The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury
The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury
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p38丝裂原激活蛋白激酶抑制剂对慢性缩窄性损伤大鼠脊髓炎性细胞因子肿瘤坏死因子α合成的影响
DOI：
10.1213/01.ane.0000287660.29297.7b
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发表时间：
2007-12-01
影响因子：
5.7
通讯作者：
Zuo, Pingping
中科院分区：
文献类型：
--
作者：
Xu, Li;Huang, Yuguang;Zuo, Pingping
背景：肿瘤坏死因子α（TNF-α）可激活p38丝裂原活化蛋白激酶（MAPK）。相反，磷酸化p38（p-p38）可诱导TNF-α的上调。在这项研究中，我们检验了坐骨神经的慢性压迫性损伤（CCI）可以通过p38 MAPK通路促进脊髓释放TNF-α并产生异常性疼痛的假设。1）幼稚对照大鼠，2）假手术大鼠，3）未治疗的CCI手术大鼠，4）CCI手术大鼠用盐水抑制剂（0.9%）治疗的CCI手术大鼠，和5）用p38 MAPK抑制剂SB 203580治疗的CCI手术大鼠。在治疗组中，从CCI前1天或CCI后1天或7天开始鞘内给予生理盐水或SB 203580（2 μ g，每日两次）。所有大鼠于术后不同时间处死，采用免疫印迹法和免疫组化法检测脊髓组织中p38 MAPK活性和TNF-α水平。结果：CCI术后3、7、14 d，p-p38 MAPK表达较假手术组显著增加（P <0.05），术后3、7、14 d，p-p38 MAPK表达较假手术组显著增加（P < 0.05）。周围神经损伤引起机械性异常性疼痛，脊髓TNF-α浓度升高（P < 0.05）。SB 203580预处理或早期处理可抑制p38 MAPK活性，导致TNF-α合成减少，机械性痛觉超敏反应减轻（P < 0.05）。结论：p38 MAPK激活是周围神经损伤后TNF-α合成的信号级联反应之一，参与了机械性痛觉超敏反应。
BACKGROUND: Tumor necrosis factor a (TNF-alpha) could trigger p38 mitogen-activated protein kinase (MAPK) activation. Conversely phosphorylated p38 (p-p38) could induce the upregulation of TNF-alpha. In this study, we examined the hypothesis that chronic constrictive injury (CCI) of the sciatic nerve could promote spinal cord release of TNF-a and produce allodynia via the p38 MAPK pathway.METHODS: Sprague-Dawley rats were divided into five groups: 1) naive control rats, 2) sham surgery rats, 3) CCI surgery rats without treatment, 4) CCI surgery rats inhibitor with saline (0.9%) treatment, and 5) CCI surgery rats with the p38 MAPK inhibitor SB203580 treatment. In treatment groups, saline or SB203580 (2 mu g, twice a day) was given intrathecally starting I day before or I day or 7 days after CCI. All rats were killed at different times after surgery to examine p38 MAPK activity and TNF-a levels in the spinal cord by Western blot analysis or immunohistochemistry. Mechanical allodynia was tested by a series of von Frey hairs 3, 7, and 14 days after surgery.RESULTS: p-p38 MAPK was significantly increased at 3, 7, and 14 days after CCI surgery compared with time-matched shams (P < 0.05). Peripheral nerve injury induced mechanical allodynia and enhanced spinal concentrations of TNF-alpha (P < 0.05). Pretreatment or early treatment with SB203580 inhibited p38 MAPK activity, resulting in reduction of TNF-a synthesis and attenuation of mechanical allodynia (P < 0.05).CONCLUSION: p38 MAPK activation is one aspect of the signaling cascade that culminates in TNF-a synthesis and contributes to mechanical allodynia after peripheral nerve injury.