Phytohormone abscisic acid ameliorates neuropathic pain via regulating LANCL2 protein abundance and glial activation at the spinal cord.
Phytohormone abscisic acid ameliorates neuropathic pain via regulating LANCL2 protein abundance and glial activation at the spinal cord.
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DOI：
10.1177/17448069221107781
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发表时间：
2022-04
期刊：
影响因子：
3.3
通讯作者：
Weng, Han-Rong
中科院分区：
文献类型：
--
作者：
Maixner, Dylan W.;Christy, David;Kong, Lingwei;Viatchenko-Karpinski, Viacheslav;Horner, Kristen A.;Hooks, Shelley B.;Weng, Han-Rong
脊髓神经炎症在神经性疼痛的发生中起着关键作用。越来越多的数据表明，脱落酸（ABA），一种植物激素，调节哺乳动物的炎症过程。在这项研究中，我们发现脊髓中LANCL2受体蛋白的减少而不是激动剂ABA的减少与神经性疼痛的发生有关。全身或鞘内给药ABA可改善部分坐骨神经结扎（pSNL）动物机械性异常痛和热痛觉过敏的发展和预先存在。LANCL2仅在脊髓背角的小胶质细胞中表达。ABA预先治疗可减弱pSNL大鼠小胶质细胞和星形胶质细胞的活化、ERK活性和背角中TNFα蛋白的丰度。这些都伴随着脊柱LANCL2蛋白丰度的恢复。用siRNA敲低LANCL2基因，反映了pSNL引起的行为和脊柱分子变化。用脂多糖激活脊髓toll样受体4 （TLR4）导致小胶质细胞的激活和TNFα的过量产生，同时伴随着LANCL2和过氧化物酶体增殖物激活受体γ蛋白水平的抑制。当ABA加入LPS后，这些变化得到改善。ABA诱导的抗炎作用不需要胃肠道蛋白活性。我们的研究表明，ABA/LANCL2系统是一个强大的内源性系统，调节脊髓神经炎症和伤害性加工，这表明ABA在神经性疼痛的治疗中具有潜在的应用价值。
Spinal neuroinflammation plays a critical role in the genesis of neuropathic pain. Accumulating data suggest that abscisic acid (ABA), a phytohormone, regulates inflammatory processes in mammals. In this study, we found that reduction of the LANCL2 receptor protein but not the agonist ABA in the spinal cord is associated with the genesis of neuropathic pain. Systemic or intrathecal administration of ABA ameliorates the development and pre-existence of mechanical allodynia and heat hyperalgesia in animals with partial sciatic nerve ligation (pSNL). LANCL2 is expressed only in microglia in the spinal dorsal horn. Pre-emptive treatment with ABA attenuates activation of microglia and astrocytes, ERK activity, and TNFα protein abundance in the dorsal horn in rats with pSNL. These are accompanied by restoration of spinal LANCL2 protein abundance. Spinal knockdown of LANCL2 gene with siRNA recapitulates the behavioral and spinal molecular changes induced by pSNL. Activation of spinal toll-like receptor 4 (TLR4) with lipopolysaccharide leads to activation of microglia, and over production of TNFα, which are concurrently accompanied by suppression of protein levels of LANCL2 and peroxisome proliferator activated-receptor γ. These changes are ameliorated when ABA is added with LPS. The anti-inflammatory effects induced by ABA do not requires Gi protein activity. Our study reveals that the ABA/LANCL2 system is a powerful endogenous system regulating spinal neuroinflammation and nociceptive processing, suggesting the potential utility of ABA as the management of neuropathic pain.
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