塞来昔布对脂多糖诱导的多巴胺能神经元变性的保护作用

Neuroprotective effects of celecoxib against degeneration of dopaminergic neurons induced by lipopolysaccharide

目的探讨选择性环氧化酶-2(COX-2)抑制剂塞来昔布对细菌脂多糖(LPS)诱导的多巴胺能神经元变性的保护作用及其机制。方法30只SD大鼠随机分成3组:PBS对照组、生理盐水+LPS(生理盐水治疗组)和塞来昔布+LPS(塞米昔布治疗组),每组10只。黑质内立体定向注射15μg LPS或PBS 14天后,采用免疫组织化学法观察大鼠黑质酪氨酸羟化酶(TH)阳性细胞的减少以及小胶质细胞的形态学变化,免疫印迹法检测黑质COX-2蛋白表达以及放射免疫法测定前列腺素E2(PGE2)和TNF-α水平。结果与PBS对照组比较,生理盐水治疗组TH阳性细胞减少到对侧的16%(P<0.01),黑质COX-2蛋白表达以及PGE2、TNF-α含量明显增加,大部分小胶质细胞呈激活形态;塞来昔布治疗组TH阳性细胞数较生理盐水治疗组明显增多,为对侧的43%(P<0.05),黑质COX-2蛋白表达以及PGE2、TNF-α含量明显减少,激活的小胶质细胞明显减少。结论COX-2涉及炎症介导的多巴胺能神经元变性机制,塞来昔布能抑制小胶质细胞激活,阻止多巴胺能神经元的变性和丢失。

Objectives To explore the effect and possible mechanism of celecoxib on degeneration of dopaminergic neurons induced by intranigral injection of lipopolysaccharide（LPS）. Methods Thirty female Sprague-Dawley rats were randomly divided into three groups：PBS group, physiologic saline ＋LPS group and celecoxib＋LPS group. On d 14 after injection of LPS 15 μg or PBS, the number of tyrosine hydroxylase （TH）-positive neurons and the morphological changes of OX-42 positive microglias in the substantia nigra（SN） were observed by immunohistochemistry. COX-2 protein expression was examined by immunoblotting,prostaglandin E2 （PGE2） and tumor necrosis factor α （TNF-α） contents were measured with radioimmunoassay. Results Compared with PBS control group,TH-positive neurons in the SN on the LPS-injected side reduced to 16% of the opposite side in saline treated group（ P （0.05） ,COX-2 protein expression and PGE2 and TNF-α contents in SN were upregulated. Compared with saline treated group,43% TH-positive neurons survived in celecoxib treated group, （ P 〈0.05） and celecoxib significantly lowered the levels of PGE2 ,TNF-α and the microglial activation. Conclusions COX-2 may be involved in LPS- induced dopaminergic neurous degeneration. Celecoxib inhibits microglial activation and the neurotoxic secretions,prevents the dopaminergic neuron degeneration and loss.