Center for Integrative Physiology, Division of Integrative Physiology, Kansai Electric Power Medical Research Institute, Kobe 650-0047, Japan; Division of System Neuroscience, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi 320-0498, Japan.
Neuropeptides. 2019 Jun;75:58-64. doi: 10.1016/j.npep.2019.03.001. Epub 2019 Mar 6.
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 modern 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 Ca concentration ([Ca]) with fura-2 fluorescence imaging, followed by immunocytochemical identification of NPY neurons. Ninjin-yoeito (1-10 μg/ml) increased [Ca] 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.
食欲减退或厌食症在包括癌症、抑郁症和心力衰竭在内的各种疾病中极大地降低了生活质量。此外，食欲减退可能是肌肉减少症和虚弱的上游因素。所有这些疾病都是现代医学和社会的沉重负担。因此，人们一直在期待能够对抗食欲减退的方法，然而，目前还没有有效的、有充分证据的物质。人参归脾丸是一种由 12 种草药组成的日本汉方药，已被用于治疗厌食症。然而，其潜在机制知之甚少。神经肽 Y（NPY）和胃饥饿素分别是最强的中枢和外周食欲诱导剂。本研究旨在确定人参归脾丸是否会影响下丘脑弓状核（ARC）中 NPY 和/或胃饥饿素反应神经元，ARC 是摄食中枢。我们从 ARC 中分离出小鼠的单个神经元，并使用 fura-2 荧光成像测量胞质 Ca 浓度 ([Ca])，随后通过免疫细胞化学鉴定 NPY 神经元。人参归脾丸（1-10μg/ml）增加了 ARC 神经元的 [Ca]，其中大多数神经元对 NPY 呈免疫反应性。这些人参归脾丸反应性 NPY 神经元中有一部分对胃饥饿素也有反应，而另一部分则没有。此外，人参归脾丸（1g/kg/天）口服给药可对抗顺铂（一种抗癌药物）引起的厌食症小鼠的食物摄入量和体重减少。这些结果表明，人参归脾丸直接靶向 ARC 中的胃饥饿素反应性和非反应性 NPY 神经元，并在顺铂治疗的厌食症小鼠中维持食物摄入量和体重。人参归脾丸通过胃饥饿素反应性和胃饥饿素非反应性 NPY 途径的信号传导可能为这种治疗癌症、抑郁症、心力衰竭、肌肉减少症、虚弱和衰老相关厌食症的药物提供强有力的机制基础。
