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一种 TRPA1 拮抗剂逆转奥沙利铂诱导的神经病理性疼痛。

A TRPA1 antagonist reverts oxaliplatin-induced neuropathic pain.

机构信息

Dipartimento di Chimica, Università di Firenze, Polo Scientifico e Tecnologico, Sesto Fiorentino, Firenze, Italy.

出版信息

Sci Rep. 2013;3:2005. doi: 10.1038/srep02005.

DOI:10.1038/srep02005
PMID:23774285
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3684817/
Abstract

Neuropathic pain (NeP) is generally considered an intractable problem, which becomes compelling in clinical practice when caused by highly effective chemotherapeutics, such as in the treatment of cancer with oxaliplatin (OXA) and related drugs. In the present work we describe a structurally new compound, ADM_09, which proved to effectively revert OXA-induced NeP in vivo in rats without eliciting the commonly observed negative side-effects. ADM_09 does not modify normal behavior in rats, does not show any toxicity toward astrocyte cell cultures, nor any significant cardiotoxicity. Patch-clamp recordings demonstrated that ADM_09 is an effective antagonist of the nociceptive sensor channel TRPA1, which persistently blocks mouse as well as human variants of TRPA1. A dual-binding mode of action has been proposed for ADM_09, in which a synergic combination of calcium-mediated binding of the carnosine residue and disulphide-bridge-forming of the lipoic acid residue accounts for the observed persistent blocking activity toward the TRPA1 channel.

摘要

神经病理性疼痛（NeP）通常被认为是一个棘手的问题，当它由高效的化疗药物引起时，如奥沙利铂（OXA）和相关药物治疗癌症时，在临床实践中就变得非常迫切。在本工作中，我们描述了一种结构新颖的化合物 ADM_09，它在体内有效地逆转了 OXA 诱导的大鼠神经病理性疼痛，而没有引起常见的不良反应。ADM_09 不会改变大鼠的正常行为，对星形胶质细胞培养物没有任何毒性，也没有明显的心脏毒性。膜片钳记录表明，ADM_09 是一种有效的伤害感受器通道 TRPA1 的拮抗剂，它能持续阻断小鼠和人源变体的 TRPA1。ADM_09 的作用机制是双重结合模式，其中肉毒碱残基的钙介导结合和硫辛酸残基的二硫键形成的协同组合，解释了对 TRPA1 通道观察到的持续阻断活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/ab5bf03b723e/srep02005-f13.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/5c056e321c7a/srep02005-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/301018d2f48d/srep02005-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/1c316af97f95/srep02005-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/6555c5d007c4/srep02005-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/33afff75d7ff/srep02005-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/0d3f58c9a537/srep02005-f11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/ce16983926e6/srep02005-f12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/ab5bf03b723e/srep02005-f13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/df95d18cf0fd/srep02005-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/4653a084b42e/srep02005-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/fe4511054478/srep02005-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/e2ce1aabc263/srep02005-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/4ddd9759775f/srep02005-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/5c056e321c7a/srep02005-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/301018d2f48d/srep02005-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/1c316af97f95/srep02005-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/6555c5d007c4/srep02005-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/33afff75d7ff/srep02005-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/0d3f58c9a537/srep02005-f11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/ce16983926e6/srep02005-f12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c0b/3684817/ab5bf03b723e/srep02005-f13.jpg

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