Chronic stress induces behavioural changes through increased kynurenic acid by downregulation of kynurenine-3-monooxygenase with microglial decline.

Autor: Hasegawa M; Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan., Kunisawa K; Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan.; International Center for Brain Science (ICBS), Fujita Health University, Aichi, Japan., Wulaer B; Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan.; Laboratory of Health and Medical Science Innovation (HMSI), Fujita Health University Graduate School of Medical Science, Aichi, Japan., Kubota H; Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan., Kurahashi H; Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan., Sakata T; Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan., Ando H; Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan., Fujigaki S; Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan., Fujigaki H; Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan., Yamamoto Y; Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan., Nagai T; International Center for Brain Science (ICBS), Fujita Health University, Aichi, Japan., Saito K; Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan.; Laboratory of Health and Medical Science Innovation (HMSI), Fujita Health University Graduate School of Medical Science, Aichi, Japan.; Japanese Drug Organization of Appropriate Use and Research, Aichi, Japan., Nabeshima T; International Center for Brain Science (ICBS), Fujita Health University, Aichi, Japan.; Laboratory of Health and Medical Science Innovation (HMSI), Fujita Health University Graduate School of Medical Science, Aichi, Japan.; Japanese Drug Organization of Appropriate Use and Research, Aichi, Japan., Mouri A; Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan.; International Center for Brain Science (ICBS), Fujita Health University, Aichi, Japan.; Japanese Drug Organization of Appropriate Use and Research, Aichi, Japan.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Dec 10. Date of Electronic Publication: 2024 Dec 10.
DOI: 10.1111/bph.17407
Abstrakt: 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.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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