Evodiamine prevents traumatic brain injury through inhibiting oxidative stress via PGK1/NRF2 pathway

Background 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. Objective 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. Materials and methods 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 H 2 O 2 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. Results 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 H 2 O 2 -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 H 2 O 2 -stimulated PC12 cells. Discussion and conclusions 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.