \\n <p>CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. <i>Kmo</i><sup>+/−</sup> mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short-term CUMS. Nicotine attenuated CUMS-induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin-releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions and Implications</h3>\\n \\n <p>CUMS-induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.</p>\\n </section>\\n </div>\",\"PeriodicalId\":9262,\"journal\":{\"name\":\"British Journal of Pharmacology\",\"volume\":\"182 7\",\"pages\":\"1466-1486\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-12-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17407\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"British Journal of Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/bph.17407\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British Journal of Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bph.17407","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Chronic stress induces behavioural changes through increased kynurenic acid by downregulation of kynurenine-3-monooxygenase with microglial decline
Background and Purpose
Alterations in tryptophan-kynurenine (TRP-KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3-monooxygenase (KMO) induces depression-like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP-KYN pathway in stress-induced behavioural changes and the regulation of the HPA axis.
Experimental Approach
Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP-KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS-induced behavioural changes and an increase in serum corticosterone (CORT) concentration.
Key Results
CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo+/− mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short-term CUMS. Nicotine attenuated CUMS-induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin-releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine.
Conclusions and Implications
CUMS-induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.
期刊介绍：
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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