Ninjin-yoeito activates ghrelin-responsive and unresponsive NPY neurons in the arcuate nucleus and counteracts cisplatin-induced anorexia
Ninjin-yoeito activates ghrelin-responsive and unresponsive NPY neurons in the arcuate nucleus and counteracts cisplatin-induced anorexia
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DOI：
10.1016/j.npep.2019.03.001
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发表时间：
2019-06-01
期刊：
影响因子：
2.9
通讯作者：
Yada, Toshihiko
中科院分区：
文献类型：
--
作者：
Goswami, Chayon;Dezaki, Katsuya;Yada, Toshihiko
食欲下降或厌食症大大恶化了各种疾病的生活质量，包括癌症，抑郁症和心力衰竭。此外，食欲下降可能是肌肉减少症和虚弱的上游。这些疾病都是现代医学和社会的沉重负担。因此，一直在等待对抗食欲下降的方法，然而，目前还没有有效且证据充分的物质。忍者yoeito，日本汉方药物包括12草药已被用来治疗厌食症。然而，其内在机制却知之甚少。神经肽Y（NPY）和生长激素释放肽分别是最有效的中枢和外周食欲诱导剂。本研究旨在确定是否Ninjin-yoeito影响下丘脑弓状核（ARC），摄食中心的NPY和/或ghrelin反应神经元。我们从小鼠ARC分离单个神经元，用Fura-2荧光成像测量胞浆Ca 2+浓度（[Ca 2 +]（i）），然后用免疫细胞化学鉴定NPY神经元。Ninjin-yoeito（1-10 μ g/ml）增加ARC神经元的[Ca ~（2+）]（t），其中大部分（80%）对NPY呈免疫反应。这些Ninjin-yoeito-responsive NPY神经元中的一部分也对ghrelin有反应，而另一部分则没有。此外，口服Ninjin-yoeito（1 g/kg/天）抵消了抗癌药物顺铂引起的小鼠摄食量和体重减少。这些结果表明，Ninjin-yoeito直接靶向ARC中的ghrelin反应性和无反应性NPY神经元，并在顺铂治疗的厌食小鼠中保持食物摄入和体重。Ninjin-yoeito通过ghrelin反应性和ghrelin无反应性NPY通路的信号传导可能为这种药物治疗与癌症、抑郁症、心力衰竭、肌肉减少症、虚弱和衰老相关的厌食症提供强有力的机制基础。
Reduced appetite or anorexia substantially deteriorates quality of life in various diseases including cancer, depression and heart failure. Furthermore, reduced appetite may stand upstream of sarcopenia and frailty. All these diseases are heavy burdens in the modem medicine and society. Therefore, the means that counteracts reduced appetite has been awaited, however, effective and well evidenced substance is not currently available. Ninjin-yoeito, a Japanese kampo medicine comprising twelve herbs has been used to treat anorexia. However, underlying mechanism is little known. Neuropeptide Y (NPY) and ghrelin are the most potent central and peripheral inducers of appetite, respectively. This study sought to determine whether Ninjin-yoeito influences NPY and/or ghrelin-responsive neurons in the hypothalamic arcuate nucleus (ARC), a feeding center. We isolated single neurons from ARC of mice and measured cytosolic Ca2+ concentration ([Ca2+](i)) with fura-2 fluorescence imaging, followed by immunocytochemical identification of NPY neurons. Ninjin-yoeito (1-10 mu g/ml) increased [Ca2+](t) in ARC neurons, the majority (80%) of which was immunoreactive to NPY. One fraction of these Ninjin-yoeito-responsive NPY neurons also responded to ghrelin, while another fraction did not. Furthermore, oral administration of Ninjin-yoeito (1 g/kg/day) counteracted the reductions in food intake and body weight by cisplatin, an anti-cancer drug, in mice. These results demonstrate that Ninjin-yoeito directly targets both ghrelin-responsive and unresponsive NPY neurons in ARC and preserves food intake and body weight in cisplatin-treated anorectic mice. Ninjin-yoeito's signaling through ghrelin-responsive and ghrelin-unresponsive NPY pathways may provide strong mechanistic basis for this medicine for treating anorectic conditions associated with cancer, depression, heart failure, sarcopenia, frailty and aging.