Department of Neurosurgery, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan 215300, Jiangsu Province, China.
Department of Neurosurgery, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215006, China.
Biomed Pharmacother. 2022 Sep;153:113435. doi: 10.1016/j.biopha.2022.113435. Epub 2022 Jul 19.
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide as well as a risk factor for neurodegenerative diseases later in life. Evodiamine (Evo), a compound derived from Evodia rutaecarpa, is known to possess pharmacological activities. However, whether Evo confers protection after TBI remains unknown.
To study whether Evo protects against TBI through inhibiting oxidative stress via the phosphoglycerate kinase 1 (PGK1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway.
In vivo, adult male C57BL/6J mice were subjected to controlled cortical impact (impact velocity: 6 m/s; penetration depth: 2 mm) to establish a murine model of TBI. Evodiamine was administrated at 24 h, 30 min prior to TBI and 2, 24, 48, 72 h post TBI. In vitro, pheochromacytoma 12 (PC12) cells were pretreated with Evo for 24 h, then exposed to 300 μM HO stimulation for another 24 h to induce oxidative stress. Furthermore, transfection of PGK1 overexpressing vectors or PGK1 siRNAs was performed to decipher the role of PGK1 in Evo-produced effect in TBI.
Treatment with Evo alleviated TBI-induced neurological dysfunction, BBB breakdown, histopathological changes in H&E staining, and increased apoptosis. Importantly, Evo enhanced catalase (CAT) and superoxide dismutase (SOD) activities, and reduced reactive oxygen species (ROS) generation through PGK1 inhibition-induced activation of the NRF2/heme oxygenase-1 (HO-1) signaling in TBI mice or HO-exposed PC12 cells. Of note, the protective effect of Evo in the in vitro TBI was similar to that of PGK1 siRNAs; overexpression of PGK1 compromised Evo-produced protection in HO-stimulated PC12 cells.
Taken together, we demonstrated that Evo improved the outcomes after TBI by targeting the PGK1/NRF2 signaling-regulated oxidative stress. Evo may represent a potential therapy to promote recovery from TBI.
创伤性脑损伤（TBI）是全球范围内导致死亡和残疾的主要原因，也是晚年神经退行性疾病的危险因素。吴茱萸碱（Evo）是一种源自吴茱萸的化合物，具有药理学活性。然而，Evo 是否能在 TBI 后提供保护尚不清楚。
研究 Evo 是否通过抑制磷酸甘油酸激酶 1（PGK1）/核因子红细胞 2 相关因子 2（NRF2）通路的氧化应激来保护 TBI。
在体内，成年雄性 C57BL/6J 小鼠接受控制皮质撞击（撞击速度：6 m/s；穿透深度：2 mm）以建立 TBI 小鼠模型。Evo 在 TBI 前 24 小时、30 分钟、TBI 后 2、24、48、72 小时给药。在体外，PC12 细胞用 Evo 预处理 24 小时，然后再用 300 μM HO 刺激 24 小时，以诱导氧化应激。此外，还进行了 PGK1 过表达载体或 PGK1 siRNA 的转染，以阐明 PGK1 在 Evo 产生的 TBI 效应中的作用。
Evo 治疗减轻了 TBI 引起的神经功能障碍、BBB 破裂、H&E 染色的组织病理学变化和细胞凋亡增加。重要的是，Evo 通过抑制 PGK1 诱导的 NRF2/血红素加氧酶-1（HO-1）信号通路的激活，增强 TBI 小鼠或 HO 暴露的 PC12 细胞中的过氧化氢酶（CAT）和超氧化物歧化酶（SOD）活性，减少活性氧（ROS）的产生。值得注意的是，Evo 在体外 TBI 中的保护作用与 PGK1 siRNA 相似；PGK1 的过表达削弱了 Evo 在 HO 刺激的 PC12 细胞中产生的保护作用。
综上所述，我们证明 Evo 通过靶向 PGK1/NRF2 信号调节的氧化应激改善了 TBI 后的结果。Evo 可能代表一种促进 TBI 恢复的潜在治疗方法。
