Stabilization of Hypoxia Inducible Factor-1α by Dimethyloxalylglycine Promotes Recovery from Acute Spinal Cord Injury by Inhibiting Neural Apoptosis and Enhancing Axon Regeneration

Abstract

Spinal cord injury (SCI) is a devastating neurological disorder that usually leads to a loss of motor and sensory function in patients. The expression of hypoxia inducible factor-1α (HIF-1α) is increased, and exerts a protective role after traumatic SCI. However, the endogenous activity of HIF-1α is insufficient for promoting functional recovery. The present study tested the potential effect of the sustained activation of HIF-1α by the prolylhydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG) on anti-apoptotic process and the regulation of axonal regeneration after SCI. Here, we found that treatment with DMOG significantly increased the expression of HIF-1α and that the stabilization of HIF-1α induced by DMOG not only decreased the expression of apoptotic proteins to promote neural survival, but also enhanced axonal regeneration by regulating microtubule stabilization in vivo and in vitro. In addition, we found that DMOG promoted neural survival and axonal regeneration by activating autophagy, which is induced by the HIF-1α/BNIP3 signaling pathway, and that the inhibition of HIF-1α or autophagy abrogated the protective effect of DMOG, as expected. Taken together, our results demonstrate that treatment with DMOG improves functional recovery after SCI and that DMOG may serve as a potential candidate for treating SCI.

Keywords: DMOG; HIF-1α; SCI; autophagy; axonal regeneration.