The therapeutic potential of plant-derived flavonoids in neurological disorders through modulation of brain insulin signaling

Brain insulin resistance has emerged as a significant etiological factor in various neurodegenerative disorders (NDs), contributing to pathological hallmarks such as protein aggregation, oxidative stress, and neuroinflammation. This review examines the mechanisms by which distinct flavonoid subclasses – anthocyanins, flavanols, flavanones, and flavonols – from phytochemical extracts enhance neuronal insulin sensitivity and maintain synaptic plasticity to mitigate pathophysiological processes driving NDs. We elucidate key molecular pathways, focusing on insulin-regulated PI3K⁄AKT signaling cascade and its downstream effects on GSK3β activity, autophagy, apoptosis, and neuroinflammation. Furthermore, we evaluate nanoencapsulation technologies as an advanced drug delivery system designed to improve the bioavailability and blood-brain barrier (BBB) permeability of various flavonoids. Overall, plant flavonoids emerge as promising compounds for addressing NDs, particularly when coupled with innovative pharmacokinetic strategies to enhance their efficacy.