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

The metabolic syndrome (MS) is a disorder characterized by metabolic disfunctions, but also memory impairment. However, the neurobiological mechanisms underlying MS-related cognitive deficits are not clear. Scientific evidence has demonstrated an involvement of N-acylethanolamides (NAEs), molecules structurally related to endocannabinoids, with which they share the inactivation by the fatty acid amide hydrolase enzyme (FAAH). The present study aims at investigating the therapeutic potential of the FAAH inhibitor URB597, which increases endogenous NAEs levels, on MS-related cognitive disorders. Sprague-Dawley rats were fed ad libitum with standard diet (CTRL) or high fat (60% Kcal from fat) and high carbohydrate (sucrose solution 20% w/v) diet (HF/HC), from postnatal day 28 until the end of the experiment. Animals were treated chronically with URB597 (0.1 mg/Kg), by daily intranasal administration. Our results demonstrated that HF/HC diet induced an increase of weight, body mass index and triglycerides. Furthermore, the HF/HC group showed spatial memory impairment in the Morris water maze task and short-term recognition memory deficits in the object recognition task. URB597 administration was able to counteract the recognition deficit effects but not the spatial ones. These findings introduce a potential therapeutic treatment to attenuate MS-related cognitive deficits.