NAC和雷帕霉素通过抑制镉诱导神经元氧化应激和mTOR通路激活抗凋亡机理研究
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摘要
本文通过体外分离培养原代小鼠皮质神经元,运用细胞培养、Western blotting等技术从细胞分子生物学角度,分析N-乙酰-L-半胱氨酸(NAC)和雷帕霉素(Rap)干预镉诱导神经元ROS和mTOR通路激活抗凋亡的机制；通过慢性镉染毒实验小鼠模型,运用HE染色、透射电镜和免疫组织化学染色等分析方法,探究了镉诱发大脑组织和细胞损伤过程中,NAC对其变化效应,综合分析了NAC拮抗镉诱导神经元介导mTOR通路激活发挥抗凋亡的机理。结果如下：
1 NAC和Rap通过抑制镉诱导神经元ROS和]mTOR通路激活抗凋亡
以原代小鼠皮质神经元为对象,将分离的原代神经元细胞悬液接种在96(1×104/孔)或6(5×105/孔或2×106/孔)孔板中培养6天后的大脑皮质神经元分别用0-120μM CdCl2处理24 h,或用N-乙酰-L-半胱氨酸(NAC,5 mM)和雷帕霉素(Rap,0.2μg/ml)预处理1h和48h后用10和20μM CdCl2暴露4h或24h。采用MTT法分析细胞活性,用荧光探针CM-H2DCFDA分析细胞ROS荧光强度。Western blot测定mTOR通路相关信号蛋白变化。我们观察到镉以浓度依赖的方式诱导神经元凋亡,这与镉诱导ROS产生和Akt/mTOR通路激活有密切关系。用ROS清除剂NAC预处理或mTOR靶向特异抑制剂Rap预处理,可以通过阻滞ROS产生和mTOR通路激活,明显削弱镉诱导的神经元凋亡。提示：NAC和Rap通过抑制镉诱导神经元ROS和mTOR通路激活抗凋亡。
2 NAC对慢性镉染毒实验小鼠大脑组织和细胞损伤的保护作用研究
选用健康成年ICR小鼠64只,分为对照组(0.9%生理盐水)和镉处理10、25或50 mg/L CdCl2处理组诱发小鼠大脑组织和细胞损伤,及NAC组,NAC加10、25或50 mg/L CdCl2处理组观察保护情况,共8组。镉采用自由饮水方式,NAC溶于生理盐水(15mg/ml)按150mg/kg体重,每隔1天腹腔注射,连续4周。采用常规HE染色观察组织学变化和透射电镜TEM观察细胞超微结构变化,以及免疫组化分析4E-BP1磷酸化表现。结果表明：在光学显微镜下,大脑皮层和海马区组织结构的变化,大脑颞叶皮层三层结构(CP1-3)出现明显的混乱等现象,而且底板区(SP)模糊、心室层(VZ)减少和底板(SP)到中间层(IZ)细胞松动现象,细胞异常集中在中间带,且以镉浓度依赖的方式呈现大脑颞叶皮层结构不清,部分神经细胞核固缩,出现筛网状结构；海马区CA1-CA2区细胞异位,呈空泡样变性,海马齿状回明显松散,细胞间出现间隙。而NAC和Cd联合处理组的小鼠在皮层组织学结构上可以看到NAC明显的保护作用,小鼠大脑皮层三层结构明显。海马结构齿状回颗粒细胞密集,排列均匀,CA1-CA2区明显。透射电镜观察皮层神经细胞内胞体缩小,神经元细胞内细胞器结构紊乱,线粒体肿胀。免疫组化结果证明mTOR信号通路的下游蛋白p-4EBP1以浓度依赖的方式在海马CA1区表达,大脑皮层犹以底板层的Ⅰ-Ⅲ层更为密集,海马区阳性细胞沿海马齿状回颗粒细胞层呈线状排列,细胞呈圆形,均匀深染,NAC对小鼠大脑皮层额叶分子层的Ⅰ-Ⅲ层和海马CA1区4E-BP1磷酸化有明显的保护作用。提示：NAC干预了慢性镉染毒实验小鼠大脑皮层和海马区组织结构变化和mTOR通路激活。
The present study studied was divided into two series. First, the primary neurons were chosen as object of study. We examined the mechanisms of N-acetyl-L-cysteine (NAC) and Rapamycin (Rap) prevention of cadmium (Cd)-induced apoptosis by suppressing reactive oxygen species (ROS) generation and activation of mammalian target of rapamycin (mTOR) pathway in in vitro neurons. In the second series, the histology and ultrastructure of cerebral cortex and/or hippocampus in chronic Cd-exposed mice were observed by light microscopy (LM) and transmission electron microscopy (TEM). Consistently, NAC inhibited 4E-BP1 phosphorylation of the cerebral cortex and hippocampus tissue cells in chronic Cd-exposed mice were discussed. The results were as follows:
1 NAC and Rap prevents Cd-induced apoptosis by suppressing ROS production and activation of mTOR pathway in neurons
The primary cortical neurons were isolated and seeded in 96- or 6-well flat-bottomed plates at a density of 1×105 or 2×106 cells/well for culture of 6 days. Then cells were exposed to different concentration of Cd (0-120μM) for 24 h, or were treated with 10 or 20μM Cd for 4 h or 24 h post pretreatment with NAC (5 mM) for 1 h or with Rap (0.2 p.g/ml) for 48 h. Cell viability was evaluated using an MTT assay, intracellular ROS