金刚烷胺对双侧轻型脑损伤大鼠的神经保护作用研究  

Neuroprotective effects of amantadine on rat models of bilateral mild TBI

作　　者：王涛[1] 史铁钧[1] 林伟[2] 贾云凤[1] 刘文鹏[1] 王培新[1] 崔绍杰[1] 

机构地区：[1]解放军第306医院神经外科,北京100101 [2]第四军医大学西京医院神经外科,陕西西安710032

出　　处：《中华神经外科疾病研究杂志》2016年第1期37-41,共5页Chinese Journal of Neurosurgical Disease Research

摘　　要：目的探讨金刚烷胺对双侧轻型颅脑损伤后神经细胞的保护作用,并对不同剂量金刚烷胺进行药效学分析。方法建立大鼠液压脑损伤模型,56只大鼠随机分为4组,分别于伤后每8 h一次,连续16 d给予三组剂量(15 mg/kg、45 mg/kg或135 mg/kg)金刚烷胺或等渗盐水,首次给药于伤后1 h完成。脑组织于伤后第48小时或16天提取行Fluoro Jade-B组织荧光染色或甲酚紫染色比较双侧海马CA3区神经细胞存活情况,液相色谱-质谱/质谱(LS-MS/MS)方法测定大鼠体内不同剂量金刚烷胺血药浓度,研究金刚烷胺经腹腔单次给药后在大鼠体内的药代动力学过程。结果 45 mg/kg或135 mg/kg两组治疗剂量在大鼠体内血药浓度与临床治疗监测浓度(717 ng/ml)相似。与安慰剂组相比,45或135 mg/kg两组剂量金刚烷胺可明显减少伤后48 h脑组织急性变性神经元数量(P<0.05),高剂量组(135 mg/kg)CA3区长期存活神经细胞数量显著增加(P=0.032)。结论治疗剂量金刚烷胺可显著减轻脑损伤后海马结构CA3区神经细胞损伤程度,为临床治疗轻型颅脑损伤提供新的治疗手段。Objective The potential effects of clinically relevant dose of amantadine on hippocampal cell survival in adult rats following bilateral mild traumatic brain injuries are evaluated. Methods Experimental TBIs were induced by fluid percussion device. Fifty-six rats were random subjected to four groups. Amantadine （15 mg/ kg, 45 mg/kg, and 135 mg/kg） or saline control were administered intraperitoneal at 1 h after TBI followed by dosing three times daily for 16 consecutive days. Brains were removed at 48 h or 16 d after TBI for measurement of acute degenerating neurons and long-term neuronal survival. Amantadine plasma concentrations were determined by liquid chromatograph/mass spectrometer-mass spectrometer （ LC/MS-MS ） for pharmacokinetic analysis, l/.esults Stereological quantification revealed that 45 mg/kg or 135 mg/kg dose of amantadine significantly reduced the numbers of degenerating neurons compared to saline treated group （P 〈0.05）, with the highest dose （135 mg/kg） producing the largest increase in surviving CA3 pyramidal neurons at 16 d post TBI （P =0. 032）. Pharmacokinetic analysis confirmed that the employed doses and dosing intervals （every 8 hours） produced plasma exposures of amantadine similar to those in humans （717 ng/ml）. Conclusion Our data shows clinically relevant dosing schedules of amantadine would be a potential novel treatment to reduce brain tissue damage after traumatic brain injury.

关 键 词：创伤性颅脑损伤 SD大鼠 海马 神经细胞 药代动力学 

分 类 号：R651.15[医药卫生—外科学]