Stress-activated leukocyte 12/15-lipoxygenase metabolite enhances struggle behaviour and tocotrienols relieve stress-induced behaviour alteration
Stress-activated leukocyte 12/15-lipoxygenase metabolite enhances struggle behaviour and tocotrienols relieve stress-induced behaviour alteration
复制标题
压力激活的白细胞 12/15-脂氧合酶代谢物增强挣扎行为，生育三烯酚缓解压力引起的行为改变
DOI：
10.1016/j.freeradbiomed.2021.08.236
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发表时间：
2021
影响因子：
7.4
通讯作者：
Hagihara Yoshihisa
中科院分区：
文献类型：
--
作者：
Shichiri Mototada;Ishida Noriko;Aoki Yoshinori;Koike Taisuke;Hagihara Yoshihisa
压力引起情绪激动，导致焦虑，易怒，夸张的惊吓行为，以及在创伤和压力相关精神障碍患者中观察到的过度警惕，包括急性压力障碍和创伤后压力障碍。中枢去甲肾上腺素释放促进压力诱导的情绪唤起。然而，情绪激动的调节器仍然未知。在这里，我们表明，花生四烯酸衍生的代谢产物产生的应激激活的白细胞12/15-脂氧合酶是显着升高的血浆和上调中枢去甲肾上腺素的释放，导致在增强的斗争行为（=逃避行为）在尾部悬挂试验。挣扎行为是模仿情绪激动的症状。这种应激诱导的斗争行为是不存在的12/15-脂氧合酶缺陷小鼠，然而，静脉注射给药的12/15-脂氧合酶代谢物，这些小鼠应激暴露后重新点燃的斗争行为。此外，生育三烯酚和香叶基香叶醇减少应激诱导的12/15-脂氧合酶代谢产物的产生，并抑制斗争行为。我们的研究结果表明，花生四烯酸衍生的12/15-脂氧合酶代谢产物参与调节应激增强的中枢去甲肾上腺素释放和斗争行为。此外，我们建议12/15-脂氧合酶作为一个潜在的治疗目标，用于治疗与压力有关的精神障碍中观察到的情绪唤醒。
Stress induces emotional arousal causing anxiety, irritability, exaggerated startle behaviour, and hypervigilance observed in patients with trauma and stress-related mental disorders, including acute stress disorder and post-traumatic stress disorder. Central norepinephrine release promotes stress-induced emotional arousal. However, the regulator of emotional arousal remains unknown. Here, we show that the arachidonate-derived metabolite produced by stress-activated leukocyte 12/15-lipoxygenase is remarkably elevated in the plasma and upregulates the central norepinephrine release, resulting in the enhancement of the struggle behaviour (= escape behaviour) in the tail suspension test. Struggle behaviour is mimicking a symptom of emotional arousal. This stress-induced struggle behaviour was absent in 12/15-lipoxygenase deficient mice; however, intravenous administration of a 12/15-lipoxygenase metabolite to these mice after stress exposure rekindled the struggle behaviour. Furthermore, tocotrienols and geranylgeraniol reduced stress-induced 12/15-lipoxygenase metabolite production and suppressed the struggle behaviour. Our findings indicate that arachidonate-derived 12/15-lipoxygenase metabolite is involved in the regulation of stress-enhanced central norepinephrine release and struggle behaviour. In addition, we propose 12/15-lipoxygenase as a potential therapeutic target for the treatment of emotional arousal observed in stress-related mental disorders.