Ketogenic diet attenuates oxidative stress and inflammation after spinal cord injury by activating Nrf2 and suppressing the NF-κB signaling pathways

Abstract

Oxidative stress and inflammation are two key secondary pathological mechanisms following spinal cord injury (SCI). Ketogenic diet (KD) and its metabolite β-hydroxybutyrate have been found to exhibit anti-oxidative and anti-inflammatory properties both in rats with SCI and in healthy rats; however, the underlying mechanisms are not yet fully understood. We investigated the effects of KD on the suppression of oxidative stress and inflammation, activation of nuclear factor-E2 related factor 2 (Nrf2), and inhibition of the nuclear factor-κB (NF-κB) signaling pathway in rats with SCI. We assessed functional recovery and evaluated the status of oxidative stress and inflammation using tests of superoxide dismutase and myeloperoxidase activity. We further assessed the presence of the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ) by ELISA. Western blotting was used to detect Nrf2 and NF-κB pathway-associated proteins in spinal cord tissue. Finally, we measured the levels of the NF-κB downstream genes TNF-α, IL-1β, and IFN-γ by western blotting and real-time quantitative PCR. Following SCI, KD improved functional recovery, attenuated oxidative stress and inflammation, and induced Nrf2 activation. In addition, KD suppressed the NF-κB pathway and the expression of TNF-α, IL-1β, and IFN-γ. Together, these findings provide new insight into the underlying regulatory mechanisms of KD.

Keywords: Anti-inflammatory; Anti-oxidative stress; Ketogenic diet; NF-κB signaling pathway; Nrf2; Spinal cord injury.