ROLES OF DIURNAL RHYTHM AND PINEAL HORMONE MELATONIN, IN THE GASTRIC MUCOSA PROTECTING MECHANISM

我们研究了褪黑素（ML）保护胃黏膜的机制及其与昼夜节律的关系。我们发现松果体在应激反应中分泌的ML具有保护胃黏膜的作用。我们还发现，ML不仅具有外周保护作用，而且具有中枢性保护作用。这些作用可能是由一种脑ML受体Ib介导的。考虑到与昼夜节律的关系，我们在光/暗时段对大鼠进行了水浸限制应激。暗期应激组的胃病变明显受到抑制，而光期应激组的胃病变明显受到抑制。轻度应激期胃黏膜前列腺素E_2分泌减少。然而，在黑暗时期，与对照组相比，减少受到抑制。在应激负荷前，暗期的ML浓度显著高于亮期的ML浓度，高于对照组的ML浓度，提示其与抑制胃病变有关。COX-2 mRNA的表达在应激后的光照期和黑暗期均被检测到。COX-2 mRNA在消化道粘膜损伤的修复过程中起重要作用。无论损伤数量多少，应激负荷后胃粘膜损伤修复前都可能出现COX-2 mRNA。这一发现可能反映了应激负荷对胃黏膜PGE_2生成的抑制作用。在切除松果体组，黑暗期应激负荷后胃粘膜病变加重。结果表明，昼夜节律显著影响应激性胃病变的发展、ML/PGE_2的产生和COX-2 mRNA的表达。此外，我们测量了健康志愿者和胃癌或消化性溃疡患者的血ML和尿ML代谢物水平，我们证实了晚期胃癌患者的尿ML代谢物水平下降。在未来，这些参数作为生化标记的有效性应该进行研究。少

We investigated the mechanism by which melatonin (ML) protected the gastric mucosa and the relation to diurnal rhythm. We found that ML, which is secreted by the pineal body in response to stress, protects the gastric mucosa. We also found that ML showed not only peripheral but also central gastric mucosa-protecting actions. It was suggested that these actions are mediated by a brain ML receptor, Ib. With respect to the relation to diurnal rhythm, water-immersion restriction stress was given to rats during the light/dark periods. In the group with stress during the dark period, gastric lesions were significantly inhibited than in the group with stress during the light period. Gastric mucosa prostaglandin (PG)E_2 production reduced after stress loading during the light period. However, during the dark period, reduction was inhibited compared to that in the control group. Furthermore, the concentration of ML during the dark period was significantly higher than that during the light perio … More d in the control group before stress loading, suggesting the association with inhibition of gastric lesions. The expression of COX-2 mRNA, which has been reported to play an important role in the repair process of digestive tract mucosal injury, was detected during both the light and dark periods after stress loading. Regardless of the number of lesions, COX-2 mRNA may appear prior to repair of gastric mucosal lesions after stress loading. This finding may reflect inhibition of gastric mucosa PGE_2 production after stress loading. In the group in which the pineal body was extirpated, gastric mucosal lesions exacerbated after stress loading during the dark period. However, exacerbation was significantly inhibited by intracisternal pretreatment with ML. These findings suggest that diurnal rhythm markedly influences the development of stress-induced gastric lesions, ML/PGE_2 production, and COX-2 mRNA expression. Furthermore, blood ML and urinary ML metabolite levels were measured in healthy volunteers and patients with gastric cancer or digestive ulcer, and we confirmed that urinary ML metabolite levels were decreased in patients with advanced gastric cancer. In the future, the usefulness of these parameters as biochemical markers should be investigated. Less