Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors
Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors
复制标题
京尼平苷及其环烯醚萜类似物通过作用于脊髓 GLP-1 受体表现出镇痛作用
DOI：
10.1016/j.neuropharm.2014.04.007
复制
发表时间：
2014-09-01
影响因子：
4.7
通讯作者：
Wang, Yong-Xiang
中科院分区：
文献类型：
--
作者：
Gong, Nian;Fan, Hui;Wang, Yong-Xiang
我们最近发现，由肽激动剂艾塞那肽激活脊髓胰高血糖素样肽-1受体（GLP-1Rs）在慢性疼痛中产生抗痛觉作用。我们认为脊髓GLP-1Rs是治疗慢性疼痛的潜在靶分子。本研究评估了京尼平苷的抗损伤活性，京尼平苷是一种假设的小分子GLP-1R激动剂。京尼平苷在表达大鼠和人GLP-1Rs的PC12和HEK293细胞中对过氧化氢诱导的氧化损伤产生浓度依赖性的完全保护，而在不表达GLP-1Rs的HEK293T细胞中则没有。正构GLP-1R拮抗剂exendin（9-39）在不改变最大保护作用的情况下，使栀子苷的浓度-响应曲线右移，两种细胞系的pA(2)值相同。皮下注射和口服京尼平苷剂量依赖性阻断福尔马林诱导的强直反应，但不阻断急性退缩反应。皮下注射和口服京尼平苷的最大抑制率分别为72%和68%，ed50分别为13.1和52.7 mg/kg。多天皮下注射京尼平苷和艾塞那肽7天未引起抗伤性耐受。鞘内geniposide诱导剂量依赖性抗痛觉，脊髓延伸蛋白（9-39）、siRNA/GLP-1R和环AMP/PKA途径抑制剂完全阻止了这种作用。京尼平苷环烯醚类似物京尼平酸、京尼平甲醚、1,10-无氢甲苷、马鞭草苷和梓醇能以延长（9-39）可逆的方式有效抑制过氧化氢诱导的氧化损伤和福尔马林疼痛。我们的研究结果表明，京尼平苷及其环烯醚酮类似物通过激活脊髓GLP-1Rs产生持续疼痛的抗痛感，京尼平苷代表的环烯醚酮是GLP-1Rs的正位激动剂，在人和大鼠中功能相似，可能与exendin在相同的结合位点起作用（9-39）。(C) 2014 Elsevier Ltd.版权所有。
We recently discovered that the activation of the spinal glucagon-like peptide-1 receptors (GLP-1Rs) by the peptidic agonist exenatide produced antinociception in chronic pain. We suggested that the spinal GLP-1Rs are a potential target molecule for the management of chronic pain. This study evaluated the antinociceptive activities of geniposide, a presumed small molecule GLP-1R agonist Geniposide produced concentration-dependent, complete protection against hydrogen peroxide-induced oxidative damage in PC12 and HEK293 cells expressing rat and human GLP-1Rs, but not in HEK293T cells that do not express GLP-1Rs. The orthosteric GLP-1R antagonist exendin(9-39) right-shifted the concentration -response curve of geniposide without changing the maximal protection, with identical pA(2) values in both cell lines. Subcutaneous and oral geniposide dose-dependently blocked the formalin-induced tonic response but not the acute flinching response. Subcutaneous and oral geniposide had maximum inhibition of 72% and 68%, and ED50s of 13.1 and 52.7 mg/kg, respectively. Seven days of multidaily subcutaneous geniposide and exenatide injections did not induce antinociceptive tolerance. Intrathecal geniposide induced dose-dependent antinociception, which was completely prevented by spinal exendin(9-39), siRNA/GLP-1R and cyclic AMP/PKA pathway inhibitors. The geniposide iridoid analogs geniposidic acid, genipin methyl ether, 1,10-anhydrogenipin, loganin and catalpol effectively inhibited hydrogen peroxide-induced oxidative damage and formalin pain in an exendin(9-39)-reversible manner. Our results suggest that geniposide and its iridoid analogs produce antinociception during persistent pain by activating the spinal GLP-1Rs and that the iridoids represented by geniposide are orthosteric agonists of GLP-1Rs that function similarly in humans and rats and presumably act at the same binding site as exendin(9-39). (C) 2014 Elsevier Ltd. All rights reserved.