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目的雄激素对缺氧缺血后脑损伤有神经保护作用,但其作用机制尚不完全清楚。该研究探讨雄激素对缺氧缺血性脑损伤(HIBD)的保护作用及其可能的机制。方法64只7日龄SD大鼠随机分为假手术组、HIBD对照组和雄激素干预组。通过结扎左颈总动脉和吸入8%氧气和92%氮气的混合气体制备新生鼠HIBD模型。假手术组仅做颈正中切口,游离左颈总动脉,不结扎,不行低氧处理。雄激素干预组在模型制成后即刻注射丙酸睾丸酮(25mg/kg)。缺氧缺血(HI)后6h、24h、72h、7d取脑组织制作石蜡切片,用免疫组化法观察Bcl-2和Bax蛋白在各组大鼠皮质和海马表达的动态变化。HI后6h、24h、48h断头取脑制作脑匀浆,测定SOD活性和MDA含量。结果假手术组大鼠左脑的皮质及海马可见少量Bcl-2蛋白和Bax蛋白免疫阳性细胞表达,与HIBD对照组和雄激素干预组比较差异均有显著性意义(P<0.01)。雄激素干预组HI后6h、24h、72hBcl-2蛋白在皮层和海马的表达水平明显高于HIBD对照组(P<0.05或0.01)。雄激素干预组Bax蛋白的表达水平在HI后24h显著低于HIBD对照组(P<0.05),其他时间点两组Bax蛋白的表达无明显差别。与假手术组比较,HIBD对照组HI后6h大鼠脑组织中SOD活性明显降低,MDA含量明显增加(P<0.05)。HIBD对照组HI后24hSOD活性降至最低值,MDA含量升至最高。雄激素干预增加了SOD活性,雄激素干预组HI后6h、24h、48hSOD活性均明显高于HIBD对照组,差异有显著性意义(P<0.05或0.01)。雄激素干预亦导致了脑组织中MDA含量降低,雄激素干预组HI后6h、24hMDA含量均明显低于HIBD对照组,差异有显著性意义(分别P<0.05、P<0.01)。结论雄激素发挥脑保护作用可能通过上调Bcl-2蛋白、下调Bax蛋白表达以及通过减少抗氧化剂的消耗和抑制氧自由基的生成,从而减轻缺氧缺血后神经细胞的损伤。
Objective Androgens have neuroprotective effects on brain injury following hypoxic-ischemic attacks, but its mechanism of action is not fully understood. This study explored the protective effect of androgen on hypoxic-ischemic brain damage (HIBD) and its possible mechanism. Methods Sixty-four 7-day-old SD rats were randomly divided into sham operation group, HIBD control group and androgen treatment group. Neonate rat HIBD models were prepared by ligating the left common carotid artery and inhaling a mixture of 8% oxygen and 92% nitrogen. Sham-operated group only incision of the middle neck, free left common carotid artery, not ligation, hypoxia treatment. Androgen intervention group injected testosterone propionate (25 mg / kg) immediately after the model was made. Paraffin sections were made at 6h, 24h, 72h, 7d after hypoxia-ischemia (HI), and the expressions of Bcl-2 and Bax in cortex and hippocampus of rats were observed by immunohistochemistry. HI 6h, 24h, 48h after brain decapitation brain homogenates were prepared to measure SOD activity and MDA content. Results A small amount of Bcl-2 protein and Bax protein expression were found in the left cortex and hippocampus of sham operation group, which were significantly different from those in HIBD control group and androgen control group (P <0.01). The expression of Bcl-2 protein in cortex and hippocampus at 6h, 24h and 72h after HI in androgen treatment group was significantly higher than that in HIBD control group (P <0.05 or 0.01). The expression of Bax protein in androgen-treated group was significantly lower than that in HIBD control group at 24 h after HI (P <0.05), and at other time points there was no significant difference between the two groups. Compared with the sham-operation group, the activity of SOD in brain tissue of HIBD control group decreased significantly and MDA content increased significantly (P <0.05) 6 h after HI. In HIBD control group, the activity of SOD decreased to the lowest level after 24 h and the content of MDA increased to the highest level. Androgen intervention increased the activity of SOD. The activity of SOD in 6h, 24h and 48h after androgen treatment in HI group was significantly higher than that in HIBD control group (P <0.05 or 0.01). Androgen intervention also resulted in the decrease of MDA content in brain tissue. The levels of MDA in 6h and 24h after HI in androgen treatment group were significantly lower than those in HIBD control group (P <0.05 and P <0.01, respectively). Conclusion Androgen may play a neuroprotective role in neuroprotection by up-regulating Bcl-2 protein, down-regulating Bax protein expression and reducing the production of oxygen free radicals by reducing the consumption of antioxidants.