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

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

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

Br J Pharmacol. 2024 Dec 10. doi: 10.1111/bph.17407. Online ahead of print.

Authors

Masaya Hasegawa¹, Kazuo Kunisawa^{1

2}, Bolati Wulaer^{3

4}, Hisayoshi Kubota¹, Hitomi Kurahashi¹, Takatoshi Sakata¹, Honomi Ando³, Suwako Fujigaki³, Hidetsugu Fujigaki³, Yasuko Yamamoto³, Taku Nagai², Kuniaki Saito^{3

4

5}, Toshitaka Nabeshima^{2

4

5}, Akihiro Mouri^{1

2

5}

Affiliations

¹ Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan.
² International Center for Brain Science (ICBS), Fujita Health University, Aichi, Japan.
³ Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Medical Sciences, Aichi, Japan.
⁴ Laboratory of Health and Medical Science Innovation (HMSI), Fujita Health University Graduate School of Medical Science, Aichi, Japan.
⁵ Japanese Drug Organization of Appropriate Use and Research, Aichi, Japan.

PMID: 39658392
DOI: 10.1111/bph.17407

Abstract

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.

Keywords: chronic unpredictable mild stress; hypothalamic–pituitary–adrenal axis; kynurenic acid; kynurenine 3‐monooxygenase; microglia; social interaction.

Abstract

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