Protective Effect of Carnosine on Subcortical Ischemic Vascular Dementia in Mice
Protective Effect of Carnosine on Subcortical Ischemic Vascular Dementia in Mice
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肌肽对小鼠皮质下缺血性血管性痴呆的保护作用
DOI：
10.1111/j.1755-5949.2012.00362.x
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发表时间：
2012-01-01
影响因子：
5.5
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Ma, Jing;Xiong, Jia-Yan;Chen, Zhong
目的肌肽通过组胺能通路对N-甲基-D-天冬氨酸（NMDA）诱导的兴奋性毒性具有保护作用。本研究的目的是确定肌肽-组氨酸-组胺通路是否也在皮质下缺血性血管性痴呆（SIVD）中发挥保护作用。方法雄性C57 BL/6小鼠建立右侧单侧颈总动脉闭塞模型（rUCCAO），分别给予肌肽和组氨酸治疗。rUCCAO后进行物体识别实验、被动回避实验、Morris水迷宫实验和免疫组化分析。结果肌肽（200、500 mg/kg）可改善缺乏内源性组胺的野生型小鼠和组氨酸脱羧酶基因敲除小鼠rUCCAO后的白色损害和物体识别实验、被动回避实验和Morris水迷宫实验中的认知功能障碍。然而，组氨酸的给药没有显示出相同的效果。rUCCAO后37 d，胼胝体髓鞘碱性蛋白明显下降，肌肽（200、500 mg/kg）可明显逆转这一变化。肌肽（200、500 mg/kg）可抑制小胶质细胞和星形胶质细胞的活化，并降低胶质细胞酸性蛋白（GFAP）和Iba-1荧光强度的升高。此外，肌肽（200，500 mg/kg）显着减弱rUCCAO后活性氧产生的增加。结论肌肽对rUCCAO小鼠的神经保护作用不依赖于组胺能通路，而可能是通过抑制活性氧的产生、胶质细胞的活化和髓鞘的变性而实现的。
Aims Recently, we found carnosine protects against N-Methyl-D-Aspartate (NMDA) induced excitotoxicity through a histaminergic pathway. The aim of this study was to determine whether the carnosine-histidine-histamine pathway also played a protective role in subcortical ischemic vascular dementia (SIVD). Methods Adult male mice (C57BL/6 strain) were subjected to right unilateral common carotid arteries occlusion (rUCCAO) and treated with carnosine or histidine. Object recognition test, passive avoidance task, Morris water maze, and immunohistochemical analyses were performed after rUCCAO. Results We found that carnosine (200, 500 mg/kg) ameliorated white matter lesion and cognitive impairment evaluated by object recognition test, passive avoidance task, and Morris water maze test after rUCCAO in both wide-type mice and histidine decarboxylase knockout mice, which are lack of endogenous histamine. However, administration of histidine did not show the same effect. The myelin basic protein in the corpus callosum decreased obviously at day 37 after rUCCAO, which was largely reversed by carnosine (200, 500 mg/kg). Carnosine (200, 500 mg/kg) suppressed the activation of microglia and astrocyte as attenuating the elevation of glial fibrillary acidic protein (GFAP) and Iba-1 fluorescent intensity. Moreover, carnosine (200, 500 mg/kg) significantly attenuated the increase in reactive oxygen species generation after rUCCAO. Conclusion These data suggest that the neuroprotective effect of carnosine on rUCCAO in mice is not dependent on the histaminergic pathway, but may be due to a suppression of reactive oxygen species generation, glia activation, and myelin degeneration.