Andoh Tsugunobu, Chock P Boon, Chiueh Chuang C
Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, Japan.
Ann N Y Acad Sci. 2002 May;962:1-7. doi: 10.1111/j.1749-6632.2002.tb04051.x.
Preconditioning adaptation induced by transient ischemia can increase brain tolerance to oxidative stress, but the underlying neuroprotective mechanisms are not fully understood. Recently, we developed a human brain-derived cell model to investigate preconditioning mechanism in SH-SY5Y neuroblastoma cells.(1) Our results demonstrate that a non-lethal serum deprivation-stress for 2 h (preconditioning stress) enhanced the tolerance to a subsequent lethal oxidative stress (24 h serum deprivation) and also to 1-methyl-4-phenyl-pyridinium (MPP(+)).(2) Two-hour non-lethal preconditioning stress increased the expression of neuronal nitric oxide (NOS1/nNOS) mRNA, Fos, Ref-1, NOS protein, and then nitric oxide (*NO) production. As well as MnSOD expression, the *NO-cGMP-PKG pathway mediated the preconditioning-induced upregulation of antiapoptotic protein Bcl-2 and the downregulation of adaptor protein p66(shc). We also propose that cGMP-mediated preconditioning-induced adaptation against oxidative stress may be due to the synthesis of a new protein, such as thioredoxin (Trx) since the protective effect can be blocked by Trx reductase inhibitor.(3) The antioxidative potency of Trx was approximately 100 and 1,000 times greater than GSNO and GSH, respectively. These results suggest that *NO-cGMP-PKG signaling pathway plays an important role in the preconditioning-induced neuroprotection, and perhaps cardioprotection, against oxidative stress.
短暂性缺血诱导的预处理适应可增强大脑对氧化应激的耐受性，但其潜在的神经保护机制尚未完全明确。最近，我们建立了一种人脑源细胞模型，以研究SH-SY5Y神经母细胞瘤细胞中的预处理机制。（1）我们的结果表明，2小时的非致死性血清剥夺应激（预处理应激）增强了对随后致死性氧化应激（24小时血清剥夺）以及1-甲基-4-苯基吡啶鎓（MPP(+)）的耐受性。（2）两小时的非致死性预处理应激增加了神经元型一氧化氮合酶（NOS1/nNOS）mRNA、Fos、Ref-1、NOS蛋白的表达，进而增加了一氧化氮（*NO）的生成。除了锰超氧化物歧化酶（MnSOD）的表达外，*NO-cGMP-PKG途径介导了预处理诱导的抗凋亡蛋白Bcl-2的上调和衔接蛋白p66(shc)的下调。我们还提出，cGMP介导的预处理诱导的抗氧化应激适应可能归因于一种新蛋白质的合成，如硫氧还蛋白（Trx），因为这种保护作用可被Trx还原酶抑制剂阻断。（3）Trx的抗氧化能力分别比亚硝基谷胱甘肽（GSNO）和谷胱甘肽（GSH）大100倍和1000倍左右。这些结果表明，*NO-cGMP-PKG信号通路在预处理诱导的针对氧化应激的神经保护以及可能的心脏保护中发挥着重要作用。
