Cytoprotection against oxidative stress-induced damage of astrocytes by extracellular ATP via P2Y1 receptors
Cytoprotection against oxidative stress-induced damage of astrocytes by extracellular ATP via P2Y1 receptors
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作者：
Shinozaki, Y;Koizumi, S;Inoue, K
氧化应激是创伤性脑损伤、缺氧/再灌注损伤和神经退行性疾病中神经元损伤的主要原因。虽然细胞外核苷，特别是腺苷，是众所周知的，以防止在这种病理条件下的神经元损伤，这些核苷或核苷酸对神经胶质细胞损伤的影响仍然在很大程度上未知。我们报告说，ATP，而不是腺苷保护对过氧化氢（H2 O2）诱导的培养星形胶质细胞的细胞死亡。ATP以时间和浓度依赖性方式改善H2 O2诱导的星形胶质细胞细胞活力下降。ATP的保护作用被P2受体拮抗剂抑制，被P2 Y（1）受体激动剂模拟，但不被腺苷抑制。证实星形胶质细胞中P2 Y（1）mRNA和功能性P2 Y（1）受体的表达。因此，ATP作用于星形胶质细胞中的P2 Y（1）受体，表现出对H2 O2的保护作用。P2 Y（1）受体激动剂2-methylthio-ADP对星形胶质细胞的保护作用可被胞内Ca ~（2+）螯合剂和磷脂酶C阻断剂所抑制，表明Gq/11偶联P2 Y（1）受体介导的胞内信号参与了保护作用。ATP诱导的保护作用被蛋白质合成抑制剂放线菌酮所抑制，并且保护作用的起效时间超过12 h。在DNA微阵列分析中，ATP诱导了各种氧化还原酶基因的显著上调。总之，ATP作用于与Gq/11偶联的P2 Y（1）受体，导致氧化还原酶基因上调，从而保护星形胶质细胞免受H2 O2的侵害。(C)2004年威利-利斯。Inc.
Oxidative stress is the main cause of neuronal damage in traumatic brain injury, hypoxia/reperfusion injury, and neurodegenerative disorders. Although extracellular nucleosides, especially adenosine, are well known to protect against neuronal damage in such pathological conditions, the effects of these nucleosides or nucleotides on glial cell damage remain largely unknown. We report that ATP but not adenosine protects against the cell death of cultured astrocytes induced by hydrogen peroxide (H2O2). ATP ameliorated the H2O2-induced decrease in cell viability of astrocytes in an incubation time- and concentration-dependent fashion. Protection by ATP was inhibited by P2 receptor antagonists and was mimicked by P2Y(1) receptor agonists but not by adenosine. The expressions of P2Y(1) mRNAs and functional P2Y(1) receptors in astrocytes were confirmed. Thus, ATP, acting on P2Y(1) receptors in astrocytes, showed a protective action against H2O2. The astrocytic protection by the P2Y(1) receptor agonist 2-methylthio-ADP was inhibited by an intracellular Ca2+ chelator and a blocker of phospholipase C, indicating the involvement of intracellular signals mediated by Gq/11-coupled P2Y(1) receptors. The ATP-induced protection was inhibited by cycloheximide, a protein synthesis inhibitor, and it took more than 12 h for the onset of the protective action. In the DNA microarray analysis, ATP induced a dramatic upregulation of various oxidoreductase genes. Taken together, ATP acts on P2Y(1) receptors coupled to Gq/11, resulting in the upregulation of oxidoreductase genes, leading to the protection of astrocytes against H2O2. (C) 2004 Wiley-Liss. Inc.