Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing.
Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing.
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酯水解不同地降低乌头碱引起的抗过敏和急性神经毒性：脊髓小胶质细胞强啡肽表达的参与及其对乌头加工的影响
DOI：
10.3389/fphar.2016.00367
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发表时间：
2016
影响因子：
5.6
通讯作者：
Wang YX
中科院分区：
文献类型：
--
作者：
Li TF;Gong N;Wang YX
乌头碱（包括草乌碱A）是一组双酯型C19-二萜生物碱，在二萜骨架的C8上连接一个乙酰酯基，在C14上连接一个苯甲酰酯基，可能是乌头植物中最具生物活性和最丰富的生物碱。这两种基团的水解都涉及到传统中药方法的加工过程。我们最近发现，草乌甲素产生抗超敏反应，这是通过刺激脊髓小胶质细胞强啡肽A的表达介导的。本研究旨在阐明乌头碱诱导的强啡肽A表达、抗过敏作用、神经毒性等是否与乙酰酯和苯甲酰酯有关。鞘内给药乌头碱和苯甲酰乌头碱（但不是乌头碱）衰减机械异常性疼痛和热痛觉过敏，标准化ED 50值分别为35 pmol和3.6 nmol。小胶质细胞抑制剂、强啡肽A抗血清和κ-阿片受体拮抗剂可完全阻断乌头碱和苯甲酰乌头碱的抗异常性疼痛作用。乌头碱和苯甲酰乌头碱（而非乌头碱）刺激培养的原代脊髓小胶质细胞中强啡肽A的表达，EC 50值分别为32 nM和3 μM。鞘内注射乌头碱、苯甲酰乌头碱和乌头碱可引起弛缓性麻痹和死亡，标准化TD 50值分别为0.5 nmol、0.2 μmol和1.6 μmol。乌头碱和苯多乌头碱的TD_（50）/ED_（50）比值分别为14：1和56：1。我们的研究结果表明，C8-乙酰基和C14-苯甲酰基基团是必不可少的乌头碱刺激脊髓小胶质细胞强啡肽A的表达和随后的抗超敏反应，这可以从神经毒性分离，因为苯甲酰乌头碱和乌头碱差异产生抗超敏反应和神经毒性，由于其不同的刺激能力对强啡肽A的表达。我们的研究结果支持乌头碱加工的科学原理，但应注意避免过度加工和过度水解苯并乌头碱。
Aconitines, including bulleyaconitine A, probably the most bioactive and abundant alkaloids in Aconitum plant, are a group of diester C19-diterpenoid alkaloids with one acetylester group attached to C8 of the diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involved in the processing of Aconitum, a traditional Chinese medicinal approach. We recently demonstrated that bulleyaconitine A produced anti-hypersensitivity, which was mediated by stimulation of spinal microglial dynorphin A expression. This study aimed to elucidate whether the acetylester and benzoylester groups are involved in aconitine-induced dynorphin A expression, anti-hypersensitivity, neurotoxicity in neuropathic rats. Intrathecal administration of aconitine and benzoylaconine (but not aconine) attenuated mechanical allodynia and heat hyperalgesia, with normalized ED50 values of 35 pmol and 3.6 nmol, respectively. Aconitine and benzoylaconine anti-allodynia was completely blocked by the microglial inhibitor, dynorphin A antiserum, and κ-opioid receptor antagonist. Aconitine and benzoylaconine, but not aconine, stimulated dynorphin A expression in cultured primary spinal microglia, with EC50 values of 32 nM and 3 μM, respectively. Intrathecal aconitine, benzoylaconine and aconine induced flaccid paralysis and death, with normalized TD50 values of 0.5 nmol, 0.2 μmol, and 1.6 μmol, respectively. The TD50/ED50 ratios of aconitine and benzolyaconine were 14:1 and 56:1. Our results suggest that both the C8-acetyl and C14-benzoyl groups are essential for aconitine to stimulate spinal microglial dynorphin A expression and subsequent anti-hypersensitivity, which can be separated from neurotoxicity, because both benzoylaconine and aconine differentially produced anti-hypersensitivity and neurotoxicity due to their different stimulatory ability on dynorphin A expression. Our results support the scientific rationale for Aconitum processing, but caution should be taken to avoid overprocessing and excess hydrolysis of benzolyaconine to aconine.
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影响因子：
2.9
作者：
Bello-Ramírez, AM;Nava-Ocampo, AA
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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