Institute of Neuroinformatics, Dalian University of Technology, 116024 Dalian, China.
Neurosci Lett. 2010 Feb 12;470(2):106-10. doi: 10.1016/j.neulet.2009.12.064. Epub 2009 Dec 30.
In the present study, to define the roles of nitric oxide (NO) signaling in amyloid-beta (A beta) production after transient cerebral ischemia, extracellular levels of NO and A beta were monitored by intracerebral microdialysis in the hippocampus of aged rats exposed to transient middle cerebral artery occlusion and reperfusion (MCAO/R). The results indicated that 1-h MCAO significantly upregulated hippocampal NO and A beta levels. In addition, the NO elevation preceded the A beta changes. The Western blotting suggested that acute hypoperfusion could increase the expression of beta-secretase 1 (BACE1) but not BACE2. The enhanced NO concentration in acute stage of MCAO/R was coincident with increased eNOS expression, while in subacute stage was coincident with increased iNOS and nNOS. Our results also indicated that pretreatment of L-NAME, one non-selective NOS inhibitor could decrease the BACE1 expression, reverse both NO and A beta changes and rescue the delayed neuronal death. These preliminary findings indicated that activation of NOS/NO signaling system could trigger A beta production through BACE1 pathway during acute ischemic episode. The present data may be important in understanding, at least in part, the pathological role of NO/NOS system involved in hippocampal A beta production and neuronal damage induced by transient cerebral ischemia.
在本研究中，为了明确一氧化氮（NO）信号在短暂性脑缺血后β淀粉样蛋白（Aβ）产生中的作用，采用脑室内微透析技术监测了老龄大鼠短暂性大脑中动脉闭塞再灌注（MCAO/R）后海马区细胞外 NO 和 Aβ的水平。结果表明，1 h MCAO 可显著上调海马区 NO 和 Aβ水平。此外，NO 的升高先于 Aβ的变化。Western blot 表明，急性低灌注可增加β-分泌酶 1（BACE1）但不增加 BACE2 的表达。急性 MCAO/R 时增强的 NO 浓度与 eNOS 表达的增加一致，而亚急性期则与 iNOS 和 nNOS 的增加一致。我们的结果还表明，非选择性 NOS 抑制剂 L-NAME 的预处理可降低 BACE1 的表达，逆转 NO 和 Aβ的变化，并挽救迟发性神经元死亡。这些初步发现表明，NOS/NO 信号系统的激活可能通过 BACE1 途径触发急性缺血期 Aβ的产生。这些数据至少在一定程度上可能有助于理解与短暂性脑缺血引起的海马 Aβ产生和神经元损伤相关的 NO/NOS 系统的病理作用。
