Kynurenine 3-monooxygenase deficiency induces depression-like behavior via enhanced antagonism of α7 nicotinic acetylcholine receptors by kynurenic acid
Kynurenine 3-monooxygenase deficiency induces depression-like behavior via enhanced antagonism of α7 nicotinic acetylcholine receptors by kynurenic acid
复制标题
犬尿氨酸 3-单加氧酶缺乏症通过犬尿酸增强 α7 烟碱乙酰胆碱受体的拮抗作用，诱导抑郁样行为
DOI：
10.1016/j.bbr.2021.113191
复制
发表时间：
2021
影响因子：
2.7
通讯作者：
Saito Kuniaki
中科院分区：
文献类型：
--
作者：
Mori Yuko;Mouri Akihiro;Kunisawa Kazuo;Hirakawa Mami;Kubota Hisayoshi;Kosuge Aika;Niijima Moe;Hasegawa Masaya;Kurahashi Hitomi;Murakami Reiko;Hoshi Masato;Nakano Takashi;Fujigaki Suwako;Fujigaki Hidetsugu;Yamamoto Yasuko;Nabeshima Toshitaka;Saito Kuniaki
色氨酸（Tryptophan，TRP）通过犬尿氨酸（kynurenine，KYN）途径代谢，与抑郁症（major depression disorder，MDD）的发病机制有关。犬尿氨酸3-单加氧酶（KMO）是KYN代谢为3-羟基犬尿氨酸的关键酶。在啮齿类动物中，KMO缺乏会诱导抑郁样行为并增加犬尿氨酸（KA）的水平，KA是由犬尿氨酸氨基转移酶（KAT）形成的KYN代谢物。KA拮抗α7烟碱乙酰胆碱受体（α 7 nAChR）。在这里，我们研究了KA参与KMO敲除（KO）小鼠的抑郁样行为。KMO KO小鼠的前额皮质中KYN、KA和邻氨基苯甲酸升高，但TRP或3-羟基邻氨基苯甲酸未升高。在KMO KO小鼠的前额皮质中，KAT 1和α 7 nAChR的mRNA水平升高，但KAT 2 −4、α 4 nAChR或β2nAChR的mRNA水平没有升高。尼古丁阻断了自发活动的增加，减少社会互动时间，并延长了强迫游泳试验中的不动性，但它没有降低KMO KO小鼠的蔗糖偏好。α 7 nAChR拮抗剂甲基乌头碱可拮抗尼古丁减少小鼠社会交往时间和延长小鼠强迫游泳不动时间的作用，但不能增加小鼠的自主活动。加兰他敏（α 7 nAChR变构激动剂）阻断KMO KO小鼠强迫游泳试验中增加的运动活动和延长的不动性，但不能阻断KMO KO小鼠减少的社会交往时间。总之，KA水平升高通过α 7 nAChR拮抗作用导致KMO KO小鼠的抑郁样行为。尼古丁和加兰他敏对KMO KO小鼠抑郁样行为的改善作用与α 7 nAChR的激活有关。
Tryptophan (TRP) is metabolized via the kynurenine (KYN) pathway, which is related to the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the metabolism of KYN to 3-hydroxykynurenine. In rodents, KMO deficiency induces a depression-like behavior and increases the levels of kynurenic acid (KA), a KYN metabolite formed by kynurenine aminotransferases (KATs). KA antagonizes α7 nicotinic acetylcholine receptor (α7nAChR). Here, we investigated the involvement of KA in depression-like behavior in KMO knockout (KO) mice. KYN, KA, and anthranilic acid but not TRP or 3-hydroxyanthranilic acid were elevated in the prefrontal cortex of KMO KO mice. The mRNA levels of KAT1 and α7nAChR but not KAT2−4, α4nAChR, or β2nAChR were elevated in the prefrontal cortex of KMO KO mice. Nicotine blocked increase in locomotor activity, decrease in social interaction time, and prolonged immobility in a forced swimming test, but it did not decrease sucrose preference in the KMO KO mice. Methyllycaconitine (an α7nAChR antagonist) antagonized the effect of nicotine on decreased social interaction time and prolonged immobility in the forced swimming test, but not increased locomotor activity. Galantamine (an α7nAChR allosteric agonist) blocked the increased locomotor activity and prolonged immobility in the forced swimming test, but not the decreased social interaction time in the KMO KO mice. In conclusion, elevation of KA levels contributes to depression-like behaviors in KMO KO mice by α7nAChR antagonism. The ameliorating effects of nicotine and galantamine on depression-like behaviors in KMO KO mice are associated with the activation of α7nAChR.
登录
查看更多内容
影响因子：
3.4
作者：
Papp M;Gruca P;Lason-Tyburkiewicz M;Willner P
通讯作者：
Willner P
影响因子：
3.4
作者：
McClernon, F. Joseph;Hiott, F. Berry;Levin, Edward D.
通讯作者：
Levin, Edward D.
影响因子：
120.7
作者：
Lasser, K;Boyd, JW;Bor, DH
通讯作者：
Bor, DH
尼古丁对甲基苯丙胺引起的感觉运动门控损伤的治疗潜力：苍白球被盖神经元的参与
影响因子：
3.4
作者：
H. Mizoguchi;S. Arai;H. Koike;D. Ibi;H. Kamei;T. Nabeshima;Hyoung‐Chun Kim;K. Takuma;Kiyofumi Yamada
通讯作者：
Kiyofumi Yamada
影响因子：
25.8
作者：
Judd, Lewis L.;Schettler, Pamela J.;Fiedorowicz, Jess G.
通讯作者：
Fiedorowicz, Jess G.