Takahashi Kohei, Kurokawa Kazuhiro, Hong Lihua, Miyagawa Kazuya, Mochida-Saito Atsumi, Takeda Hiroshi, Tsuji Minoru
Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.
Department of Pharmacology, School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka 831-8501, Japan.
Exp Neurol. 2024 Mar;373:114671. doi: 10.1016/j.expneurol.2023.114671. Epub 2023 Dec 30.
Patients with inflammatory bowel disease, including ulcerative colitis (UC) and Crohn's disease, have a high incidence of psychiatric disorders, including depression and anxiety. However, the underlying pathogenic mechanism remains unknown. Dextran sulfate sodium (DSS)-treated mice, a model of UC, exhibit depressive-like behavior and reduced adenosine monophosphate-activated protein kinase (AMPK) activity, which regulates various physiological functions in the brain and gut. However, comprehensive studies on UC pathophysiology with co-occurring depression focused on brain-gut AMPK activity are lacking. Therefore, we aimed to investigate whether resveratrol (RES), an AMPK activator, prevented DSS-induced UC-like symptoms and depressive-like behavior. DSS treatment induced UC-like pathology and depressive-like behavior, as assessed via the tail suspension test. Moreover, western blotting and immunohistochemical studies revealed that DSS increased p-p70S6 kinase (Thr389), p62, tumor necrosis factor-α, interleukin (IL)-1β, IL-18, NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, cleaved Gasdermin-D (GSDMD), and cleaved caspase-3 expression levels in the rectum and hippocampus, and increased CD40, iNOS, and Kelch-like ECH-associated protein 1 expression levels, and the number of Iba1-positive cells in the hippocampus, and decreased p-AMPK and LC3II/I expression levels, and the number of NF-E2-related factor 2 (Nrf2)-positive cells, and reduced neurogenesis in the hippocampus. These changes were reversed by the RES administration. RES also enhanced PGC1α and SOD1 expression in the hippocampus of DSS-treated male mice. Moreover, NLRP3 staining was observed in the neurons and microglia, and cleaved GSDMD staining in neurons in the hippocampus of DSS-treated mice. Notably, RES prevented UC-like pathology and depressive-like behavior and enhancement of autophagy, decreased rectal and hippocampal inflammatory cytokines and inflammasome, and induced the Nrf2-PGC1α-SOD1 pathway in the hippocampus, resulting in neurogenesis in the hippocampal dentate gyrus. Our findings suggest that brain-gut AMPK activation may be an important therapeutic strategy in patients with UC and depression.
炎症性肠病患者，包括溃疡性结肠炎（UC）和克罗恩病患者，患精神疾病（包括抑郁症和焦虑症）的发生率很高。然而，其潜在的致病机制仍不清楚。葡聚糖硫酸钠（DSS）处理的小鼠是UC的一种模型，表现出抑郁样行为且腺苷单磷酸激活蛋白激酶（AMPK）活性降低，AMPK可调节大脑和肠道的各种生理功能。然而，缺乏针对同时患有抑郁症的UC病理生理学且聚焦于脑-肠AMPK活性的全面研究。因此，我们旨在研究AMPK激活剂白藜芦醇（RES）是否能预防DSS诱导的UC样症状和抑郁样行为。通过悬尾试验评估，DSS处理诱导了UC样病理变化和抑郁样行为。此外，蛋白质免疫印迹法和免疫组织化学研究表明，DSS增加了直肠和海马中磷酸化p70核糖体蛋白S6激酶（Thr389）、p62、肿瘤坏死因子-α、白细胞介素（IL）-1β、IL-18、NLR家族含pyrin结构域蛋白3（NLRP3）、裂解的半胱天冬酶-1、裂解的Gasdermin-D（GSDMD）和裂解的半胱天冬酶-3的表达水平，增加了海马中CD40、诱导型一氧化氮合酶（iNOS）和 Kelch样ECH相关蛋白1的表达水平以及Iba1阳性细胞的数量，降低了磷酸化AMPK和LC3II/I的表达水平以及核因子E2相关因子2（Nrf2）阳性细胞的数量，并减少了海马中的神经发生。RES给药可逆转这些变化。RES还增强了DSS处理的雄性小鼠海马中PGC1α和超氧化物歧化酶1（SOD1）的表达。此外，在DSS处理小鼠的海马神经元和小胶质细胞中观察到NLRP3染色，在神经元中观察到裂解的GSDMD染色。值得注意的是，RES预防了UC样病理变化和抑郁样行为，增强了自噬，降低了直肠和海马中的炎性细胞因子和炎性小体，并在海马中诱导了Nrf2-PGC1α-SOD1通路，从而导致海马齿状回中的神经发生。我们的研究结果表明，脑-肠AMPK激活可能是UC和抑郁症患者的一种重要治疗策略。
