Valproic acid attenuates blood-spinal cord barrier disruption by inhibiting matrix metalloprotease-9 activity and improves functional recovery after spinal cord injury
Valproic acid attenuates blood-spinal cord barrier disruption by inhibiting matrix metalloprotease-9 activity and improves functional recovery after spinal cord injury
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DOI：
10.1111/j.1471-4159.2012.07731.x
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发表时间：
2012-06-01
影响因子：
4.7
通讯作者：
Yune, Tae Y.
中科院分区：
文献类型：
--
作者：
Lee, Jee Y.;Kim, Hwang S.;Yune, Tae Y.
J·神经化学。(2012年)121,818829。摘要脊髓损伤(SCI)后血脊髓屏障(BSCB)的破坏，通过中性粒细胞和巨噬细胞等血细胞的侵袭，引起局部严重炎症反应，导致细胞死亡和永久性神经功能障碍。脊髓损伤可激活基质金属蛋白酶-9(MMP9)，而基质金属蛋白酶-9可诱导BSCB断裂。在这里，我们研究了组蛋白脱乙酰酶抑制剂丙戊酸(VPA)是否会通过抑制MMP9的活性来减轻BSCB的破坏，从而改善SCI后的功能结局。T9脊髓中度挫伤后，立即皮下注射VPA(300 mg/kg)，每隔12h再注射一次，连续5d。我们的数据显示，VPA在损伤后抑制了基质金属蛋白酶-9的活性，并减弱了BSCB的通透性和紧密连接分子如occludin和ZO-1的降解。此外，VPA还减少了包括肿瘤坏死因子-a在内的炎症介质的表达。此外，VPA还可增加乙酰化组蛋白3、PAKT、热休克蛋白27和70的水平，这些蛋白在脊髓损伤后具有抗凋亡作用。VPA可抑制细胞凋亡和caspase3的激活，缩小损伤体积，促进损伤后功能恢复。因此，我们的结果表明，VPA通过抑制脊髓损伤后MMP9的活性来减轻BSCB的破坏，从而促进功能恢复。
J. Neurochem. (2012) 121, 818829. Abstract The disruption of bloodspinal cord barrier (BSCB) after spinal cord injury (SCI) elicits an intensive local inflammation by the infiltration of blood cells such as neutrophils and macrophages, leading to cell death and permanent neurological disability. SCI activates matrix metalloprotease-9 (MMP-9), which is known to induce BSCB disruption. Here, we examined whether valproic acid (VPA), a histone deacetylase inhibitor, would attenuate BSCB disruption by inhibiting MMP-9 activity, leading to improvement of functional outcome after SCI. After moderate spinal cord contusion injury at T9, VPA (300 mg/kg) were immediately injected subcutaneously and further injected every 12 h for 5 days. Our data show that VPA inhibited MMP-9 activity after injury, and attenuated BSCB permeability and degradation of tight junction molecules such as occludin and ZO-1. In addition, VPA reduced the expression of inflammatory mediators including tumor necrosis factor-a. Furthermore, VPA increased the levels of acetylated histone 3, pAkt, and heat-shock protein 27 and 70, which have anti-apoptotic functions after SCI. Finally, VPA inhibited apoptotic cell death and caspase 3 activation, reduced the lesion volume and improved functional recovery after injury. Thus, our results demonstrated that VPA improves functional recovery by attenuating BSCB disruption via inhibition of MMP-9 activity after SCI.