Department of Regional Medicine and Education, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
Eur J Pharmacol. 2019 Jun 5;852:198-206. doi: 10.1016/j.ejphar.2019.03.037. Epub 2019 Mar 29.
Stress-induced altered visceral sensation and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). These responses were demonstrated to be peripheral corticotropin-releasing factor (CRF) dependent and also mediated via proinflammatory cytokine in animal IBS model. Dehydroepiandrosterone sulfate (DHEA-S) is known to have anti-inflammatory properties by suppressing proinflammatory cytokine release. We hypothesized that DHEA-S improves stress-induced visceral changes and is beneficial for IBS treatment. We explored the effects of DHEA-S on lipopolysaccharide (LPS)- or repeated water avoidance stress (WAS)-induced visceral allodynia and increased colonic permeability (rat IBS models). The threshold of visceromotor response, i.e. abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue. DHEA-S abolished visceral allodynia and colonic hyperpermeability induced by LPS in a dose-dependent manner. It also blocked repeated WAS- or peripheral injection of CRF-induced visceral changes. These effects by DHEA-S in LPS model were reversed by bicuculline, a γ-aminobutyric acid (GABA) receptor antagonist, N-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, naloxone, an opioid receptor antagonist, or sulpiride, a dopamine D receptor antagonist. However, domperidone, a peripheral dopamine D receptor antagonist did not modify the effects. Peripheral injection of astressin-B, a selective CRF receptor subtype 2 (CRF) antagonist also reversed these effects. In conclusion, DHEA-S blocked stress-induced visceral changes via GABA, NO, opioid, central dopamine D and peripheral CRF signaling. DHEA-S may be useful for IBS treating.
应激引起的内脏感觉改变和肠道屏障功能障碍在肠易激综合征（IBS）的病理生理学中起着重要作用。这些反应被证明是外周促肾上腺皮质释放因子（CRF）依赖性的，并且在动物 IBS 模型中也通过促炎细胞因子介导。脱氢表雄酮硫酸盐（DHEA-S）通过抑制促炎细胞因子的释放而具有抗炎特性。我们假设 DHEA-S 可改善应激引起的内脏变化，有益于 IBS 的治疗。我们探讨了 DHEA-S 对脂多糖（LPS）或反复水回避应激（WAS）引起的内脏痛觉过敏和结肠通透性增加（大鼠 IBS 模型）的影响。通过电生理学测量结肠球囊扩张引起的内脏运动反应（即腹壁肌肉收缩）来测量内脏感觉阈值。通过定量测量结肠组织中吸收的 Evans 蓝来估计体内结肠通透性。DHEA-S 以剂量依赖性方式消除 LPS 诱导的内脏痛觉过敏和结肠高通透性。它还阻断了反复 WAS 或外周注射 CRF 引起的内脏变化。在 LPS 模型中，DHEA-S 的这些作用被 GABA 受体拮抗剂bicuculline、一氧化氮（NO）合成抑制剂 N-硝基-L-精氨酸甲酯、阿片受体拮抗剂纳洛酮或多巴胺 D 受体拮抗剂sulpiride 逆转。然而，外周多巴胺 D 受体拮抗剂 domperidone 并没有改变这些作用。外周注射选择性 CRF 受体亚型 2（CRF）拮抗剂 astressin-B 也逆转了这些作用。总之，DHEA-S 通过 GABA、NO、阿片、中枢多巴胺 D 和外周 CRF 信号通路阻断应激引起的内脏变化。DHEA-S 可能对 IBS 的治疗有用。
