Effect of Histone Deacetylase Inhibitor JNJ-26481585 in Pain
Effect of Histone Deacetylase Inhibitor JNJ-26481585 in Pain
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DOI：
10.1007/s12031-014-0391-7
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发表时间：
2015-03-01
影响因子：
3.1
通讯作者：
Ajit, Seena K.
中科院分区：
文献类型：
--
作者：
Capasso, Kathryn E.;Manners, Melissa T.;Ajit, Seena K.
最近的研究表明，组蛋白去乙酰化酶（HDAC）抑制剂可以减轻炎症和神经病理性疼痛。我们研究了JNJ-26481585（一种泛HDAC抑制剂）对基础机械敏感性的影响。与先前关于HDAC抑制剂的报告不同，JNJ-26481585在小鼠中诱导了机械超敏反应。加巴喷丁可逆转该效应。JNJ-26481585给药小鼠脊髓中电压依赖性钙通道亚基α-2/δ-1（加巴喷丁的假定靶点之一）上调。JNJ-26481585给药小鼠的脊髓转录谱显示轴突导向相关通路发生显著改变，表明其他已知化疗药物引起的神经毒性的潜在机制存在重叠。为了研究疼痛发生的潜在机制，使用JNJ-26481585处理RAW 264.7小鼠巨噬细胞。核因子-κ B和白细胞介素-1 β的激活呈剂量和时间依赖性增加。因此，轴突引导通路的改变、电压依赖性钙通道α（2）δ-1亚基的增加以及JNJ-26481585对促炎介质的诱导均可能导致机械敏感性增加。我们的数据表明，HDAC抑制剂的作用可能是所研究的化合物所独有的，并突出了使用泛HDAC抑制剂治疗癌症时发生化疗诱导的周围神经病变的潜力，这种疼痛可能会被加巴喷丁缓解。
Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585-treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose-and time-dependent activation of nuclear factor-kappaB and interleukin-1 beta increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2) delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin.