Combined NADPH and the NOX inhibitor apocynin provides greater anti-inflammatory and neuroprotective effects in a mouse model of stroke
Combined NADPH and the NOX inhibitor apocynin provides greater anti-inflammatory and neuroprotective effects in a mouse model of stroke
复制标题
NADPH 和 NOX 抑制剂夹竹桃麻素联合使用，可在小鼠中风模型中提供更强的抗炎和神经保护作用
DOI：
10.1016/j.freeradbiomed.2017.01.034
复制
发表时间：
2017-03-01
影响因子：
7.4
通讯作者：
Qin, Zheng-Hong
中科院分区：
文献类型：
--
作者：
Qin, Yuan-Yuan;Li, Mei;Qin, Zheng-Hong
我们以前的研究报告，戊糖磷酸途径产物烟酰胺腺嘌呤二核苷酸磷酸（NADPH）保护神经元免受缺血/再灌注诱导的脑损伤。NADPH既可以作为辅酶产生GSH，也可以作为NADPH氧化酶（NOX）的底物产生ROS。本研究旨在阐明NADPH和NOX抑制剂apocynin联合治疗对缺血/再灌注诱导的脑炎症和神经元损伤的影响。结果表明，NADPH和夹竹桃麻素均显著减弱缺血/再灌注诱导的NOX 2、NOX 4和ROS水平的升高。NADPH和夹竹桃苷能显著抑制I κ Ba的磷酸化和降解、NF-κ Bp 65的核定位以及NF-κ 3靶基因COX 2和iNOS的表达。此外，NADPH和夹竹桃麻素抑制炎症体蛋白的表达，包括NLRP 3 ASC，caspase-1，白细胞介素（IL）-1 β和IL-18在缺血皮质中，如通过蛋白质印迹分析和免疫荧光显示。NADPH和夹竹桃素的联合作用可显著增强上述效应。NADPH和夹竹桃苷都能显著减少脑梗死体积，改善脑卒中后小鼠的生存率和神经功能的恢复。因此，NADPH和夹竹桃麻素的组合在对抗缺血性脑损伤方面产生更大的有益作用。这些研究表明，除了抗氧化作用外，NADPH还可能具有抗炎作用，NADPH和NOX抑制剂的组合可以在缺血性卒中中产生更大的神经保护作用。
Our previous study has reported that the pentose phosphate pathway product nicotinamide adenine dinucleotide phosphate (NADPH) protected neurons against ischemia/reperfusion-induced brain injury. NADPH can either act as a co-enzyme to produce GSH or a substrate of NADPH oxidase (NOX) to generate ROS. This study was designed to elucidate the effects of co-treatment with NADPH and NOX inhibitor apocynin on ischemia/ reperfusion-induced brain inflammation and neuronal injury. The results showed that both NADPH and apocynin markedly attenuated ischemia/reperfusion-induced increases in the levels of NOX2, NOX4 and ROS. NADPH and apocynin significantly inhibited the phosphorylation and degradation of I kappa Ba, NF-kappa Bp65 nuclear localization, and the expression of NF-kappa 3 target gene cyclooxygenase (COX2) and inducible nitric oxide synthase (iNOS). Furthermore, both NADPH and apocynin suppressed the expression of inflammasome proteins including NLRP3 ASC, caspase-1, interleukin (IL) -1 beta and IL-18 in the ischemic cortex as revealed by Western blot analysis and immunofluorescence. Moreover, all these effects were greatly amplified by combination of NADPH and apocynin. Both NADPH and apocynin significantly reduced infarct volume, improved post-stroke survival, and recovery of neurological functions in mouse model of stroke. Consistently, the combination of NADPH and apocynin produced greater beneficial effects in against ischemic brain damage. These studies suggest that, beyond anti-oxidative effects, NADPH may also have anti-inflammatory effects and combination of NADPH and NOX inhibitors could produce a greater neuroprotective effect in ischemic stroke.