Different responses of astrocytes and neurons to nitric oxide:: The role of glycolytically generated ATP in astrocyte protection
Different responses of astrocytes and neurons to nitric oxide:: The role of glycolytically generated ATP in astrocyte protection
复制标题
DOI：
10.1073/pnas.261560998
复制
发表时间：
2001-12-18
影响因子：
11.1
通讯作者：
Moncada, S
中科院分区：
文献类型：
--
作者：
Almeida, A;Almeida, J;Moncada, S
最近有人提出，在Jurkat细胞中，在NO抑制呼吸后，糖酵解产生的ATP在防止线粒体膜电位(Delta psi(M))崩溃从而防止细胞凋亡方面发挥关键作用。我们在大鼠皮质神经元和星形胶质细胞的原代培养中进一步研究了这一观察结果-这两种细胞类型在糖酵解能力上存在很大差异。由二氧二乙酸二乙酯([(z)-1-[2-aminoethyl]-N-[2-ammonioethyl]amino]diazen-1-ium-1，2-NO)产生的NO(1.4um，175um O(2))持续而显著地(约85%)抑制呼吸，最初(10min)使两种细胞的ATP值降低约25%，并增加星形胶质细胞的糖酵解速率，但对神经元没有影响。激活星形胶质细胞中的糖酵解，通过乳酸的产生来判断，可以防止进一步的ATP耗竭，而在不启动这一机制的神经元中，在接下来的60分钟内，ATP浓度逐渐下降。在此期间，星形胶质细胞存在持续的线粒体超极化，没有细胞凋亡，而在神经元中，Delta psi(M)进行性下降，细胞凋亡率增加。在去糖或用F(1)F(0)-ATPase和腺嘌呤核苷酸转位酶抑制剂处理后，星形胶质细胞对NO的反应是，psi(M)下降，细胞凋亡与神经元的反应相似。最后，虽然用NO处理星形胶质细胞部分地阻止了星形孢菌素诱导的psi(M)的崩溃和细胞死亡，但NO和星形孢菌素在降低Delta psi(M)和诱导神经元凋亡方面具有协同作用。这些结果表明，尽管NO抑制细胞呼吸会导致神经毒性，但它也可能导致最初的神经保护，这取决于特定细胞的糖酵解能力。
was recently proposed that in Jurkat cells, after inhibition of respiration by NO, glycolytically generated ATP plays a critical role in preventing the collapse of mitochondrial membrane potential (Delta psi (m)) and thus apoptotic cell death. We have investigated this observation further in primary cultures of rat cortical neurons and astrocytes-cell types that differ greatly in their glycolytic capacity. Continuous and significant (approximate to 85%) inhibition of respiration by NO (1.4 muM at 175 muM O(2)) generated by [(z)-1-[2-aminoethyl]-N-[2-ammonioethyl]amino]diazen-1-ium-1,2 diolate (DETA-NO) initially (10 min) depleted ATP concentrations by approximate to 25% in both cell types and increased the rate of glycolysis in astrocytes but not in neurons. Activation of glycolysis in astrocytes, as judged by lactate production, prevented further ATP depletion, whereas in neurons, which do not invoke this mechanism, there was a progressive decrease in ATP concentrations over the next 60 min. During this time, there was a persistent mitochondrial hyperpolarization and absence of apoptotic cell death in astrocytes, whereas in the neurons there was a progressive fall in Delta psi (m) and increased apoptosis. After glucose deprivation or treatment with inhibitors of the F(1)F(0)-ATPase and adenine nucleotide translocase, astrocytes responded to NO with a fall in Delta psi (m) and apoptotic cell death similar to the response in neurons. Finally, although treatment of astrocytes with NO partially prevented staurosporin-induced collapse in Delta psi (m), and cell death, NO and staurosporin synergized in decreasing Delta psi (m) and inducing apoptosis in neurons. These results demonstrate that although inhibition of cellular respiration by NO leads to neurotoxicity, it may also result in initial neuroprotection, depending on the glycolytic capacity of the particular cell.