Dihydroquercetin ameliorates spinal cord injury in rats by modulating the AKT/Nrf2/GPX4 signaling pathway-mediated ferroptosis

Dihydroquercetin (DHQ), a plant-derived flavonoid, possesses significant antioxidant and neuroprotective properties. However, the specific mechanisms underlying its effects on spinal cord injury (SCI) remain unclear. This study aimed to investigate whether DHQ could alleviate Ferroptosis, oxidative stress, reduce neuroinflammation, and exert neuroprotective effects by upregulating the Akt/Nrf2/GPX4 pathway. In a rat model of SCI, DHQ was administered orally daily. Motor and sensory function was assessed using the Basso, Beattie, and Bresnahan (BBB) score, and paw withdrawal test (PWT) on days -1, 7, 14, 21, and 28 after surgery. On day 29, tissue samples were collected to analyze the effects of DHQ on histopathology, Ferroptosis, oxidative stress, the Akt/Nrf2/GPX4 signaling pathway, and inflammatory cytokines. DHQ produced dose-dependent improvements in SCI rats, with improved motor and sensory function and histopathological outcomes, restored ferrous ion (Fe²⁺) levels, superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH) and Reactive Oxygen Species (ROS) levels, attenuated inflammatory cytokines, alongside upregulated Akt/Nrf2/GPX4 signaling pathway. Furthermore, administration of the Akt Inhibitor, LY294002 antagonized the neuroprotective effects of DHQ. These results suggested that DHQ exerted its neuroprotective effects by upregulating the Akt/Nrf2/GPX4 pathway, reducing Ferroptosis, oxidative stress, and inflammation, thereby mitigating motor and sensory function following SCI.

Dihydroquercetin; Ferroptosis; Neuroinflammation; Oxidative stress; Spinal cord injury.