Flavonoid‐Rich Ethanol Extract from the Leaves of Diospyros kaki Attenuates D‐Galactose‐Induced Oxidative Stress and Neuroinflammation‐Mediated Brain Aging in Mice

Aging is a major factor that contributes to neurological impairment and neuropathological changes, such as inflammation, oxidative stress, neuronal apoptosis, and synaptic dysfunction. Flavonoids act as protective antioxidant and anti‐inflammatory agents against various age‐related neurodegenerative diseases. Here, we investigated the protective effect and mechanisms of the flavonoid‐rich ethanol extract from the leaves of Diospyros kaki (FELDK) in the cortex and hippocampus of D‐galactose‐ (gal‐) aged mice. Our results showed that FELDK treatment restored memory impairment in mice as determined by the Y‐maze and Morris water maze tests. FELDK decreased oxidative stress levels via inhibiting reactive oxygen species (ROS) and malondialdehyde (MDA) production and elevating antioxidative enzymes. FELDK also alleviated D‐gal‐induced neuroinflammation via suppressing the expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) and activating microgliosis and astrocytosis, nuclear factor kappa B (NF‐κB) nuclear translocation, and downstream inflammatory mediators. Moreover, FELDK inhibited the phosphatidylinositol 3‐kinase (PI3K)/Akt and C‐jun N‐terminal kinase (JNK) apoptotic signaling pathways and ameliorated the impairment of synapse‐related proteins. Hence, these results indicate that FELDK exerts neuroprotective effects on D‐gal‐induced brain aging. Thus, FELDK may be a potential therapeutic strategy for preventing and treating age‐related neurodegenerative diseases such as Alzheimer’s disease.