Department of Anesthesiology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Rd, Wuhan, 430071, Hubei, China.
Neurochem Res. 2019 Feb;44(2):450-464. doi: 10.1007/s11064-018-2698-1. Epub 2018 Dec 17.
Histone acetylation levels can be upregulated by treating cells with histone deacetylase inhibitors (HDACIs), which can induce autophagy. Autophagy flux in the spinal cord of rats following the left fifth lumber spinal nerve ligation (SNL) is involved in the progression of neuropathic pain. Suberoylanilide hydroxamic acid (SAHA), one of the HDACIs can interfere with the epigenetic process of histone acetylation, which has been shown to ease neuropathic pain. Recent research suggest that SAHA can stimulate autophagy via the mammalian target of rapamycin (mTOR) pathway in some types of cancer cells. However, little is known about the role of SAHA and autophagy in neuropathic pain after nerve injury. In the present study, we aim to investigate autophagy flux and the role of the mTOR pathway on spinal cells autophagy activation in neuropathic pain induced by SNL in rats that received SAHA treatment. Autophagy-related proteins and mTOR or its active form were assessed by using western blot, immunohistochemistry, double immunofluorescence staining and transmission electron microscopy (TEM). We found that SAHA decreased the paw mechanical withdrawal threshold (PMWT) of the lower compared with SNL. Autophagy flux was mainly disrupted in the astrocytes and neuronal cells of the spinal cord dorsal horn on postsurgical day 28 and was reversed by daily intrathecal injection of SAHA (n = 100 nmol/day or n = 200 nmol/day). SAHA also decreased mTOR and phosphorylated mTOR (p-mTOR) expression, especially p-mTOR expression in astrocytes and neuronal cells of the spinal dorsal horn. These results suggest that SAHA attenuates neuropathic pain and contributes to autophagy flux in astrocytes and neuronal cells of the spinal dorsal horn via the mTOR signaling pathway.
组蛋白乙酰化水平可以通过用组蛋白去乙酰化酶抑制剂 (HDACIs) 处理细胞来上调，这可以诱导自噬。左第五腰椎脊神经结扎 (SNL) 后大鼠脊髓中的自噬流与神经性疼痛的进展有关。丁酰肼 (SAHA) 是 HDACIs 之一，可以干扰组蛋白乙酰化的表观遗传过程，已被证明可以缓解神经性疼痛。最近的研究表明，SAHA 可以通过哺乳动物雷帕霉素靶蛋白 (mTOR) 途径刺激某些类型癌细胞的自噬。然而，对于神经损伤后 SAHA 和自噬在神经性疼痛中的作用知之甚少。在本研究中，我们旨在研究自噬流和 mTOR 途径在 SAHA 治疗大鼠 SNL 诱导的神经性疼痛中脊髓细胞自噬激活中的作用。通过 Western blot、免疫组织化学、双免疫荧光染色和透射电子显微镜 (TEM) 评估自噬相关蛋白和 mTOR 或其活性形式。我们发现 SAHA 降低了与 SNL 相比的下肢爪机械退缩阈值 (PMWT)。自噬流主要在脊髓背角的星形胶质细胞和神经元细胞中在术后第 28 天被破坏，并通过鞘内每日注射 SAHA 逆转 (n = 100 nmol/天或 n = 200 nmol/天)。SAHA 还降低了 mTOR 和磷酸化 mTOR (p-mTOR) 的表达，特别是在脊髓背角的星形胶质细胞和神经元细胞中的 p-mTOR 表达。这些结果表明，SAHA 通过 mTOR 信号通路减轻神经性疼痛，并有助于脊髓背角星形胶质细胞和神经元细胞中的自噬流。
