Cyclodextrins inhibit TRPV1 and TRPA1 activation-induced nociception via cholesterol depletion.

IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Andrea Nehr-Majoros, Lajos Karakai, Maja Payrits, Noémi Bencze, Ágnes Kemény, György Sétáló, Rita Börzsei, Csaba Hetényi, Zsuzsanna Helyes, Éva Szőke
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引用次数: 0

Abstract

The nociceptive Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) channels are predominantly expressed on peptidergic sensory nerves, being involved in pain sensation and neurogenic inflammation induced by local release of pro-inflammatory neuropeptides in the innervation area. Their activation is facilitated by cholesterol-rich lipid microdomains (lipid rafts) in the plasma membrane. Cyclodextrin (CD) derivatives deplete cholesterol from membrane rafts, reducing receptor activation in vitro, anticipating in vivo analgesic effects. We compared three different CD derivatives selected based on our previous results: random methylated β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin and sulfobutylether-β-cyclodextrin. The effects of the topical CD pretreatments were evaluated in acute pain and neurogenic vasodilatation models in mice 30 minutes after TRPV1 (resiniferatoxin) or TRPA1 (formalin or mustard oil) receptor agonist administration. Intraplantar CD pretreatments significantly reduced the duration of nocifensive behaviors during the neurogenic inflammatory phase of the formalin test, as well as mechanical, but not thermal hyperalgesia following resiniferatoxin injection. CD-pretreatment significantly reduced mustard oil-induced acute neurogenic vasodilatation in the mouse ear and decreased the total cholesterol content in the plantar skin and ear tissues. Cholesterol depletion was restored by cholesterol loaded CDs. However, overloading cells with cholesterol did not significantly affect the cholesterol depletion. In silico modeling showed that the methylated derivative RAMEB has different cholesterol binding mode compared to HPBCD and SBECD. We present the first in vivo results showing that these CD derivatives are promising agents for exerting peripheral analgesia and anti-inflammation via cholesterol depletion, also supported by our in vitro and in silico findings.

环糊精通过胆固醇消耗抑制TRPV1和TRPA1激活诱导的伤害感受。
痛觉性瞬时受体电位香草样蛋白1 (TRPV1)和锚蛋白1 (TRPA1)通道主要在多肽能感觉神经上表达,参与神经支配区局部释放促炎神经肽诱导的疼痛感觉和神经源性炎症。它们的激活是由质膜上富含胆固醇的脂质微域(脂筏)促进的。环糊精(CD)衍生物从膜筏中消耗胆固醇,减少受体的体外激活,预测体内镇痛作用。我们比较了三种不同的CD衍生物:随机甲基化β-环糊精,(2-羟丙基)-β-环糊精和磺基丁醚-β-环糊精。在TRPV1(树脂素毒素)或TRPA1(福尔马林或芥菜油)受体激动剂给药30分钟后,在小鼠急性疼痛和神经源性血管扩张模型中评估局部CD预处理的效果。足底CD预处理显著减少了福尔马林试验中神经源性炎症期的有害行为持续时间,以及树脂干扰素注射后的机械性痛觉过敏,但没有热痛觉过敏。cd预处理可显著降低芥菜油诱导的小鼠耳内急性神经源性血管舒张,降低足底皮肤和耳组织中总胆固醇含量。含有胆固醇的cd恢复了胆固醇的消耗。然而,胆固醇超载细胞对胆固醇消耗没有显著影响。计算机模拟表明,甲基化衍生物RAMEB与HPBCD和SBECD相比具有不同的胆固醇结合模式。我们提出的第一个体内结果表明,这些CD衍生物是通过胆固醇消耗发挥外周镇痛和抗炎症的有希望的药物,我们的体外和计算机研究结果也支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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