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[摘要]
目的探讨羟基积雪草苷对铜锌超氧化物歧化酶(Cu,Zn superoxide dismutase,SOD 1)-G 93A突变肌萎缩侧索硬化(amyotrophic lateral scleros is,ALS)小鼠的治疗作用。方法通过行为学和组织学测定,观察羟基积雪草苷对SOD 1-G 93A突变ALS小鼠发病时间、生存时间、运动功能变化和神经元病理改变的影响。结果羟基积雪草苷(61.1±11.0)和(185.6±18.7)m g/(kg.d)在小鼠日龄70 d时开始给药至死亡,能分别延长SOD 1-G 93A突变ALS小鼠的生存时间11.4和9.4 d,但对发病时间无影响;同时(61.1±11.0)m g/(kg.d)组小鼠在肌力缓慢下降期运动功能降低减缓,与对照组比较差异显著(P<0.05)。120 d时L 2~5组织切片显示两治疗组脊髓前角运动神经元数明显高于SOD 1-G 93A对照组(P<0.05),多数运动神经元胞浆中仍有尼氏体存在。结论羟基积雪草苷对SOD 1-G 93A突变转基因小鼠运动神经元变性有保护作用,能延长小鼠的生存时间。
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[Abstract]
Objective To investigate the therapeutic potential of madecassoside in mice expressing a mutant human Cu,Zn superoxide dismutase(SODl)-G93A linked to human amyotrophic lateral sclerosis (ALS).Methods Effects of madecassoside on onset of clinical disease,survival of mice,decline of motor function,and motor neuron(MN)degeneration were observed by behavioral analysis and histological evaluation.Results Madecassoside(61.1土11.O)and(185.6±18.7)rag/(kg·d)ig administration,beginning at 70 d of age until death,prolonged survival of SODl-G93A ALS mice by 11.4 and 9.4 d,respec-tively(P<0.05),but did not delay the onset of disease.Madecassoside(61.1--4-_11.0)rag/(kg·d)decreased significantly the decline of motor strength of SODl-G93A ALS mice during the slower declining stage until end-stage of disease(P<0.05).Histological evaluation of the lumbar spinal cord revealed that madecassoside treatment prevented the pathological changes typical of the transgenic disease model at 1 20d of age. Average MN counts per section in the lumbar spinal cord in madecassoside-treated animals were significant more than these of untreated SODl-G93A ALS mice(P<0.05).Nissl bodies were found in cytoplasm of more motor neurons.Conclusion Madecassoside could protect motor neuron degeneration and increase the longevity of SODl-G93A ALS mice.
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[基金项目]
日本岛根县难病研究所、重庆市自然科学基金资助(CSTC,2005BB5036)