Neuroprotective effects of caspase-3 inhibition on functional recovery and tissue sparing after acute spinal cord injury
Neuroprotective effects of caspase-3 inhibition on functional recovery and tissue sparing after acute spinal cord injury
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DOI：
10.1097/brs.0b013e3181831f7e
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发表时间：
2008-10-01
期刊：
影响因子：
3
通讯作者：
Festoff, Barry W.
中科院分区：
文献类型：
--
作者：
Citron, Bruce A.;Arnold, Paul M.;Festoff, Barry W.
研究设计.我们使用基因微阵列，发现半胱天冬酶相关的死亡基因上调。我们测试了半胱天冬酶的抑制作用，并评估了其对创伤性损伤后脊髓的影响。先前研究的逻辑延伸是确定下游CASP基因是否也可能参与，以及抑制是否可以防止损伤诱导的细胞死亡。凋亡性细胞死亡发生在脊髓的所有内源性细胞区室中，在神经元、星形胶质细胞和小胶质细胞中在损伤后3天达到峰值。下游效应器caspase-3在被上游起始器caspase激活后切割几个重要的细胞位点。沿着其他人，我们先前已经鉴定了损伤的大鼠脊髓中PARP、α-胞衬蛋白和DFF 45/ICAD的半胱天冬酶标记裂解。我们还发现脊髓损伤后半胱天冬酶3基因表达沿着快速上调，并在神经元和活化的小胶质细胞中定位有活性的半胱天冬酶3。另一些研究报道了一种更普遍的活性位点模拟肽酮，苄基羰基-Val-Ala-Asp-fluromethylketone（zVAD-fetamine）对大鼠脊髓损伤具有神经保护作用。在本研究中，我们在大鼠椎板切除术和中度（25 g cm力）SCI后1 h腹腔内给予caspase-3亚家族四肽细胞渗透性抑制剂Z-Asp（O-Me）-Glu（O-Me）-Val-Asp（O-Me）fluoromethyl ketone（DEVDfetamine）。我们在14天的过程中使用了开放场地运动评级（LRS），发现DEVD-fmk治疗的大鼠有统计学显着改善，LRS为9.8 +/- 0.93 SEM，而溶剂为6.6 +/- 0.4（P < 0.05）。组织学分析显示，DEVD组脊髓组织体积百分比比对照组高50%（P < 0.5）。这些结果表明，在细胞水平和大量的功能恢复的神经保护，这表明半胱天冬酶-3抑制可能是一个可行的治疗在实验性SCI后的早期。
Study Design. We used gene microarrays and found that caspase-related death genes were upregulated. We tested caspase inhibition and evaluated its effect on the spinal cord after traumatic injury.Objective. The logical extension of previous studies was to determine whether downstream CASP genes might also be involved and whether inhibition might prevent injury-induced cell death.Summary of Background Data. Apoptotic cell death occurs in all endogenous cellular compartments of the spinal cord, peaking at 3 days after injury in neurons, astrocytes, and microglia. The downstream effector caspase-3 cleaves several important cellular sites after being activated by upstream initiator caspases. Along with others, we have previously identified caspase signature cleavage of PARP, a-fodrin, and DFF45/ICAD in the injured rat spinal cord. We also showed rapid upregulation of caspase-3 gene expression along with localization of active caspase-3 in neurons and activated microglia after SCI. Others have reported that a more general active-site mimetic peptide ketone, benzylocarbonyl-Val-Ala-Asp-fluromethylketone (zVAD-fmk) was neuroprotective after rat spinal cord injury (SCI).Methods. In this study, we administered the caspase-3 subfamily tetrapeptide cell permeable inhibitor Z-Asp(O-Me)-Glu(O-Me)-Val-Asp(O-Me) fluoromethyl ketone (DEVDfmk) intraperitoneally 1 hour after laminectomy and moderate (25 g cm force) SCI in rats.Results. We used the open field locomotor rating (LRS) over a 14-day course and found statistically significant improvement in DEVD-fmk-treated rats, LRS, 9.8 +/- 0.93 SEM, compared with vehicle, 6.6 +/- 0.4 (P < 0.05). Histologic analysis of percent spinal cord tissue volume spared was 50% greater for DEVD-fmk versus control (P < 0.5).Conclusion. These results indicate neuroprotection at both the cellular level and with substantial functional recovery, suggesting caspase-3 inhibition may be a viable therapy in the early hours after experimental SCI.