Link N as a therapeutic agent for discogenic pain.
Link N as a therapeutic agent for discogenic pain.
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Link N 作为椎间盘源性疼痛的治疗剂。
DOI：
10.1002/jsp2.1008
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Mwale,Fackson
中科院分区：
文献类型：
--
作者：
Noorwali,Hussain;Grant,MichaelP;Epure,LauraM;Madiraju,Padma;Sampen,Hee-Jeong;Antoniou,John;Mwale,Fackson
神经营养因子（NTs）是感觉轴突发芽、神经存活、伤害性感觉神经元的调节、炎症性痛觉过敏和神经性疼痛的主要贡献者。椎间盘(IVD)细胞组成性表达nt。在退变过程中，它们的表达被IVD中存在的促炎细胞因子上调，这可以促进周围神经向内生长和神经过度支配，导致椎间盘源性疼痛。目前，还没有针对退行性椎间盘疾病的靶向治疗方法来减少过度神经支配。链接N是一种天然存在的肽，在IVD中具有很高的再生潜力。因此，研究了Link N作为抑制NTs的治疗肽的适用性，NTs是已知的疼痛调节剂和介质。本研究的目的是确定Link N对NTs表达、神经生长因子（NGF）、脑源性神经营养因子（BDNF）及其同源受体TrkA和TrkB的影响，因为它们与症状性背痛直接相关。此外，神经递质（P物质）也在细胞因子刺激的人纤维环（AF）细胞中进行了评估。用白细胞介素- 1β (IL - 1β)和肿瘤坏死因子- α (TNF - α)刺激正常体外培养的人AF细胞，无论是否存在Link n。提取总RNA，用实时PCR检测基因表达。与仅受IL - 1β或TNF - α刺激的细胞相比，在IL - 1β或TNF - α补充Link N刺激的人椎间盘细胞中，NGF、BDNF、TrkA和TrkB的基因表达显著降低。与仅受IL - 1β刺激的细胞相比，与Link N和IL - 1β共孵育的AF细胞中NGF蛋白的表达也受到抑制。在炎症环境下，Link N可以抑制AF细胞中NGF、BDNF及其受体TrkA和TrkB的刺激。因此，结合先前的观察结果，这表明Link N的施用不仅有可能在疾病的早期修复椎间盘，而且还可以抑制疼痛。
Neurotrophins (NTs) are the major contributors of sensory axonal sprouting, neural survival, regulation of nociceptive sensory neurons, inflammatory hyperalgesia, and neuropathic pain. Intervertebral disc (IVD) cells constitutively express NTs. Their expression is upregulated by proinflammatory cytokines present in the IVD during degeneration, which can promote peripheral nerve ingrowth and hyperinnervation, leading to discogenic pain. Currently, there are no targeted therapies that decrease hyperinnervation in degenerative disc disease. Link N is a naturally occurring peptide with a high regenerative potential in the IVD. Therefore, the suitability of Link N as a therapeutic peptide for suppressing NTs, which are known modulators and mediators of pain, was investigated. The aim of the present study is to determine the effect of Link N on NTs expression, nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), and their cognate receptors TrkA and TrkB as they are directly correlated with symptomatic back pain. Furthermore, the neurotransmitter (substance P) was also evaluated in human annulus fibrosus (AF) cells stimulated with cytokines. Human AF cells isolated from normal IVDs were stimulated with interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α) in the presence or absence of Link N. NGF release in the media was evaluated by Western blotting. Total RNA was isolated and gene expression was measured using real‐time PCR. Gene expression of NGF, BDNF, TrkA, and TrkB significantly decreased in human disc cells stimulated with either IL‐1β or TNF‐α supplemented with Link N when compared to the cells stimulated only with IL‐1β or TNF‐α. NGF protein expression was also suppressed in AF cells coincubated with Link N and IL‐1β when compared to the cells stimulated only with IL‐1β. Link N can suppress the stimulation of NGF, BDNF, and their receptors TrkA and TrkB in AF cells in an inflammatory milieu. Thus, coupled with previous observations, this suggests that administration of Link N has the potential to not only repair the discs in early stages of the disease but also suppress pain.