generation was detected using fluorescent probe CM-H2DCFDA, and morphological analysis was taken to assess the protective effect of NAC and Rap on Cd-induced neurons. Simultaneously, Western Blotting was used to investigate protein expression associated with mTOR pathways. We found Cd induced a concentration-dependent increase of apoptosis in neurons, which was associated with ROS production and activation of mTOR pathway in Cd-induced neurons. Pretreatment with NAC, a ROS scavenger or with mTOR inhibitor Rap, we observed that NAC and Rap significantly rescued Cd-induced neuronal apoptosis by inhibiting ROS production and activation of mTOR pathways. The findings reveal that NAC and Rap prevent Cd-induced apoptosis by suppressing ROS production and activation of mTOR pathway in neurons.
2 Studies on protective effects of NAC administered on the cerebral tissue and cell injuries in chronic Cd-exposed mice
Sixty-four healthy adult ICR mice were chosen and randomly divided into 8 sets:control group (treated with 0.9% physiological saline),10,25, or 50 mg/L CdGl2 group, NAC group, NAC+10,25, or 50 mg/LCdCl2 group. CdCl2 was dissolved into water and mice with ad libitum access to food and water. NAC (150 mg/Kg body weight) was dissolved in 0.9% NaCl (15 mg/ml) and administered by intraperitoneal injection every 1 days. The entire experiment lasted 4 weeks. Changes of cerebral cortex and hippocampus in mice were observed by light microscopy (LM) for histology, transmission electron microscopy (TEM) for ultrastructure, and immunohistochemistry for phosphorylation of 4E-BP1. We showed NAC protected the disorganization of the cerebral cortex and hippocampus in chronic Cd-exposed mice at LM and TEM level. The cerebral cortex in control and NAC groups contained a sharply defined three zones. In contrast, Cd-exposed mice's one displayed a hypotrophic cortical plate, a reduced ventricular zone, and a loose band of cells positioned below the subplate in the normally clear intermediate zone. NAC apparently protected the disorganization of the cerebral cortex in the morphological and the vacuolization of neuron were reduced significantly. An abnormal laminar pattern was also evident in the hippocampus. The hippocampus also displayed striking heterotopia in the CA1-CA2 regions. Consistent with these observations, TEM revealed the change of cytoplasmic organelles includings welling and hollowed mitochondria. The results of immunohistochemistry exhibited Cd-induced a marked increase phosphorylation of 4E-BP1, at the same time, there was considerable decreased phospho-4EBPl levels by NAC combined with CdC12 in mouse brain. These data suggests NAC protected the disorganization of the cerebral cortex and hippocampus and suppressed mTOR associated with phosphorylation of 4E-BP1.
