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BIX01294，一种G9a抑制剂，在发育和维持期均能减轻神经损伤诱导的疼痛超敏反应。

BIX01294, a G9a inhibitor, alleviates nerve injury-induced pain hypersensitivities during both development and maintenance periods.

作者信息

Liang Lingli, Zhao Jian-Yuan, Kathryn Ticehurst, Bekker Alex, Tao Yuan-Xiang

机构信息

Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.

Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.

出版信息

Transl Perioper Pain Med. 2019;6(4):106-114. doi: 10.31480/2330-4871/097. Epub 2019 Aug 14.

DOI:10.31480/2330-4871/097
PMID:31497620
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6730651/
Abstract

Genetic knockdown or knockout of the histone methytransferase G9a in the injured dorsal root ganglion (DRG) has been shown to alleviate neuropathic pain development. However, the application of genetic strategy in clinic is highly limited. The present study sought to examine the effect of intrathecal BIX01294, a specific G9a inhibitor, on the development and maintenance of pain hypersensitivities caused by unilateral L5 spinal nerve injury (SNL) or chronic constriction injury (CCI) to the sciatic nerve in rats. We found that intrathecal administration of BIX01294 reduced SNL- or CCI-induced mechanical allodynia, thermal hyperalgesia and cold allodynia not only in the development period but also in the maintenance period. These effects were dose-dependent. Intrathecal administration of BIX01294 also blocked the SNL-induced increase in the level of H3K9me2, a marker of G9a activity, and reversed SNL-induced downregulation of mRNA, mRNA, mRNA, mRNA, and mRNA, the downstream targets of G9a, in the ipsilateral L5 DRG. These findings further implicate that G9a as a potential target in the management of neuropathic pain.

摘要

已证实，在受损背根神经节（DRG）中对组蛋白甲基转移酶G9a进行基因敲低或敲除可减轻神经性疼痛的发展。然而，基因策略在临床上的应用非常有限。本研究旨在检测鞘内注射特异性G9a抑制剂BIX01294对大鼠单侧L5脊神经损伤（SNL）或坐骨神经慢性压迫损伤（CCI）所致疼痛超敏反应的发生和维持的影响。我们发现，鞘内注射BIX01294不仅在疼痛超敏反应的发展期，而且在维持期均能减轻SNL或CCI诱导的机械性异常性疼痛、热痛觉过敏和冷异常性疼痛。这些效应呈剂量依赖性。鞘内注射BIX01294还可阻断SNL诱导的G9a活性标志物H3K9me2水平升高，并逆转SNL诱导的同侧L5 DRG中G9a下游靶点mRNA、mRNA、mRNA、mRNA和mRNA的下调。这些发现进一步表明，G9a是治疗神经性疼痛的潜在靶点。

相似文献

[1]
BIX01294, a G9a inhibitor, alleviates nerve injury-induced pain hypersensitivities during both development and maintenance periods.

Transl Perioper Pain Med. 2019

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain.

JCI Insight. 2024-5-21

[2]
Roles of KCNA2 in Neurological Diseases: from Physiology to Pathology.

Mol Neurobiol. 2024-11

[3]
Neuropathic pain; what we know and what we should do about it.

Front Pain Res (Lausanne). 2023-9-22

[4]
Systemic administration of NIS-lncRNA antisense oligonucleotide alleviates neuropathic pain.

Neurosci Lett. 2023-11-20

[5]
Transcription factor EBF1 mitigates neuropathic pain by rescuing Kv1.2 expression in primary sensory neurons.

Transl Res. 2024-1

[6]
Intrathecal administration of the fat-mass and obesity-associated protein inhibitor mitigates neuropathic pain in female rats.

Transl Perioper Pain Med. 2022

[7]
Effect of intrathecal NIS-lncRNA antisense oligonucleotides on neuropathic pain caused by nerve trauma, chemotherapy, or diabetes mellitus.

Br J Anaesth. 2023-2

[8]
Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets.

Front Pain Res (Lausanne). 2021-12-13

[9]
Downregulation of a Dorsal Root Ganglion-Specifically Enriched Long Noncoding RNA is Required for Neuropathic Pain by Negatively Regulating RALY-Triggered Ehmt2 Expression.

Adv Sci (Weinh). 2021-7

[10]
Effect of Pharmacological Inhibition of Fat-Mass and Obesity-Associated Protein on Nerve Trauma-Induced Pain Hypersensitivities.

Neurotherapeutics. 2021-7

本文引用的文献

[1]
Contribution of DNMT1 to Neuropathic Pain Genesis Partially through Epigenetically Repressing in Primary Afferent Neurons.

J Neurosci. 2019-6-10

[2]
MBD1 Contributes to the Genesis of Acute Pain and Neuropathic Pain by Epigenetic Silencing of and Genes in Primary Sensory Neurons.

J Neurosci. 2018-9-28

[3]
DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons.

Nat Commun. 2017-3-8

[4]
Nerve injury-induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons.

Pain. 2017-6

[5]
G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury.

Mol Pain. 2016-12-7

[6]
G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons.

Sci Rep. 2016-11-22

[7]
Contribution of the Suppressor of Variegation 3-9 Homolog 1 in Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury-induced Nociceptive Hypersensitivity.

Anesthesiology. 2016-10

[8]
Dorsal root ganglion transcriptome analysis following peripheral nerve injury in mice.

Mol Pain. 2016-3-11

[9]
Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons.

J Biol Chem. 2016-4-15

[10]
G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition.

Nat Neurosci. 2015-12

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