INTRANASAL LEMON-DERIVED NANOVESICLES AMELIORATE COGNITIVE IMPAIRMENT IN A HIGH-FAT DIET RAT MODEL OF METABOLIC SYNDROME: FOCUS ON MODULATORY HIPPOCAMPAL SIGNALING PATHWAYS

Cognitive dysfunction is a core feature of Metabolic Syndrome (MetS), associated with neuroinflammation, oxidative stress and dysregulated neurotrophic signaling. High-fat diet (HFD) reliably models these brain alterations, affecting cognitive and affective domains, and therefore represents a suitable platform for testing neuroprotective interventions. Among these, industrial lemon-derived nanovesicles (iLNVs) have recently stood out for their potent antioxidant and anti-inflammatory properties in preclinical models. This study aimed to determine whether daily administration of iLNVs intranasally - a brain-targeting delivery route - could serve as a preventive approach in rats fed with HFD for 12 weeks, compared to vehicle-treated HFD rats and normal-fed controls. Cognitive and affective dimensions were evaluated via behavioural tests measuring declarative memory, reactivity and anxiety-like behavior. In parallel, metabolic and biometric biomarkers were monitored as well. Ex-vivo molecular profiling by Western blot and PCR was performed in selected brain regions to assess signaling pathways involved in neuronal plasticity, survival, and inflammation. Our outcomes revealed that iLNV treatment improved dysmetabolism alongside recognition memory index, burrowing behavior and anxiety-like state, suggesting that the treatment effectively prevents the cognitive impairments observed in HFD rats. In the hippocampus of iLNVs-treated HFD rats, we observed increased p-ERK, FGF2 and FASL levels activating Fas-induced non-apoptotic signaling and pro-survival effects. This possibly raises an early modulatory effect of iLNV treatment on molecular signaling pathways involved in cellular responses and neuroplasticity, potentially underlying the observed improvements in cognitive and affective domains. Collectively, these results support intranasal iLNV delivery as a promising approach against MetS-associated cognitive dysfunction.