选择性组蛋白脱乙酰化酶抑制剂MS1568对创伤性颅脑损伤大鼠的神经保护潜能研究

目的通过建立临床相关的颅脑创伤动物模型并于伤后注射选择性Ⅱa类HDAC抑制剂MC1568,研究其对于脑损伤后神经炎性反应及急性神经细胞变性死亡的保护作用。方法建立中度颅脑损伤模型,比较不同组别脑组织损伤同侧海马CA2-3区乙酰化组蛋白H4、小胶质细胞及急性变性神经元数量。结果与安慰剂治疗组比较,2组剂量MC1568均可明显减少脑外伤后巨噬细胞样小胶质细胞的数量(P<0.05)。结论 MC1568可通过参与改善脑外伤后小胶质细胞介导炎性反应及急性神经元凋亡变性等一系列病理改变发挥其潜在神经保护作用,为临床治疗创伤性颅脑损伤提供实验室依据及有效的治疗手段。

Neuroprotective potential of selective histone deacetylases inhibitor MC1568 following experimental brain injury in rats

Objective To evaluate the effect of post-injury administration MC1568,a novel selective class Ⅱa histone deacetylas inhibitor,on reducing inflammation and acute neuronal degeneration in the clinical relevant fluid percussion brain injury model.Methods Experimental fluid percussion TBI was induced with injury magnitude approximately 2.12-2.18 atmosphere.MC1568 was dissolved in DMSO and two doses of MC1568(25 and 50 mg/kg) or an equal volume of vehicle control were administered intraperitoneally at 30 minutes post injury.Brains were removed on 24 hours after TBI and tissue sections from CA2-3 region of ipsilateral hippocampus were selected for measurement of Acetyl-Histone H4,microglia and acute degenerating neurons using immunohistochemistry and Fluoro-Jade histofluorescence techniques.Results There was a trend for MC1568 to increase the acetylated histone H4 levels which showed no significant difference compared with sham-TBI group.MC1567 treatment,at all dose examined,significantly attenuate the increasing of phagocytic microglia following TBI(P<0.05).Stereological quantification revealed that MC1568 reduced the numbers of degenerating neurons compared to vehicle treated group,with the highest dose(50 mg/kg) producing the largest reduction in neurodegeneration at 24 hours after TBI(P=0.037).Conclusion The data conclude HDAC inhibitor MC1568 may make underlying specific repairs and protective mechanisms on reducing microglia inflammatory and brain damage.Post-injury adminstration of MC1568 could be a potential novel therapeutics for patients sustaining brain injury.