中国神经再生研究(英文版) ›› 2017, Vol. 12 ›› Issue (5): 702-713.doi: 10.4103/1673-5374.206633

• 综述:脊髓损伤修复保护与再生 • 上一篇    下一篇

米诺环素靶向外伤性脊髓损伤的多发性二级损伤机制

  

  • 收稿日期:2017-04-28 出版日期:2017-05-15 发布日期:2017-05-15

Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury

Robert B. Shultz, Yinghui Zhong   

  1. School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
  • Received:2017-04-28 Online:2017-05-15 Published:2017-05-15
  • Contact: Yinghui Zhong, Ph.D.,yz348@drexel.edu.

摘要:

米诺环素盐酸盐(MH),半合成四环素衍生物,是临床上可获得的抗生素和抗炎药物,其还表现出强大的神经保护活性。已有研究显示其通过抗炎、抗氧化和抗凋亡性质靶向脊髓损伤中的多种继发性损伤机制。MH可能潜在靶向的继发性损伤机制包括炎症、自由基、氧化应激、谷氨酸兴奋性毒性、钙内流、线粒体功能障碍、缺血、出血和水肿。这篇综述文章讨论了MH对这些潜在机制的多方面行动。其抗炎和神经保护作用部分通过保守机制实现,如调节p38促分裂原活化蛋白激酶和PI3K/Akt信号通路以及抑制基质金属蛋白酶(MMPs)。此外,MH可以通过N-甲基-D-天冬氨酸(NMDA)受体,线粒体钙摄取,聚(ADP-核糖)聚合酶-1(PARP-1)酶活性和铁毒性直接抑制钙内流。它也可以直接清除自由基。因为它可以针对许多继发性损伤机制,MH治疗具有减少组织损伤和促进脊髓损伤后功能恢复的巨大前景。

 

ORCID:0000-0002-1363-9466(Yinghui Zhong)

Abstract:

Minocycline hydrochloride (MH), a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways as well as inhibition of matrix metalloproteinases (MMPs). Additionally, MH can directly inhibit calcium influx through the N-methyl-D-aspartate (NMDA) receptors, mitochondrial calcium uptake, poly(ADP-ribose) polymerase-1 (PARP-1) enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional recovery following spinal cord injury.

Key words: minocycline, inflammation, anti-oxidant, neuroprotection, oxidative stress, glutamate exitotoxicity, cytochrome c, P38 MAPK, PI3K/Akt, calcium influx