Dexmedetomidine protects against cerebral ischemia-reperfusion injury in mice by interfering with the crosstalk between autophagy and ferroptosis.

Abstract

OBJECTIVE: Previous studies show DEX protects against focal cerebral ischemia by hindering autophagy. However, the exact mechanisms are unclear. This study hypothesizes DEX may protect neurons by regulating the crosstalk between autophagy and ferroptosis. METHODS: In this study, male C57/BL6 mice were used in an MCAO model divided into five groups. After MCAO and reperfusion, treatments with DEX, DEX+Erastin, or DEX+rapamycin were administered. Neurological deficits and cerebral infarction volumes were measured 24&#x2009;hours later. Electron microscopy and molecular techniques were used to analyze autophagy and ferroptosis markers to explore DEX's neuroprotective mechanism. RESULTS: Compared to sham controls, the model group showed significantly increased cerebral infarction volume and neurobehavioral scores (&#x2009;<&#x2009;0.05). DEX treatment reversed these effects, demonstrating neuroprotection against ischemic injury. Simultaneously, DEX treatment safeguards mitochondrial integrity by suppressing autophagy lysosomes. It also upregulates the expression of glutathione (GSH) protein, solute carrier family 7 member 11 (SLC7A11) protein, and glutathione peroxidase 4 (GPX4). Moreover, DEX inhibits the levels of malondialdehyde (MDA), ferrous ion (Fe2+), microtubule-associated protein 1A/1B-light chain 3 (LC3), and Beclin1 proteins (allvalues&#x2009;<&#x2009;0.05), thereby intervening in the crosstalk between the autophagy and ferroptosis pathways and ultimately exerting its neuroprotective function. Notably, DEX's effects were negated by ferroptosis inducer Erastin or autophagy inducer RAPA. CONCLUSION: Dexmedetomidine modulates the crosstalk between autophagy and ferroptosis pathways, thereby protecting the mouse brain against ischemia-reperfusion injury and providing novel insights for the future treatment of ischemic stroke.