Abstract

Background Postoperative cognitive dysfunction (POCD) is a frequent neurological complication characterized by memory and learning impairments in the elderly, while effective pharmacological interventions remain limited. Palmitoylethanolamide (PEA), an endogenous lipid mediator with anti-inflammatory and neuroprotective properties, has emerged as a potential therapeutic candidate. Methods An aged mouse model of POCD was used to evaluate the effects of PEA. Cognitive performance was assessed by the open field test, novel object recognition, and Barnes maze. Neuroinflammation, microglial activation, neuronal integrity, and synaptic plasticity–related proteins were assessed using immunostaining and molecular analyses both in vivo and in vitro. To determine the role of peroxisome proliferator-activated receptor-α (PPARα), stereotaxic delivery of shPPARα virus to prefrontal cortex (PFC) microglia was performed. Results PEA treatment significantly improved both short- and long-term memory in aged POCD mice. Mechanistically, PEA attenuated microglial activation, shifted microglial activation toward the anti-inflammatory phenotype, preserved neuronal survival, and upregulated synaptic plasticity-associated proteins. Importantly, PEA restored PPARα activity, and knockdown of PPARα abolished these protective effects both in vivo and in vitro, confirming its essential role. Conclusions PEA alleviates cognitive deficits in aged POCD mice by enhancing PPARα signaling, reducing neuroinflammation, and promoting neuronal protection. These findings support PEA as a promising therapeutic strategy for the treatment of aged POCD.