CBD: A Potential Shield Against Newborn Brain Injury

Perinatal hypoxia-ischemia is a major cause of long-term neurological impairments in newborns, with ferroptosis recognized as a key mechanism of injury. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid with antioxidant and neuroprotective properties. CBD is a potential modulator of hypoxic-ischemic brain damage, however its effects on ferroptosis-related pathways remain unclear. In this study, we examined whether CBD can alleviate ferroptosis-associated damage in differentiated human neuroblastoma (neuron-like SH-SY5Y) cell model of hypoxic-ischemic injury. Differentiated human neuroblastoma cells were exposed to oxygen-glucose deprivation (OGD) to simulate hypoxic-ischemic conditions. Neuron-like SH-SY5Y cells were subjected to OGD to induce hypoxic-ischemic injury. CBD was applied to assess its neuroprotective effects. Oxidative stress markers, antioxidant enzyme activity, transcription factor activation Nrf2 (nuclear factor erythroid 2-related factor 2), iron metabolism proteins (ferroportin), hypoxia-inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) expression were evaluated. CBD application significantly reduced oxidative stress by improving antioxidant capacity and lowering total oxidant status. CBD also preserved the expression and enzymatic activity of glutathione peroxidase 4, a central enzyme protecting against lipid peroxidation, and enhanced the activation of Nrf2, a key regulator of antioxidant defence. Additionally, CBD prevented OGD-induced downregulation of ferroportin, potentially supporting iron efflux and reducing ferroptotic risk. HIF-1α and its downstream target VEGF were upregulated under hypoxic conditions, and CBD further enhanced VEGF expression. CBD mitigates ferroptosis by modulating redox balance, antioxidant defence, and iron metabolism, supporting its potential role as a therapeutic strategy for neonatal hypoxic-ischemic brain injury.