中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2014, Vol. 9 ›› Issue (24): 2164-2173.doi: 10.4103/1673-5374.147949

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

PP2长程治疗可增加脊髓损伤后幸存组织和促进运动功能恢复

  

  • 收稿日期:2014-10-08 出版日期:2014-12-25 发布日期:2014-12-25

Long-term treatment with PP2 after spinal cord injury resulted in functional locomotor recovery and increased spared tissue

Odrick R. Rosas 1, Aranza I. Torrado 1, Jose M. Santiago 2, Ana E. Rodriguez 1, Iris K. Salgado 1, Jorge D. Miranda 1   

  1. 1 Department of Physiology, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA
    2 Department of Natural Sciences, University of Puerto Rico Carolina Campus, Carolina, PR, USA
  • Received:2014-10-08 Online:2014-12-25 Published:2014-12-25
  • Contact: Jorge D. Miranda, Ph.D., Physiology Department, University of Puerto Rico School of Medicine, San Juan, PR 00936-5067, USA, jorge.miranda3@upr.edu.
  • Supported by:

    The project was partially supported by the MBRS-RISE Program (R25 GM061838), MBRS-SCORE (SO6-GM08224), COBRE (5P20-GM103642), SNRP (NS39405) and RCMI (8G12MD007600).

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摘要：

抑制Src家族激酶活性可对脑和脊髓损伤微环境发生变化，从而产生神经保护作用。但已有研究也只限于损伤后最初几小时至几天内（7d内），而伤后28d的研究则未见。我们假设，抑制Src家族激酶抑制剂PP2的长程干预可创造有利于脊髓挫伤慢性期轴突生长的微环境。结果显示，长程PP2干预可使损伤后7，14，21，28d运动功能明显改善，同时也可使幸存白质组织和5-羟色胺能神经纤维密度明显增加，但伤后28d，并未使星形胶质细胞反应和巨噬细胞浸润发生改变。另外，长程PP2干预导致的抑制Src家族激酶活性下降还在伤后4d的急性期阻止了神经细胞鸟苷酸转换因子Ephexin的磷酸化。这些证实了抑制Src家族激酶在脊髓损伤后影响脊髓幸存组织和/或轴突生长运动和功能恢复中的作用。同时还证实了抑制原癌基因Src家族激酶介导的ephexin1磷酸可能参与髓损伤后抑制轴突生长微环境的产生。

关键词: 神经再生, 脊髓挫伤, Src家族激酶, Eph受体, Ephexin, 幸存组织, 运动功能, 神经胶质纤维酸性蛋白, ED1, 5-羟色胺能神经纤维

Abstract:

The spinal cord has the ability to regenerate but the microenvironment generated after trauma reduces that capacity. An increase in Src family kinase (SFK) activity has been implicated in neuropathological conditions associated with central nervous system trauma. Therefore, we hypothesized that a decrease in SFK activation by a long-term treatment with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyramidine (PP2), a selective SFK inhibitor, after spinal cord contusion with the New York University (NYU) impactor device would generate a permissive environment that improves axonal sprouting and/or behavioral activity. Results demonstrated that long-term blockade of SFK activation with PP2 increases locomotor activity at 7, 14, 21 and 28 days post-injury in the Basso, Beattie, and Bresnahan open field test, round and square beam crossing tests. In addition, an increase in white matter spared tissue and serotonin fiber density was observed in animals treated with PP2. However, blockade of SFK activity did not change the astrocytic response or infiltration of cells from the immune system at 28 days post-injury. Moreover, a reduced SFK activity with PP2 diminished Ephexin (a guanine nucleotide exchange factor) phosphorylation in the acute phase (4 days post-injury) after trauma. Together, these findings suggest a potential role of SFK in the regulation of spared tissue and/or axonal outgrowth that may result in functional locomotor recovery during the pathophysiology generated after spinal cord injury. Our study also points out that ephexin1 phosphorylation (activation) by SFK action may be involved in the repulsive microenvironment generated after spinal cord injury.

Key words: nerve regeneration, trauma, regeneration, Src family kinase, Eph receptors, ephexin, spared tissue, locomotor recovery, GFAP, ED1, serotonin fibers, neural regeneration