1 NAC和Rap通过抑制镉诱导神经元ROS和]mTOR通路激活抗凋亡
以原代小鼠皮质神经元为对象,将分离的原代神经元细胞悬液接种在96(1×104/孔)或6(5×105/孔或2×106/孔)孔板中培养6天后的大脑皮质神经元分别用0-120μM CdCl2处理24 h,或用N-乙酰-L-半胱氨酸(NAC,5 mM)和雷帕霉素(Rap,0.2μg/ml)预处理1h和48h后用10和20μM CdCl2暴露4h或24h。采用MTT法分析细胞活性,用荧光探针CM-H2DCFDA分析细胞ROS荧光强度。Western blot测定mTOR通路相关信号蛋白变化。我们观察到镉以浓度依赖的方式诱导神经元凋亡,这与镉诱导ROS产生和Akt/mTOR通路激活有密切关系。用ROS清除剂NAC预处理或mTOR靶向特异抑制剂Rap预处理,可以通过阻滞ROS产生和mTOR通路激活,明显削弱镉诱导的神经元凋亡。提示：NAC和Rap通过抑制镉诱导神经元ROS和mTOR通路激活抗凋亡。
2 NAC对慢性镉染毒实验小鼠大脑组织和细胞损伤的保护作用研究
选用健康成年ICR小鼠64只,分为对照组(0.9%生理盐水)和镉处理10、25或50 mg/L CdCl2处理组诱发小鼠大脑组织和细胞损伤,及NAC组,NAC加10、25或50 mg/L CdCl2处理组观察保护情况,共8组。镉采用自由饮水方式,NAC溶于生理盐水(15mg/ml)按150mg/kg体重,每隔1天腹腔注射,连续4周。采用常规HE染色观察组织学变化和透射电镜TEM观察细胞超微结构变化,以及免疫组化分析4E-BP1磷酸化表现。结果表明：在光学显微镜下,大脑皮层和海马区组织结构的变化,大脑颞叶皮层三层结构(CP1-3)出现明显的混乱等现象,而且底板区(SP)模糊、心室层(VZ)减少和底板(SP)到中间层(IZ)细胞松动现象,细胞异常集中在中间带,且以镉浓度依赖的方式呈现大脑颞叶皮层结构不清,部分神经细胞核固缩,出现筛网状结构；海马区CA1-CA2区细胞异位,呈空泡样变性,海马齿状回明显松散,细胞间出现间隙。而NAC和Cd联合处理组的小鼠在皮层组织学结构上可以看到NAC明显的保护作用,小鼠大脑皮层三层结构明显。海马结构齿状回颗粒细胞密集,排列均匀,CA1-CA2区明显。透射电镜观察皮层神经细胞内胞体缩小,神经元细胞内细胞器结构紊乱,线粒体肿胀。免疫组化结果证明mTOR信号通路的下游蛋白p-4EBP1以浓度依赖的方式在海马CA1区表达,大脑皮层犹以底板层的Ⅰ-Ⅲ层更为密集,海马区阳性细胞沿海马齿状回颗粒细胞层呈线状排列,细胞呈圆形,均匀深染,NAC对小鼠大脑皮层额叶分子层的Ⅰ-Ⅲ层和海马CA1区4E-BP1磷酸化有明显的保护作用。提示：NAC干预了慢性镉染毒实验小鼠大脑皮层和海马区组织结构变化和mTOR通路激活。
The present study studied was divided into two series. First, the primary neurons were chosen as object of study. We examined the mechanisms of N-acetyl-L-cysteine (NAC) and Rapamycin (Rap) prevention of cadmium (Cd)-induced apoptosis by suppressing reactive oxygen species (ROS) generation and activation of mammalian target of rapamycin (mTOR) pathway in in vitro neurons. In the second series, the histology and ultrastructure of cerebral cortex and/or hippocampus in chronic Cd-exposed mice were observed by light microscopy (LM) and transmission electron microscopy (TEM). Consistently, NAC inhibited 4E-BP1 phosphorylation of the cerebral cortex and hippocampus tissue cells in chronic Cd-exposed mice were discussed. The results were as follows:
1 NAC and Rap prevents Cd-induced apoptosis by suppressing ROS production and activation of mTOR pathway in neurons
The primary cortical neurons were isolated and seeded in 96- or 6-well flat-bottomed plates at a density of 1×105 or 2×106 cells/well for culture of 6 days. Then cells were exposed to different concentration of Cd (0-120μM) for 24 h, or were treated with 10 or 20μM Cd for 4 h or 24 h post pretreatment with NAC (5 mM) for 1 h or with Rap (0.2 p.g/ml) for 48 h. Cell viability was evaluated using an MTT assay, intracellular ROS generation was detected using fluorescent probe CM-H2DCFDA, and morphological analysis was taken to assess the protective effect of NAC and Rap on Cd-induced neurons. Simultaneously, Western