Activation of central adenosine A2B receptors mediate brain ghrelin-induced improvement of intestinal barrier function through the vagus nerve in rats
Activation of central adenosine A2B receptors mediate brain ghrelin-induced improvement of intestinal barrier function through the vagus nerve in rats
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DOI：
10.1016/j.expneurol.2021.113708
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发表时间：
2021-03-25
影响因子：
5.3
通讯作者：
Okumura, Toshikatsu
中科院分区：
文献类型：
--
作者：
Ishioh, Masatomo;Nozu, Tsukasa;Okumura, Toshikatsu
肠漏是一种反映肠屏障功能障碍的疾病，因其与肠易激综合征或阿尔茨海默氏痴呆等多种疾病的关系而引起人们的关注。我们最近已经证明，ghrelin在大脑中通过迷走神经起作用，以改善肠漏。在本研究中，我们试图阐明ghrelin通过迷走神经改善肠屏障功能的确切中枢机制。通过定量大鼠结肠组织中吸收的伊文思蓝来估计体内结肠通透性。腺苷受体拮抗剂1，3-二丙基-8-环戊基黄嘌呤（DPCPX）可阻断脑池内ghrelin引起的肠通透性增加，而多巴胺、大麻素或阿片受体拮抗剂则不能阻断这一作用。脑池内注射腺苷A2 B激动剂而非腺苷A1激动剂可改善结肠通透性增高，而外周注射腺苷A2 B激动剂则不能改善结肠通透性增高，脑池内注射腺苷A2 B激动剂对结肠通透性增高的改善作用可被迷走神经切断术阻断。腺苷A2 B特异性拮抗剂咯嗪阻断了2-脱氧-D-葡萄糖引起的肠通透性增加对ghrelin或中枢迷走神经的刺激。这些结果表明，腺苷A2 B受体在中枢神经系统的激活能够通过迷走神经通路改善肠屏障功能，腺苷A2 B受体可能介导的ghrelin诱导的漏肠的改善迷走神经依赖的方式。这些发现可能有助于我们了解不仅在胃肠道疾病，但也与肠道通透性改变相关的非胃肠道疾病的病理生理。
Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelininduced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-D-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.