Sex- and cell type-specific effects of dexmedetomidine on ferroptosis in neurons and microglia following traumatic brain injury in juvenile mice

Ferroptosis plays a key role in neuronal death and functional outcomes following traumatic brain injury (TBI). While TBI affects diverse cell types in injured brain regions, the sex- and cell type-specific responses to ferroptosis during the acute phase in the immature brain remain poorly understood. Dexmedetomidine (DEX), a selective alpha-2 adrenergic receptor agonist, has been shown to reduce inflammation and improve survival outcomes in TBI patients, but its sex- and cell type-specific effects on ferroptosis are unclear. This study investigated whether TBI induces sex- and cell type-specific ferroptotic responses and examined the effects of DEX during the acute post-injury phase in a juvenile mouse model. By concurrently isolating neurons and microglia from the same animals, we demonstrate that TBI prompts distinct sex- and cell type-specific ferroptosis responses, including differential regulation of genes involved in iron and lipid metabolism, oxidative stress, and proinflammatory pathways in neurons and microglia. DEX treatment significantly improved behavioral outcomes and reduced iron overload, lipid peroxidation, and neuroinflammation, thereby decreasing ferroptosis in both neurons and microglia. However, its effects were less prominent in neurons from female mice. Further analysis indicated that these sex- and cell type-specific responses to DEX may be partially due to differences in alpha-2 adrenergic receptor expression in neurons and microglia following TBI. Overall, our findings offer new insights into the mechanisms underlying sex- and cell type-specific responses to ferroptosis and DEX treatment, highlighting the broader implications for lipid metabolism, oxidative stress, and inflammation in the immature brain during the acute phase after TBI.