Xu Meng, Wu Hai-Yun, Liu Hao, Gong Nian, Wang Yi-Rui, Wang Yong-Xiang
King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
Br J Pharmacol. 2017 Apr;174(7):580-590. doi: 10.1111/bph.13720. Epub 2017 Feb 16.
Iridoid glycosides containing the double bond scaffold of cyclopentapyran are reversible and orthosteric agonists of glucagon-like peptide-1 (GLP-1) receptors and exert anti-nociceptive and neuroprotective actions. Morroniside, derived from the medicinal herb Cornus officinalis, is an atypical secoiridoid containing a six-membered cyclic inner ether fragment. Here we investigated whether morroniside was an orthosteric GLP-1 receptor agonist and had anti-hypersensitivity activities in a model of neuropathic pain.
We used a model of neuropathic pain, induced by tight ligation of L5/L6 spinal nerves in rats. Hydrogen peroxide-induced oxidative damage was also assayed in N9 microglial cells and human HEK293 cells stably expressing GLP-1 receptors.
Morroniside protected against hydrogen peroxide-induced oxidative damage in N9 microglial and HEK293 cells that expressed mouse or human GLP-1 receptors, but not in HEK293T cells without GLP-1 receptors. The GLP-1 receptor orthosteric antagonist exendin(9-39) also concentration-dependently shifted the concentration-protective response curves of morroniside and exenatide to the right without affecting maximal protection, with similar pA values. Furthermore, morroniside given by oral gavage or intrathecally in neuropathic rats dose-dependently attenuated mechanical allodynia, with comparable E values and ED s of 335 mg·kg and 7.1 μg and completely blocked thermal hyperalgesia. Daily intrathecal injections of morroniside over 7 days did not induce anti-allodynic tolerance. Pretreatment with intrathecal exendin(9-39) completely blocked systemic and intrathecal morroniside-induced mechanical anti-allodynia.
Our data demonstrated that morroniside was an orthosteric agonist of GLP-1 receptors and produced antihypersensitivity in a neuropathic pain model by activation of spinal GLP-1 receptors.
含有环戊吡喃双键支架的环烯醚萜苷是胰高血糖素样肽-1（GLP-1）受体的可逆性正构激动剂，具有抗伤害感受和神经保护作用。山茱萸苷是从药用植物山茱萸中提取的一种非典型裂环环烯醚萜，含有一个六元环状内醚片段。在此，我们研究了山茱萸苷是否为GLP-1受体的正构激动剂，以及在神经性疼痛模型中是否具有抗超敏反应活性。
我们使用了大鼠L5/L6脊神经紧密结扎诱导的神经性疼痛模型。还在N9小胶质细胞和稳定表达GLP-1受体的人HEK293细胞中检测了过氧化氢诱导的氧化损伤。
山茱萸苷可保护表达小鼠或人GLP-1受体的N9小胶质细胞和HEK293细胞免受过氧化氢诱导的氧化损伤，但对不表达GLP-1受体的HEK293T细胞无保护作用。GLP-1受体正构拮抗剂艾塞那肽（9-39）也浓度依赖性地将山茱萸苷和艾塞那肽的浓度-保护反应曲线向右移动，而不影响最大保护作用，pA值相似。此外，在神经性大鼠中经口灌胃或鞘内注射山茱萸苷剂量依赖性地减轻机械性异常性疼痛，其E值和ED50分别为335mg·kg和7.1μg，并完全阻断热痛觉过敏。连续7天每天鞘内注射山茱萸苷未诱导抗异常性疼痛耐受性。鞘内注射艾塞那肽（9-39）预处理可完全阻断全身和鞘内注射山茱萸苷诱导的机械性抗异常性疼痛。
我们的数据表明，山茱萸苷是GLP-1受体的正构激动剂，通过激活脊髓GLP-1受体在神经性疼痛模型中产生抗超敏反应。
