AMPK/PINK1/Parkin pathway-associated mitochondrial quality control contributes to magnesium sulfate-induced neuroprotection in postoperative cognitive dysfunction

Introduction Postoperative cognitive dysfunction (POCD) is associated with neuroinflammation and mitochondrial dysregulation, but the mechanisms linking these processes remain incompletely defined. We investigated the neuroprotective effects of magnesium sulfate (MgSO₄) and the involvement of AMP-activated protein kinase (AMPK)/PTEN-induced kinase 1 (PINK1)/Parkin signaling in experimental POCD. Methods POCD was induced in mice by open tibial fracture under isoflurane anesthesia, and an in vitro inflammatory model was established in lipopolysaccharide (LPS)-treated BV2 microglia. Behavioral tests, enzyme-linked immunosorbent assay, western blotting, TUNEL staining, JC-1 analysis, and adenosine triphosphate (ATP) measurement were used to assess cognition, inflammatory responses, mitochondrial-related metabolic alterations, and pathway-associated changes. Results MgSO₄ improved postoperative behavioral deficits, reduced hippocampal inflammatory cytokines, normalized microglial activation-associated markers, improved cellular ATP levels and mitochondrial membrane potential alterations, and partially normalized mitochondrial dynamics-related protein changes. POCD or LPS reduced PINK1, Parkin, and LC3-II while increasing p62; MgSO₄ partially reversed these changes. MgSO₄ also restored p-AMPK levels, whereas the pharmacological AMPK inhibitor Compound C partially attenuated the effects of MgSO₄ on PINK1/Parkin signaling, ATP levels, inflammatory responses, mitochondrial markers, and behavioral outcomes. Discussion These findings support a model in which AMPK/PINK1/Parkin-related mitochondrial quality control is involved in the neuroprotective effects of MgSO₄ in experimental POCD.