Chronic intranasal URB597 treatment reverts short-term memory deficits in a rat model of metabolic syndrome

AIMS: Metabolic syndrome (MetS) is characterized by several metabolic alterations that may increase the risk of memory alterations. While metabolic consequences of MetS are well documented, its memory impact remains underexplored. This study aimed at investigating the progression of MetS-associated impairments and evaluating the therapeutic potential of URB597, a fatty-acid amide hydrolase inhibitor, that increases the N-acylethanolamine levels. MATERIALS AND METHODS: In Experiment 1, male Sprague-Dawley rats were fed a control (CTRL), high-fat (HF), high-carbohydrate (HC), or combined HF/HC diet for 12 weeks to identify the most effective model of MetS-induced metabolic and memory changes. In Experiment 2, rats received intranasal URB597 (0.1 mg/kg) for 10 weeks following the HF/HC diet to assess its therapeutic impact. Body weight, body mass index (BMI), and triglycerides were measured; memory function was assessed using the Object Recognition, Morris Water Maze, and Y-maze tasks. KEY FINDINGS: Results from Experiment 1 showed that the HF/HC diet induced metabolic dysfunctions and impairments in both recognition and long-term spatial memory, while short-term spatial memory remained intact. In Experiment 2, the prolonged diet reproduced the same metabolic and memory deficits observed in Experiment 1, and URB597 treatment reversed recognition memory impairments but did not improve spatial memory performance, suggesting a domain-specific vulnerability to MetS and to the treatment response. SIGNIFICANCE: These findings highlight memory deficits associated with MetS and point to N-acylethanolamine signaling as a potential modulatory pathway, with URB597 serving as a pharmacological tool to investigate its therapeutic relevance.