Dehydroepiandrosterone sulfate improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome.
Dehydroepiandrosterone sulfate improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome.
复制标题
硫酸脱氢表雄酮可改善肠易激综合征大鼠模型的内脏感觉和肠道屏障。
DOI：
10.1016/j.ejphar.2019.03.037
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Okumura T.
中科院分区：
文献类型：
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作者：
Nozu T;Miyagishi S;Nozu R;Takakusaki K;Okumura T.
应激引起的内脏感觉改变和肠道屏障功能受损在肠易激综合征（IBS）的病理生理中起重要作用。在IBS动物模型中，这些反应被证明是外周促肾上腺皮质激素释放因子（CRF）依赖性的，也通过促炎细胞因子介导。已知硫酸脱氢表雄酮（DHEA-S）通过抑制促炎细胞因子释放而具有抗炎特性。我们假设DHEA-S可以改善应激引起的内脏变化，并有利于IBS的治疗。我们探讨了DHEA-S对脂多糖（LPS）或重复避水应激（WAS）诱导的内脏异常性疼痛和结肠通透性增加（大鼠IBS模型）的影响。电生理学测量内脏反应阈值，即由结肠球囊扩张引起的腹肌收缩。通过定量结肠组织中吸收的伊文思蓝来估计体内结肠渗透性。DHEA-S能剂量依赖性地消除LPS诱导的内脏痛觉超敏和结肠通透性增高。它还阻断了反复WAS或外周注射CRF诱导的内脏变化。γ-氨基丁酸（GABA）A受体拮抗剂荷包牡丹碱、一氧化氮（NO）合成抑制剂NG-硝基-L-精氨酸甲酯、阿片受体拮抗剂纳洛酮和多巴胺D2受体拮抗剂舒必利可逆转DHEA-S的上述作用。而外周多巴胺D2受体拮抗剂多潘立酮对上述作用无明显影响。外周注射astressin 2-B，一种选择性CRF受体亚型2（CRF 2）拮抗剂也逆转了这些作用。结论：DHEA-S通过GABAA、NO、阿片、中枢多巴胺D2和外周CRF 2信号通路阻断应激引起的内脏变化。DHEA-S可能对IBS的治疗有一定作用。
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)Areceptor antagonist, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, naloxone, an opioid receptor antagonist, or sulpiride, a dopamine D2receptor antagonist. However, domperidone, a peripheral dopamine D2receptor antagonist did not modify the effects. Peripheral injection of astressin2-B, a selective CRF receptor subtype 2 (CRF2) antagonist also reversed these effects. In conclusion, DHEA-S blocked stress-induced visceral changes via GABAA, NO, opioid, central dopamine D2and peripheral CRF2signaling. DHEA-S may be useful for IBS treating.