Department of Emergency, 12480The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi Province, People's Republic of China.
These authors contributed equally to this work.
Hum Exp Toxicol. 2021 Jul;40(7):1084-1094. doi: 10.1177/0960327120984220. Epub 2020 Dec 30.
JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL) that has neuroprotective effect. However, the role of JZL184 in cerebral ischemia/reperfusion (I/R) injury and the exact mechanism have not been fully understood. This study was designed to elucidate the role of JZL184 in cerebral I/R injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons. Hippocampal neurons were pretreated with various concentrations of JZL184 for 2 h, followed by OGD for 3 h and reoxygen for 24 h. Our results showed that JZL184 improved cell viability in hippocampal neurons in response to OGD/R. JZL184 treatment significantly inhibited the production of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in OGD/R-induced hippocampal neurons. The increased TNF-α, IL-1β, and IL-6 productions in OGD/R-induced hippocampal neurons were decreased after treatment with JZL184. Moreover, the OGD/R-caused intense TUNEL staining in hippocampal neurons was attenuated by JZL184. JZL184 treatment prevented OGD/R-caused increases in bax and cleaved caspase-3 expression and a decrease in bcl-2 expression. Furthermore, JZL184 treatment significantly promoted the activation of Nrf2/ARE signaling pathway in OGD/R-induced hippocampal neurons. Additionally, silencing of Nrf2 reversed the protective effect of JZL184 on hippocampal neurons under OGD/R condition. Taken together, these findings suggested that JZL184 exerted protective effect against OGD/R-induced injury in hippocampal neurons via activating Nrf2/ARE signaling pathway, which provided experimental support for the therapeutic benefit of JZL184 in cerebral ischemia.
JZL184 是一种单酰基甘油脂肪酶（MAGL）的选择性抑制剂，具有神经保护作用。然而，JZL184 在脑缺血/再灌注（I/R）损伤中的作用及其确切机制尚未完全阐明。本研究旨在阐明 JZL184 在氧葡萄糖剥夺/再氧合（OGD/R）诱导的海马神经元脑 I/R 损伤中的作用。海马神经元用不同浓度的 JZL184 预处理 2 h，然后进行 OGD 3 h 及再氧合 24 h。结果显示，JZL184 可改善 OGD/R 后海马神经元的细胞活力。JZL184 处理可显著抑制 OGD/R 诱导的海马神经元中活性氧（ROS）和丙二醛（MDA）的产生，并增加超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GPx）的活性。JZL184 处理可降低 OGD/R 诱导的海马神经元中 TNF-α、IL-1β和 IL-6 的产生。此外，JZL184 可减轻 OGD/R 引起的海马神经元中 TUNEL 染色的增强。JZL184 处理可防止 OGD/R 引起的 bax 和 cleaved caspase-3 表达增加及 bcl-2 表达降低。此外，JZL184 处理可显著促进 OGD/R 诱导的海马神经元中 Nrf2/ARE 信号通路的激活。另外，沉默 Nrf2 可逆转 JZL184 在 OGD/R 条件下对海马神经元的保护作用。综上所述，这些结果表明，JZL184 通过激活 Nrf2/ARE 信号通路对 OGD/R 诱导的海马神经元损伤发挥保护作用，为 JZL184 在脑缺血中的治疗益处提供了实验支持。
