NPY Y2 受体激动剂 PYY(3-36)通过减少肠道液体分泌和减缓结肠转运来抑制小鼠腹泻。
NPY Y2 receptor agonist PYY(3-36) inhibits diarrhea by reducing intestinal fluid secretion and slowing colonic transit in mice.
机构信息
Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Okubo 3, Tsukuba 300-2611, Japan.
出版信息
Peptides. 2010 Apr;31(4):671-5. doi: 10.1016/j.peptides.2009.11.005. Epub 2009 Nov 17.
Peptide YY (PYY)(3-36), a neuropeptide Y (NPY) Y2 receptor agonist, is a powerful inhibitor of intestinal secretion. Based on this anti-secretory effect, NPY Y2 receptor agonists may be useful as novel anti-diarrheal agents, but anti-diarrheal efficacy has yet to be determined. We therefore examined the anti-diarrheal efficacy of PYY(3-36) and a selective Y2 receptor agonist, N-acetyl-[Leu28, Leu31]-NPY(24-36), in experimental mouse models of diarrhea. Intraperitoneal administration of PYY(3-36) (0.01-1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) significantly inhibited diarrhea (increase in wet fecal weight and diarrhea score) induced by dimethyl-prostaglandin E2, 5-hydroxytryptamine, and castor oil. Anti-diarrheal activities of PYY(3-36) and N-acetyl-[Leu28, Leu31]-NPY(24-36) were comparable to the effects of loperamide (1mg/kg), a widely used anti-diarrheal drug. To clarify the anti-diarrheal mechanisms of NPY Y2 receptor agonists, we investigated the effects of PYY(3-36) and N-acetyl-[Leu28, Leu31]-NPY(24-36) on intestinal fluid secretion and colonic transit. PYY(3-36) (1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) significantly reduced dimethyl-prostaglandin E2-induced intestinal fluid accumulation in conscious mice, suggesting that NPY Y2 receptor agonists inhibit diarrhea, at least in part, by reducing intestinal secretion. In addition, PYY(3-36) (0.01-1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) potently inhibited normal fecal output, suggesting that NPY Y2 receptor activation inhibits colonic motor function and NPY Y2 receptor agonists inhibit diarrhea partly by slowing colonic transit. These results indicate that NPY Y2 receptor agonists inhibit diarrhea in mice by not only reducing intestinal fluid secretion, but also slowing colonic transit, and illustrate the therapeutic potential of NPY Y2 receptor agonists as effective treatments for diarrhea.
肽 YY（PYY）（3-36）是一种神经肽 Y（NPY）Y2 受体激动剂，是一种强大的肠道分泌抑制剂。基于这种抗分泌作用，NPY Y2 受体激动剂可能作为新型抗腹泻药物有用，但抗腹泻疗效尚未确定。因此，我们在实验性腹泻小鼠模型中研究了 PYY（3-36）和选择性 Y2 受体激动剂 N-乙酰基-[Leu28，Leu31]-NPY（24-36）的抗腹泻作用。腹腔内给予 PYY（3-36）（0.01-1mg/kg）和 N-乙酰基-[Leu28，Leu31]-NPY（24-36）（10mg/kg）可显著抑制二甲基前列腺素 E2、5-羟色胺和蓖麻油诱导的腹泻（湿粪重和腹泻评分增加）。PYY（3-36）和 N-乙酰基-[Leu28，Leu31]-NPY（24-36）的抗腹泻作用与洛哌丁胺（1mg/kg）的作用相当，洛哌丁胺是一种广泛使用的抗腹泻药物。为了阐明 NPY Y2 受体激动剂的抗腹泻机制，我们研究了 PYY（3-36）和 N-乙酰基-[Leu28，Leu31]-NPY（24-36）对肠道液体分泌和结肠转运的影响。PYY（3-36）（1mg/kg）和 N-乙酰基-[Leu28，Leu31]-NPY（24-36）（10mg/kg）显著减少了清醒小鼠中二甲基前列腺素 E2 诱导的肠道液体积聚，表明 NPY Y2 受体激动剂通过减少肠道分泌至少部分抑制腹泻。此外，PYY（3-36）（0.01-1mg/kg）和 N-乙酰基-[Leu28，Leu31]-NPY（24-36）（10mg/kg）强烈抑制正常粪便排出，表明 NPY Y2 受体激活抑制结肠运动功能，NPY Y2 受体激动剂通过减缓结肠转运部分抑制腹泻。这些结果表明，NPY Y2 受体激动剂通过减少肠道液体分泌和减缓结肠转运抑制小鼠腹泻，并说明 NPY Y2 受体激动剂作为有效的腹泻治疗药物具有治疗潜力。
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