Probucol is anti-hyperalgesic in a mouse peripheral nerve injury model of neuropathic pain.
Probucol is anti-hyperalgesic in a mouse peripheral nerve injury model of neuropathic pain.
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DOI：
10.1016/j.ynpai.2023.100141
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发表时间：
2023-08
期刊：
影响因子：
--
通讯作者：
Goldstein, Peter A.
中科院分区：
文献类型：
--
作者：
Joyce, Rebecca L.;Tibbs, Gareth R.;Warren, J. David;Costa, Christopher J.;Aromolaran, Kelly;Sanford, R. Lea;Andersen, Olaf S.;Li, Zhucui;Zhang, Guoan;Willis, Dianna E.;Goldstein, Peter A.
HCN1抑制剂，2,6-二叔丁基苯酚（2,6- dtbp）是临床使用的2,6- dtbp的非麻醉二聚体同系物，单次800 mg/kg剂量的Probucol可缓解小鼠神经性疼痛（SNI模型）游离Probucol的水溶性< 10 nM（通过LC-MS/MS测定）Probucol的体内药效和体外机制尚需澄清小鼠坐骨神经结扎，选择性抑制HCN1通道门控。我们假设临床上使用的2,6- dtbp的非麻醉二聚体同属物普罗布考（2,6-二叔丁基-4-[2-（3,5-二叔丁基-4-羟基苯基）磺胺基丙烷-2-基磺胺基]苯酚）可以缓解周围神经损伤引起的神经病变表型，并且体内抗痛觉作用可能与体外抑制HCN1通道有关。单次口服probucol （800 mg/kg）可减轻小鼠神经损伤神经性疼痛模型的机械异常性痛和热痛觉过敏。虽然普罗布考的低水溶性阻碍了对其与HCN1通道可能相互作用的评估，但我们的研究结果，结合最近的数据表明，普罗布考可以减少脂多糖诱导的机械异常性疼痛和热痛觉过敏，支持普罗布考作为一种非阿片类药物的测试/开发，口服抗痛觉过敏，尽管机制作用未知。
The HCN1 inhibitor, 2,6-di-tert-butylphenol (2,6-DTBP) is antihyperalgesic in mice Probucol is a clinically utilized non-anesthetic dimerized congener of 2,6-DTBP A single 800 mg/kg dose of probucolrelieves neuropathic pain in mice (SNI model) The aqueous solubility of free probucol is < 10 nM (determined by LC-MS/MS) Probucol’s reported in vivo potencyand in vitro mechanisms require clarification 2,6-di-tert-butylphenol (2,6-DTBP) ameliorates mechanical allodynia and thermal hyperalgesia produced by partial sciatic nerve ligation in mice, and selectively inhibits HCN1 channel gating. We hypothesized that the clinically utilized non-anesthetic dimerized congener of 2,6-DTBP, probucol (2,6-di-tert-butyl-4-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)sulfanylpropan-2-ylsulfanyl]phenol), would relieve the neuropathic phenotype that results from peripheral nerve damage, and that the anti-hyperalgesic efficacy in vivo would correlate with HCN1 channel inhibition in vitro. A single oral dose of probucol (800 mg/kg) relieved mechanical allodynia and thermal hyperalgesia in a mouse spared-nerve injury neuropathic pain model. While the low aqueous solubility of probucol precluded assessment of its possible interaction with HCN1 channels, our results, in conjunction with recent data demonstrating that probucol reduces lipopolysaccharide-induced mechanical allodynia and thermal hyperalgesia, support the testing/development of probucol as a non-opioid, oral antihyperalgesic albeit one of unknown mechanistic action.
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