Nehr-Majoros Andrea, Karakai Lajos, Payrits Maja, Bencze Noémi, Kemény Ágnes, Sétáló György, Börzsei Rita, Hetényi Csaba, Helyes Zsuzsanna, Szőke Éva
Department of Pharmacology and Pharmacotherapy & Centre for Neuroscience, Faculty of Medicine, University of Pécs, Pécs, Hungary; National Laboratory for Drug Research and Development, Budapest, Hungary.
Department of Pharmacology and Pharmacotherapy & Centre for Neuroscience, Faculty of Medicine, University of Pécs, Pécs, Hungary.
J Lipid Res. 2025 Jul;66(7):100844. doi: 10.1016/j.jlr.2025.100844. Epub 2025 Jun 16.
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 min 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 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.
伤害性瞬态受体电位香草酸亚型1（TRPV1）和锚蛋白1（TRPA1）通道主要表达于肽能感觉神经上，参与由神经支配区域内促炎神经肽局部释放所诱导的痛觉和神经源性炎症。它们的激活由质膜中富含胆固醇的脂质微区（脂筏）促进。环糊精（CD）衍生物可从膜脂筏中耗尽胆固醇，在体外降低受体激活，预期具有体内镇痛作用。我们基于之前的结果比较了三种不同的CD衍生物：随机甲基化β-环糊精、（2-羟丙基）-β-环糊精和磺丁基醚-β-环糊精。在给予TRPV1（树脂毒素）或TRPA1（福尔马林或芥子油）受体激动剂30分钟后，在小鼠的急性疼痛和神经源性血管舒张模型中评估局部CD预处理的效果。足底内注射CD预处理显著缩短了福尔马林试验神经源性炎症阶段的伤害性防御行为持续时间，以及树脂毒素注射后机械性而非热性痛觉过敏。CD预处理显著降低了芥子油诱导的小鼠耳部急性神经源性血管舒张，并降低了足底皮肤和耳部组织中的总胆固醇含量。负载胆固醇的CD可恢复胆固醇耗竭。然而，用胆固醇使细胞过载并未显著影响胆固醇耗竭。计算机模拟显示，与HPBCD和SBECD相比，甲基化衍生物RAMEB具有不同的胆固醇结合模式。我们首次展示了体内结果，表明这些CD衍生物是通过胆固醇耗竭发挥外周镇痛和抗炎作用的有前景的药物，我们的体外和计算机模拟研究结果也支持这一点。
