CAJ | 학술논문

目的探讨组蛋白去乙酰化酶(histone deacetylases,HDAC)抑制剂MS-275对大鼠中度创伤性颅脑损伤(traumatic brain injury,TBI)的神经保护作用. 方法 68只SD成年雄性大鼠按随机数字表法分为4组:无损伤对照+安慰剂组(对照组)、脑损伤+安慰剂组(损伤组)、脑损伤+ 15mg/kg MS-275组(治疗Ⅰ组)和脑损伤+45mg/kg MS-275组(治疗Ⅱ组).大鼠侧方液压打击装置诱导形成中度实验性TBI模型.MS-275溶解于二甲基亚砜中,15,45 mg/kg两种浓度的MS-275伤后连续7d(1次/d)腹腔注射大鼠体内,首次给药于伤后30 min完成.伤后记录各组大鼠体重变化,伤后10 ～ 14 d行Morris水迷宫测试评估大鼠空间探索及记忆存储功能.脑组织经提取固定后通过免疫组化及甲酚紫组织染色方法比较不同组别海马CA2 ～3区乙酰化组蛋白H3水平和存活神经细胞数量的差异. 结果与对照组比较,其余3组伤后前3d体重均显著下降(P＜0.05),伤后4～5d体重逐渐增加至伤前基础体重水平,但各组间差异无统计学意义(F=0.149,P＞0.05).行为学测试结果显示,与损伤组比较,两治疗组均可明显改善大鼠伤后认知行为表现(P＜0.01).组织染色结果显示,两治疗组均可明显增加脑组织乙酰化组蛋白H3水平,与对照组比较差异无统计学意义;伤后14 d两治疗组均表现出脑组织海马CA2 ～3区神经细胞存活数量增加的趋势(P＞0.05). 结论 MS-275可显著改善大鼠TBI后急性期乙酰化组蛋白水平及认知行为功能,同时改善TBI后的病理变化,对神经起到一定的保护作用.
목적 탐토조단백거을선화매(histone deacetylases,HDAC)억제제MS-275대대서중도창상성로뇌손상(traumatic brain injury,TBI)적신경보호작용. 방법 68지SD성년웅성대서안수궤수자표법분위4조:무손상대조+안위제조(대조조)、뇌손상+안위제조(손상조)、뇌손상+ 15mg/kg MS-275조(치료Ⅰ조)화뇌손상+45mg/kg MS-275조(치료Ⅱ조).대서측방액압타격장치유도형성중도실험성TBI모형.MS-275용해우이갑기아풍중,15,45 mg/kg량충농도적MS-275상후련속7d(1차/d)복강주사대서체내,수차급약우상후30 min완성.상후기록각조대서체중변화,상후10 ～ 14 d행Morris수미궁측시평고대서공간탐색급기억존저공능.뇌조직경제취고정후통과면역조화급갑분자조직염색방법비교불동조별해마CA2 ～3구을선화조단백H3수평화존활신경세포수량적차이. 결과 여대조조비교,기여3조상후전3d체중균현저하강(P＜0.05),상후4～5d체중축점증가지상전기출체중수평,단각조간차이무통계학의의(F=0.149,P＞0.05).행위학측시결과현시,여손상조비교,량치료조균가명현개선대서상후인지행위표현(P＜0.01).조직염색결과현시,량치료조균가명현증가뇌조직을선화조단백H3수평,여대조조비교차이무통계학의의;상후14 d량치료조균표현출뇌조직해마CA2 ～3구신경세포존활수량증가적추세(P＞0.05). 결론 MS-275가현저개선대서TBI후급성기을선화조단백수평급인지행위공능,동시개선TBI후적병리변화,대신경기도일정적보호작용.
Objective To evaluate the neuroprotective benefits of histone deacetylases (HDAC)inhibitor MS-275 in rats with moderate traumatic brain injury (TBI).Methods Sixty-eight adult male SD rats were assigned to sham injury + placebo treatment (control group),TBI + placebo treatment (injury group),TBI + MS-275 (15 mg/kg) treatment (treatment group Ⅰ) and TBI + MS-275 (45 mg/kg)treatment (treatment group Ⅱ) according to the random number table.An experimental model of moderate TBI in the rat was induced using a lateral fluid percussion device.MS-275 was dissolved in DMSO and administered (15 and 45 mg/kg) intraperitoneally in seven consecutive days(once a day).The first administration was done in 30 minutes postinjury.Alteration in body weight of rats in each group was recorded after injury.Spatial learning and memory retention in rats was assessed using the Morris Water Maze in days 10-14 after TBI.Brain tissues were sectioned to measure acetyl-histone H3 and neuronal survivals in the hippocampus CA2-3 region using immunohistochemistry and cresyl-violet staining techniques.Results TBI rats showed significant body weight loss in 3 days postinjury as compared with the controls (P ＜0.05) and then gradually gained the body weight in 4-5 days postinjury.No significant difference in actual body weight loss after injury was found among injury group and treatment groups (F =0.149,P ＞0.05).Behavioral result revealed that the animals in treatment groups had significant improvement in cognitive performance as compared with injury group (P ＜ 0.01).Immunohistochemical results presented a markedly increased level of acetyl-histone H3 in both treatment groups,with no significant difference as compared with control group and a trend of increase in the survived neurons in the CA2-3 hippocampus in 14 days postinjury (P ＞ 0.05).Conclusions MS-275 achieves visible improvement of acetyl-histone H3 level and cognitive performance in the acute phase of TBI.Simultaneously,this treatment has an ameliorative effect on pathological changes associated with TBI as well and provides a neuroprotective effect against TBI.