Calcium Signaling Involvement in Cadmium-Induced Astrocyte Cytotoxicity and Cell Death Through Activation of MAPK and PI3K/Akt Signaling Pathways
Calcium Signaling Involvement in Cadmium-Induced Astrocyte Cytotoxicity and Cell Death Through Activation of MAPK and PI3K/Akt Signaling Pathways
复制标题
钙信号通过激活 MAPK 和 PI3K/Akt 信号通路参与镉诱导的星形胶质细胞毒性和细胞死亡。
DOI：
10.1007/s11064-015-1686-y
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发表时间：
2015-09-01
影响因子：
4.4
通讯作者：
Yu, Albert Cheung-Hoi
中科院分区：
文献类型：
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作者：
Jiang, Jiao Hua;Ge, Guo;Yu, Albert Cheung-Hoi
镉（Cd）是一种高度普遍存在的有毒重金属，可通过工业径流和其他污染源污染环境，包括农业土壤、水和空气。镉通过直接接触或通过食物链在体内积累，导致神经变性和许多其他疾病。以往关于其对中枢神经系统（CNS）毒性的研究主要集中在神经元。为了更全面地了解镉对中枢神经系统的毒性，我们研究了星形胶质细胞对急性和慢性镉暴露的反应及其毒性分子机制。当原代培养的大脑皮质星形胶质细胞与1-300 μ M氯化镉孵育时，观察到形态学变化，LDH释放和细胞死亡的时间和剂量依赖性的方式。进一步的研究表明，急性和慢性镉处理使JNK、p38和Akt发生不同程度的磷酸化，而ERK 1/2仅在低剂量镉（10 μ M）下发生磷酸化。抑制JNK和PI 3 K/Akt，而不是p38，可以部分保护星形胶质细胞免受慢性和急性镉暴露的细胞毒性。此外，镉还诱导了一个强的钙信号，而BAPTA，一个特定的细胞内钙（Ca 2+）螯合剂，阻止镉诱导的星形胶质细胞内钙水平的增加，抑制镉诱导的ERK 1/2，JNK，p38和Akt的激活，并显着减少星形胶质细胞的细胞死亡。上述结果提示，Cd-Ca ~（2+）-MAPK和PI 3 K/Akt信号通路参与了镉对星形胶质细胞的毒性作用。这种毒性参与表明，这些途径可被利用作为预防镉诱导的神经退行性疾病的目标。
Cadmium (Cd), a highly ubiquitous toxic heavy metal, can contaminate the environment, including agricultural soil, water and air, via industrial runoff and other sources of pollution. Cd accumulated in the body via direct exposure or through the food chain results in neurodegeneration and many other diseases. Previous studies on its toxicity in the central nervous system (CNS) focused mainly on neurons. To obtain a more comprehensive understanding of Cd toxicity for the CNS, we investigated how astrocytes respond to acute and chronic Cd exposure and its toxic molecular mechanisms. When primary cultures of cerebral cortical astrocytes incubated with 1-300 mu M CdCl2, morphological changes, LDH release and cell death were observed in a time and dose-dependent manner. Further studies demonstrated that acute and chronic Cd treatment phosphorylated JNK, p38 and Akt to different degrees, while ERK1/2 was only phosphorylated under low doses of Cd (10 mu M) exposure. Inhibition of JNK and PI3K/Akt, but not of p38, could partially protect astrocyte from cytotoxicity in chronic and acute Cd exposure. Moreover, Cd also induced a strong calcium signal, while BAPTA, a specific intracellular calcium (Ca2+) chelator, prevented Cd-induced intracellular increase of calcium levels in astrocytes; inhibited the Cd-induced activation of ERK1/2, JNK, p38 and Akt; and also significantly reduced astrocyte cell death. All of these results suggested that the Cd-Ca2+-MAPK and PI3K/Akt signaling pathways were involved in Cd-induced toxicity in astrocytes. This toxicity involvement indicates that these pathways may be exploited as a target for the prevention of Cd-induced neurodegenerative diseases.