The 5-HT4 receptor agonist mosapride attenuates NSAID-induced gastric mucosal damage
The 5-HT4 receptor agonist mosapride attenuates NSAID-induced gastric mucosal damage
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DOI：
10.1007/s00535-009-0170-3
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发表时间：
2010-02-01
影响因子：
6.3
通讯作者：
Ozaki, Hiroshi
中科院分区：
文献类型：
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作者：
Fujisawa, Masahiko;Murata, Takahisa;Ozaki, Hiroshi
胆碱能抗炎通路是一种新的生理机制，存在于体内不同部位，其中涉及通过自主神经系统对炎性细胞的烟碱调节。在这项研究中，我们验证了一个假设，即5-HT 4激动剂刺激胆碱能神经可能调节非甾体抗炎药（NSAID）诱导的胃粘膜溃疡的进展。大鼠口服吲哚美辛诱导急性胃溃疡。胃损伤分析表明，预先给予莫沙必利（一种选择性5-HT 4激动剂），0.25，0.5，0.75mg/kg对消炎痛引起的粘膜损伤有明显的抑制作用。在胃排空分析中，在3.0 mg/kg莫沙必利预处理组中观察到排空效应，但在较低剂量（0.5 mg/kg）组中未观察到该效应。莫沙必利治疗（0.5 mg/kg）的抗溃疡活性被5-HT 4特异性拮抗剂GR 113808（1 mg/kg，静脉注射）阻断。此外，我们证明了甲基卡乌头碱（0.29和0.87 mg/kg i. p.），α 7烟碱乙酰胆碱（ACh）受体（α 7 nAChRs）的选择性抑制剂，消除了莫沙必利的抗溃疡作用。这些结果表明，莫沙必利的粘膜保护作用可能是通过激活5-HT 4受体，然后激活烟碱抗炎系统，加速副交感神经释放ACh，从而对免疫细胞起作用。α 7 nAChR可能参与莫沙必利的抗溃疡作用。
The cholinergic anti-inflammatory pathway is a novel physiological mechanism found at various locations in the body where the nicotinic regulation of inflammatory cells through the autonomic nervous system is involved. In this study, we tested the hypothesis that cholinergic nerve stimulation by a 5-HT4 agonist may modulate the progression of gastric mucosal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs).Acute gastric ulcers were induced in rats by the oral administration of indomethacin.Gastric damage analysis indicated that pretreatment with mosapride, a selective 5-HT4 agonist, at 0.25, 0.5, and 0.75 mg/kg, inhibited the mucosal damage induced by indomethacin. In gastric emptying analysis, an evacuation effect was observed in the 3.0 mg/kg mosapride pretreatment group, but this effect was not observed in the lower dose (0.5 mg/kg) group. The antiulcerogenic activity of mosapride treatment (at 0.5 mg/kg) was blocked by a 5-HT4-specific antagonist, GR113808 (1 mg/kg, i.v.). Additionally, we demonstrated that methyllycaconitine (0.29 and 0.87 mg/kg i.p.), a selective inhibitor of alpha 7 nicotinic acetylcholine (ACh) receptors (alpha 7nAChRs), ablated the antiulcerogenic action of mosapride.These results suggest that the mucosal protective action of mosapride may be mediated by an action on immune cells through the acceleration of ACh release from parasympathetic nerves via the activation of 5-HT4 receptors, followed by activation of the nicotinic anti-inflammatory system. It appears that the alpha 7nAChR may be involved in the antiulcerogenic action of mosapride.