Blotting was used to investigate protein expression associated with mTOR pathways. We found Cd induced a concentration-dependent increase of apoptosis in neurons, which was associated with ROS production and activation of mTOR pathway in Cd-induced neurons. Pretreatment with NAC, a ROS scavenger or with mTOR inhibitor Rap, we observed that NAC and Rap significantly rescued Cd-induced neuronal apoptosis by inhibiting ROS production and activation of mTOR pathways. The findings reveal that NAC and Rap prevent Cd-induced apoptosis by suppressing ROS production and activation of mTOR pathway in neurons.
2 Studies on protective effects of NAC administered on the cerebral tissue and cell injuries in chronic Cd-exposed mice
Sixty-four healthy adult ICR mice were chosen and randomly divided into 8 sets:control group (treated with 0.9% physiological saline),10,25, or 50 mg/L CdGl2 group, NAC group, NAC+10,25, or 50 mg/LCdCl2 group. CdCl2 was dissolved into water and mice with ad libitum access to food and water. NAC (150 mg/Kg body weight) was dissolved in 0.9% NaCl (15 mg/ml) and administered by intraperitoneal injection every 1 days. The entire experiment lasted 4 weeks. Changes of cerebral cortex and hippocampus in mice were observed by light microscopy (LM) for histology, transmission electron microscopy (TEM) for ultrastructure, and immunohistochemistry for phosphorylation of 4E-BP1. We showed NAC protected the disorganization of the cerebral cortex and hippocampus in chronic Cd-exposed mice at LM and TEM level. The cerebral cortex in control and NAC groups contained a sharply defined three zones. In contrast, Cd-exposed mice's one displayed a hypotrophic cortical plate, a reduced ventricular zone, and a loose band of cells positioned below the subplate in the normally clear intermediate zone. NAC apparently protected the disorganization of the cerebral cortex in the morphological and the vacuolization of neuron were reduced significantly. An abnormal laminar pattern was also evident in the hippocampus. The hippocampus also displayed striking heterotopia in the CA1-CA2 regions. Consistent with these observations, TEM revealed the change of cytoplasmic organelles includings welling and hollowed mitochondria. The results of immunohistochemistry exhibited Cd-induced a marked increase phosphorylation of 4E-BP1, at the same time, there was considerable decreased phospho-4EBPl levels by NAC combined with CdC12 in mouse brain. These data suggests NAC protected the disorganization of the cerebral cortex and hippocampus and suppressed mTOR associated with phosphorylation of 4E-BP1.
引文
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