Flavonols as a Potential Pharmacological Intervention for Alleviating Cognitive Decline in Diabetes: Evidence from Preclinical Studies.

Diabetes mellitus is a complex metabolic disease associated with reduced synaptic plasticity, atrophy of the hippocampus, and cognitive decline. Cognitive impairment results from several pathological mechanisms, including increased levels of advanced glycation end products (AGEs) and their receptors, prolonged oxidative stress and impaired activity of endogenous mechanisms of antioxidant defense, neuroinflammation driven by the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), decreased expression of brain-derived neurotrophic factor (BDNF), and disturbance of signaling pathways involved in neuronal survival and cognitive functioning. There is increasing evidence that dietary interventions can reduce the risk of various diabetic complications. In this context, flavonols, a highly abundant class of flavonoids in the human diet, are appreciated as a potential pharmacological intervention against cognitive decline in diabetes. In preclinical studies, flavonols have shown neuroprotective, antioxidative, anti-inflammatory, and memory-enhancing properties based on their ability to regulate glucose levels, attenuate oxidative stress and inflammation, promote the expression of neurotrophic factors, and regulate signaling pathways. The present review gives an overview of the molecular mechanisms involved in diabetes-induced cognitive dysfunctions and the results of preclinical studies showing that flavonols have the ability to alleviate cognitive impairment. Although the results from animal studies are promising, clinical and epidemiological studies are still needed to advance our knowledge on the potential of flavonols to improve cognitive decline in diabetic patients.