Region-Dependent Responses to Oxygen–Glucose Deprivation and Melatonin in Neonatal Brain Organotypic Slices

Hypoxic-ischemic encephalopathy remains a major cause of neonatal mortality and long-term neurological disability. Therapeutic hypothermia is currently the only available treatment in hospitals, but its efficacy is limited, making the search for alternative neuroprotective strategies essential. Melatonin has shown promising results in other models of hypoxia-ischemia, acting as a potent antioxidant and anti-inflammatory molecule. Here, we studied the effects of hypoxia-ischemia and melatonin treatment in two brain regions that are particularly vulnerable to hypoxic-ischemic injury. Neonatal rat organotypic slice cultures from the corticostriatal and hippocampal regions were subjected to oxygen-glucose deprivation and reperfusion (OGDR) and treated with melatonin (50 μM). Cell death (propidium iodide staining), redox state (GSH/GSSG ratio) and the inflammatory profile (Proteome Profiler) were analyzed. OGDR markedly increased cell death in both regions and melatonin treatment significantly reduced it. The GSH/GSSG ratio decreased only in the hippocampus after OGDR, but melatonin treatment elevated this ratio in both regions. In contrast, the inflammatory profile was more pronounced in the corticostriatal region, where the treatment strongly reduced proinflammatory mediators. These findings reveal region-specific mechanisms involved in the response to hypoxic-ischemic damage and support the potential of melatonin as a promising therapy for neonatal brain injury.