HDAC抑制剂ITF2357在脊髓损伤中的神经保护作用研究  

Neuroprotective effect of HDAC inhibitor ITF2357 in spinal cord injury

作　　者：侯秦汉 闫宪磊[1] 吴宣远 刘全[1] 付锦龙 陈宏谋[1] Hou Qinhan;Yan Xianlei;Wu Xuanyuan;Liu Quan;Fu Jinlong;Chen Hongmou(Neurosurgery Department,Liuzhou Worker’s Hospital,Fourth Affiliated Hospital of Guangxi Medical University,Liuzhou 545005,China;Pathology Department,Liuzhou Worker’s Hospital,Fourth Affiliated Hospital of Guangxi Medical University,Liuzhou 545005,China)

机构地区：[1]广西柳州市工人医院神经外科,柳州545005 [2]广西柳州市工人医院病理科,柳州545005

出　　处：《广西医科大学学报》2020年第9期1610-1616,共7页Journal of Guangxi Medical University

基　　金：广西自然科学基金面上项目(No.2018GXNSFAA294026);广西自然科学基金青年基金项目(No.2016GXNSFBA380133);广西自治区卫生和计划生育委员会自筹经费科研课题(No.Z2015151);柳州市科学研究技术开发计划(No.2016G020207)。

摘　　要：目的:探讨I类组蛋白去乙酰化酶(HDAC)抑制剂ITF2357(Givinostat)对脊髓损伤(SCI)大鼠的神经保护作用及其机制。方法:将30只SD大鼠首先随机分为假手术组、SCI组、低剂量组、中剂量组与高剂量组,每组6只,SCI组及低、中、高剂量组采用改良Allen’s打击法造模,假手术组打开椎板而不损伤脊髓;低、中、高剂量组术后连续14 d每日分别以5 mg/kg、10 mg/kg、15 mg/kg浓度腹腔注射ITF2357,SCI组腹腔注射等量生理盐水,检测14 d后大鼠脊髓HDAC 1/3的表达。后再将36只SD大鼠随机分为假手术组、脊髓损伤组与中剂量组,每组12只,以同样方式造模及给药;以Basso-Beatlie-Bresnahn(BBB)评分记录术后28 d内后肢运动功能变化;检测14 d后脑源性神经营养因子(BDNF)、核因子(NF)-κβ、与剪切含半胱氨酸的天冬氨酸蛋白水解酶(Cleaved caspase)-3的表达水平;酶联免疫吸附试验(ELISA)法比较假手术组、脊髓损伤组及中剂量组3组14 d时白细胞介素(IL)-1β、IL-10、肿瘤坏死因子(TNF)-α的表达;脊髓组织HE染色评价28 d后损伤情况。结果:14 d时,中、高剂量组大鼠HDAC 1与HDAC 3水平相较于SCI组显著降低(P<0.05);中剂量组14 d、21 d、28 d BBB评分显著高升高(P<0.05);中剂量组IL-1β与TNF-α水平较SCI组显著降低(P<0.05),IL-10水平显著升高(P<0.05);同时,中剂量组BDNF表达较SCI组显著升高(P<0.05),而NF-κβ与cleaved caspase-3水平显著降低(P<0.05);脊髓HE染色提示中剂量组坏死程度较SCI组轻。结论:组蛋白去酰化酶抑制剂ITF2357可通过抑制HDAC 1与HDAC 3减轻SCI大鼠炎症及凋亡,从而起到神经保护作用。Objective:To investigate the neuroprotective effects and mechanism of class I histone deacetylase(HDAC)on Givinostat(ITF2357)in rats with spinal cord injury(SCI).Methods:A total of 30 SD rats were randomly divided into sham operation group,SCI group,low dose group,middle dose group and high dose group,with 6 rats in each group.The rat SCI model was established by a modified impinger of Allen’s in SCI group,low,middle and high dose groups.The vertebral plate was opened without spinal cord injury in sham operation group.The low,middle and high dose groups were intraperitoneally injected with ITF2357 daily at the concentration of 5 mg/kg,10 mg/kg and 15 mg/kg for 14 days after operation,respectively.SCI group was injected intraperitoneally with the same amount of normal saline.The expressions of HDAC 1 and HDAC 3 in spinal cord of rats were detected 14 days after operation.36 SD rats were randomly divided into sham operation group,SCI group and middle dose group,with 12 rats in each group.The model was made and administered in the same way.The changes of hindlimb motor function within 28 days after operation were recorded by Basso-Beatlie-Bresnahn(BBB)score.The expression levels of brain-derived neurotrophic factor(BDNF),nuclear factor-κβ(NF-κβ),Caspase 3 mRNA and proteins were detected 14 days after operation.The expressions of interleukin-1β(IL-1β),interleukin-10(IL-10)and tumor necrosis factor-α(TNF-α)in sham operation group,SCI group and middle dose group were measured by ELISA.HE staining was used to evaluate the injury of spinal cord tissue after 28 days.Results:On the 14th day,the levels of HDAC 1 and HDAC 3 in the middle and high dose groups were significantly lower than those in the SCI group(P<0.05).The BBB scores in the middle dose group on the d 14,21 and 28 were significantly higher than those in the SCI group(P<0.05).The levels of IL-1βand TNF-αin the middle dose group were significantly lower than those in the SCI group(P<0.05).The level of IL-10 was significantly higher than that in the S

关 键 词：组蛋白去乙酰化 脊髓损伤 ITF2357 

分 类 号：R651.2[医药卫生—外科学]