Activation of the Nrf2/ARE signaling pathway by probucol contributes to inhibiting inflammation and neuronal apoptosis after spinal cord injury

Abstract

// Zipeng Zhou 1,* , Chang Liu 2,* , Shurui Chen 1,* , Haosen Zhao 1 , Kang Zhou 1 , Wei Wang 1 , Yajiang Yuan 1 , Zhuo Li 3 , Yue Guo 1 , Zhaoliang Shen 3 and Xifan Mei 1 1 Department of Orthopedics, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China 2 Department of Endocrinology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China 3 Department of Orthopedics, Second Hospital of Jinzhou, Jinzhou, China * These authors have contributed equally to this work and should be considered co-first authors Correspondence to: Xifan Mei, email: // Keywords : inflammation, spinal cord injury, Nrf2/ARE, apoptosis, probucol, Autophagy Received : May 27, 2017 Accepted : June 28, 2017 Published : July 08, 2017 Abstract The nuclear erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway plays an essential role in the cellular antioxidant and anti-inflammatory responses. Spinal cord injury (SCI) results in a massive release of inflammatory factors and free radicals, which seriously compromise nerve recovery and axon regeneration. In this study, we examined the efficacy of probucol on anti-inflammatory responses and functional recovery after SCI by activating the Nrf2/ARE signaling pathway. We also investigated the mechanism by which inflammation is inhibited in this process. We found that treatment of injured rats with probucol significantly increased levels of Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1), while levels of inflammatory cytokines, interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were decreased. This was associated with a reduction in neural cell apoptosis and promotion of nerve function recovery. These results demonstrate that the neuroprotective effects of probucol after SCI are mediated by activation of the Nrf2/ARE signaling pathway. These findings indicate that the anti-inflammatory effects of probucol represent a viable treatment for improving functional recovery following SCI.