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

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。

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

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.