Alpha‐Lipoic Acid Alleviates Isoflurane‐Induced Cognitive Dysfunction in Juvenile Mice by Activating Peroxisome Proliferator Activated Receptor Gamma Coactivator ‐1 Alpha

ABSTRACT Millions of children undergo general anesthesia annually, yet preclinical studies suggest early life exposure to anesthetics may disrupt central nervous system development and impair cognition. Effective neuroprotective strategies remain limited. α‐Lipoic acid (ALA), a dietary antioxidant found in red meat and carrots, has demonstrated therapeutic potential in diabetic neuropathy, but its role in anesthesia‐induced neurotoxicity is unclear. This study integrates mechanistic and functional analyses to evaluate ALA's neuroprotective effects. Isoflurane‐exposed neonatal mice exhibited hippocampal metabolic dysregulation, with altered lactate, pyruvate, and adenosine triphosphate (ATP) levels, leading to cognitive dysfunction. Mechanistically, isoflurane suppressed peroxisome proliferator activated receptor gamma coactivator ‐1 alpha ( PGC‐1α ), a key regulator of mitochondrial metabolism in astrocytes. Using in vitro models and in vivo cyclization recombinase (Cre)‐lentivirus (LV)‐mediated PGC‐1α overexpression, we identified a PGC‐1α ‐dependent pathway regulating pyruvate dehydrogenase (PDH) and lactate dehydrogenase B (LDHB), restoring astrocytic bioenergetics. Functionally, ALA supplementation not only activated PGC‐1α but also provided direct metabolic substrates for PDH, enhancing mitochondrial function and reversing cognitive deficits. High‐performance liquid chromatography revealed reduced endogenous ALA levels in isoflurane‐exposed hippocampi, whereas dietary ALA restored its physiological concentration. This dual mechanism— PGC‐1α activation and metabolic substrate provision—supports ALA's role in both mechanistic restoration and functional recovery. These findings provide the first evidence that dietary ALA supplementation mitigates anesthesia‐induced neurotoxicity via PGC‐1α ‐mediated metabolic reprogramming, highlighting its potential as a perioperative dietary intervention to reduce neurodevelopmental risks in pediatric populations.