Department of Respiratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Respiratory Disease, Ministry of Health, Wuhan 430030, China.
Sleep Med. 2010 Feb;11(2):205-12. doi: 10.1016/j.sleep.2009.05.015. Epub 2010 Jan 18.
The long-term intermittent hypoxia (LTIH) that characterizes sleep-disordered breathing impairs spatial learning and increases oxidative stress in rodents. We hypothesized that LTIH activated brain NADPH oxidase, which served as a critical source of superoxide in the oxidation injury, and that apocynin might attenuate LTIH-induced spatial learning deficits by reducing LTIH-induced NADPH oxidase expression.
To investigate the effects of apocynin on spatial learning and oxidative responses to LTIH in rats.
Forty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups of 10 each: a LTIH group, an apocynin-treated LTIH group, a sham LTIH group and an apocynin-treated sham group. Spatial learning in each group was assessed with the Morris water maze test. RT-PCR and Western blot were used to examine mRNA and protein expression of NADPH oxidase subunit p47phox and p22phox in the hippocampus region. The level of MDA and SOD were detected by colorimetric method. The terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling (TUNEL) method was used to display the apoptotic cells of the hippocampus tissue.
Apocynin treatment prevented LTIH-induced decreases in spatial learning during the Morris water maze as well as LTIH-induced decrease in SOD levels. In untreated animals, LTIH exposure was related to increase of MDA levels in comparison to sham LTIH animals, and apocynin-treated animal exposure to LTIH showed reduction in MDA levels. Increases in hippocampus NADPH oxidase subunit p47phox mRNA and protein expression were observed in LTIH-exposed animals; there was no statistical difference of p47phox mRNA and protein expression between LTIH group and apocynin treatment group. Treatment with apocynin significantly ameliorated cell apoptosis in LTIH-exposed animals.
These results indicate that apocynin attenuates LTIH-induced spatial learning deficits and mitigates LTIH-induced oxidative stress through multiple beneficial effects on oxidant pathways. NADPH oxidase up-expression is closely associated with oxidative processes in LTIH rats, and inhibition of NADPH oxidase activity may hopefully serve as a useful strategy for cognitive function impairment from chronic intermittent hypoxia.
睡眠呼吸障碍的特征是长期间歇性低氧（LTIH），这会损害啮齿动物的空间学习能力并增加氧化应激。我们假设 LTIH 激活了脑 NADPH 氧化酶，后者是氧化损伤中超氧的重要来源，而 apocynin 可能通过降低 LTIH 诱导的 NADPH 氧化酶表达来减轻 LTIH 诱导的空间学习缺陷。
研究 apocynin 对大鼠 LTIH 诱导的空间学习和氧化反应的影响。
将 40 只健康雄性 Sprague-Dawley（SD）大鼠随机分为 4 组，每组 10 只：LTIH 组、apocynin 治疗的 LTIH 组、假 LTIH 组和 apocynin 治疗的假 LTIH 组。每组的空间学习能力均通过 Morris 水迷宫测试进行评估。RT-PCR 和 Western blot 用于检测海马区 NADPH 氧化酶亚基 p47phox 和 p22phox 的 mRNA 和蛋白表达。通过比色法检测 MDA 和 SOD 的水平。末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）法用于显示海马组织的凋亡细胞。
apocynin 治疗可预防 LTIH 诱导的 Morris 水迷宫空间学习能力下降以及 LTIH 诱导的 SOD 水平下降。在未治疗的动物中，与假 LTIH 动物相比，LTIH 暴露导致 MDA 水平升高，而用 apocynin 治疗的 LTIH 暴露动物的 MDA 水平降低。在 LTIH 暴露的动物中观察到海马 NADPH 氧化酶亚基 p47phox mRNA 和蛋白表达增加；LTIH 组和 apocynin 治疗组之间 p47phox mRNA 和蛋白表达无统计学差异。apocynin 治疗可显著改善 LTIH 暴露动物的细胞凋亡。
这些结果表明，apocynin 通过对氧化途径的多种有益影响，减轻 LTIH 诱导的空间学习缺陷并减轻 LTIH 诱导的氧化应激。NADPH 氧化酶的过度表达与 LTIH 大鼠的氧化过程密切相关，抑制 NADPH 氧化酶活性有望成为治疗慢性间歇性低氧引起的认知功能障碍的一种有用策略。
