1 Neuroscience Center of Excellence, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
J Neurotrauma. 2013 Oct 1;30(19):1672-9. doi: 10.1089/neu.2013.2898. Epub 2013 Aug 28.
Traumatic brain injury (TBI) in children less than 8 years of age leads to decline in intelligence and executive functioning. Neurological outcomes after TBI correlate to development of cerebral edema, which affect survival rates after TBI. It has been shown that myosin light-chain kinase (MLCK) increases cerebral edema and that pretreatment with an MLCK inhibitor (ML-7) reduces cerebral edema. The aim of this study was to determine whether inhibition of MLCK after TBI in postnatal day 24 (PND-24) mice would prevent breakdown of the blood-brain barrier (BBB) and development of cerebral edema and improve neurological outcome. We used a closed head injury model of TBI. ML-7 or saline treatment was administered at 4 h and every 24 h until sacrifice or 5 days after TBI. Mice were sacrificed at 24 h, 48 h, and 72 h and 7 days after impact. Mice treated with ML-7 after TBI had decreased levels of MLCK-expressing cells (20.7±4.8 vs. 149.3±40.6), less albumin extravasation (28.3±11.2 vs. 116.2±60.7 mm(2)) into surrounding parenchymal tissue, less Evans Blue extravasation (339±314 vs. 4017±560 ng/g), and showed a significant difference in wet/dry weight ratio (1.9±0.07 vs. 2.2±0.05 g), compared to saline-treated groups. Treatment with ML-7 also resulted in preserved neurological function measured by the wire hang test (57 vs. 21 sec) and two-object novel recognition test (old vs. new, 10.5 touches). We concluded that inhibition of MLCK reduces cerebral edema and preserves neurological function in PND-24 mice.
儿童创伤性脑损伤（TBI）导致智力和执行功能下降。TBI 后的神经学结果与脑水肿的发展相关，脑水肿影响 TBI 后的生存率。已经表明肌球蛋白轻链激酶（MLCK）增加脑水肿，并且用 MLCK 抑制剂（ML-7）预处理可减少脑水肿。本研究旨在确定在出生后 24 天（PND-24）的小鼠 TBI 后抑制 MLCK 是否会防止血脑屏障（BBB）破裂和脑水肿的发展，并改善神经学结果。我们使用 TBI 的闭合性颅脑损伤模型。在 4 h 时给予 ML-7 或生理盐水治疗，并在 TBI 后每 24 h 直至处死或 5 天。在冲击后 24、48、72 h 和 7 天处死小鼠。TBI 后用 ML-7 治疗的小鼠，MLCK 表达细胞的水平降低（20.7±4.8 与 149.3±40.6），白蛋白渗出（28.3±11.2 与 116.2±60.7 毫米 2）到周围实质组织中减少，伊文思蓝渗出减少（339±314 与 4017±560 纳克/克），与生理盐水处理组相比，湿/干重比有显著差异（1.9±0.07 与 2.2±0.05 克）。用 ML-7 治疗还导致通过线悬挂试验（57 与 21 秒）和两个物体新识别试验（旧与新，10.5 次触摸）测量的神经功能得到保存。我们得出结论，抑制 MLCK 可减少 PND-24 小鼠的脑水肿并保存神经功能。
