Zakaria Aya, Hamdi Nabila, Abdel-Kader Reham Mahmoud
Department of Pharmacology & Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
Mol Neurobiol. 2016 Mar;53(2):1220-1228. doi: 10.1007/s12035-014-9088-8. Epub 2015 Jan 20.
Methylene blue (MB) phase II clinical trials reported improvements in cognitive functions of Alzheimer's disease (AD) patients. Regarding MB mechanism of action, its antioxidant and mitochondrial protective effects have been previously described. In relation to AD, it has been recently reported that MB reduced amyloid beta (Aβ) levels in AD models. The mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) has been shown to bind Aβ inducing mitochondrial dysfunction, providing a direct relation between Aβ toxicity and mitochondrial dysfunction occurring in AD. Since it has been reported that inhibiting ABAD protects mitochondrial functions and prevents Aβ-induced toxicity, the aim of the current study was to investigate if the protective effects of MB could be associated with an effect on ABAD levels and functions. The current study shows that MB is able to enhance cell viability, reduce both reactive oxygen species levels and importantly Aβ oligomers in a lipopolysaccharide (LPS) mouse model. Interestingly, ABAD levels were increased in the brains of the LPS mouse model and MB treatment was able to reduce its levels. Given that regulation of the estradiol level is a well-established function of ABAD, brain estradiol level was compared in LPS mouse model and in MB-treated mice. The results of the current study show that MB treatment is able to improve significantly the LPS-induced decrease of estradiol levels in mice brains, indicating its ability to modulate both levels and function of ABAD. These results give a new insight to possible mechanisms of MB in AD.
亚甲蓝（MB）的II期临床试验报告称，阿尔茨海默病（AD）患者的认知功能有所改善。关于MB的作用机制，其抗氧化和线粒体保护作用此前已有描述。关于AD，最近有报道称MB可降低AD模型中的淀粉样β蛋白（Aβ）水平。线粒体酶淀粉样蛋白结合醇脱氢酶（ABAD）已被证明可结合Aβ，诱导线粒体功能障碍，这为AD中发生的Aβ毒性与线粒体功能障碍之间提供了直接联系。由于有报道称抑制ABAD可保护线粒体功能并预防Aβ诱导的毒性，因此本研究的目的是调查MB的保护作用是否与对ABAD水平和功能的影响有关。本研究表明，在脂多糖（LPS）小鼠模型中，MB能够提高细胞活力，降低活性氧水平，重要的是还能降低Aβ寡聚体水平。有趣的是，LPS小鼠模型大脑中的ABAD水平升高，而MB治疗能够降低其水平。鉴于调节雌二醇水平是ABAD的一项既定功能，对LPS小鼠模型和接受MB治疗的小鼠的大脑雌二醇水平进行了比较。本研究结果表明，MB治疗能够显著改善LPS诱导的小鼠大脑中雌二醇水平的降低，表明其具有调节ABAD水平和功能的能力。这些结果为MB在AD中的可能作用机制提供了新的见解。
