Botulinum toxin type A (BTX-A) was considered to be a new potential drug for neuropathic pain (NP) treatment. In vivo, BTX-A attenuated chronic compression injury (CCI)-induced pain in rats, and reduced production of pro-inflammatory factors. The inhibition of BTX-A to expression and phosphorylation of SNAP23 were partly reversed by TLR2/MyD88 upregulation. In LPS-stimulated microglia, we also found that BTX-A suppressed TLR2, MyD88, p-SNAP23 and SNAP23 expression, and reduced pro-inflammatory factors secretion. Upregulation of TLR2 and MyD88 recued the inhibition of BTX-A to LPS-induced activation of SNAP23. Then, we demonstrated that BTX-A reduced expression of SNAP23 through inhibition of IKKα/β phosphorylation. Besides, the inhibition of BTX-A to LPS-induced upregulation of SNAP23 can be reversed by proteasome inhibitor. NEDD4, an E3 ubiquitin ligase, was proved to be bind with SNAP23. BTX-A reduced expression of SNAP23 via facilitating ubiquitin-mediated degradation of SNAP23. Overall, our data demonstrated that BTX-A attenuated NP via reducing the secretion of pro-inflammatory factors from microglia by inhibition of TLR2/MyD88 signaling. BTX-A downregulated expression of SNAP23 via reducing phosphorylation of IKKα/β, and enhancing ubiquitination of SNAP23 by suppressing TLR2/MyD88 signaling.

中文翻译：

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A型肉毒杆菌毒素通过靶向TLR2 / MyD88和SNAP23减轻神经性疼痛并抑制小胶质细胞释放的炎性细胞因子

A型肉毒杆菌毒素（BTX-A）被认为是治疗神经性疼痛（NP）的一种新的潜在药物。在体内，BTX-A减轻了大鼠的慢性压迫损伤（CCI）引起的疼痛，并减少了促炎因子的产生。TTX2 / MyD88上调部分逆转了BTX-A对SNAP23表达和磷酸化的抑制作用。在LPS刺激的小胶质细胞中，我们还发现BTX-A抑制TLR2，MyD88，p-SNAP23和SNAP23的表达，并减少促炎因子的分泌。TLR2和MyD88的上调可以抑制BTX-A对LPS诱导的SNAP23的激活。然后，我们证明了BTX-A通过抑制IKKα/β磷酸化减少了SNAP23的表达。此外，蛋白酶体抑制剂可以逆转BTX-A对LPS诱导的SNAP23上调的抑制作用。NEDD4，E3泛素连接酶被证明与SNAP23结合。BTX-A通过促进遍在蛋白介导的SNAP23降解来降低SNAP23的表达。总体而言，我们的数据表明BTX-A通过抑制TLR2 / MyD88信号传导来减少小胶质细胞促炎因子的分泌，从而降低NP。BTX-A通过减少IKKα/β的磷酸化并通过抑制TLR2 / MyD88信号传导增强SNAP23的泛素化来下调SNAP23的表达。