Black rice anthocyanin extract alleviates cognitive impairment by regulating the MAPK/NF-κB/Nrf2 pathways and modulates gut microbiota dysbacteriosis in D-galactose induced mice

Anthocyanins are a plant active ingredient in black rice. Here, we used black rice anthocyanin extract (BRAE) as the object of study and explored its protective mechanism against age-related cognitive decline. Briefly, C57BL/6J mice were fed a purified diet containing BRAE and injected with D-galactose (120 mg/kg) for 24 weeks. The results indicated that BRAE retarded cognitive decline, mitigated the degree of morphological lesions in the hippocampus, restored the levels of brain-derived neurotrophic factor (BDNF) and neurotransmitters, enhanced the antioxidant capacity of brain tissue, reduced the contents of proinflammatory factors, inhibited dysbacteriosis. Spearman’s rank correlation analysis indicated a positive correlation between alterations in gut microbiota and the antioxidant capacity of brain tissue, as well as a negative correlation between changes in gut microbiota and the severity of inflammation in brain tissue. Importantly, the hyperphosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase (ERK1/2 MAPK) was weakened by BRAE in the brain. Meanwhile, BRAE inhibited the protein degradation of inhibitor of nuclear factor κB α (IκBα) and the expression of nuclear factor κB (NF-κB) along with its downstream genes, upregulated the expression of nuclear factor E2 related factor 2 (Nrf2) and its downstream genes. Furthermore, molecular docking showed that differential metabolites of brain could bind to the IκBα/NF-κB complex, suppressing the dissociation of the IκBα/NF-κB complex, which is composed of p65, p50, and IκBα. Therefore, these results suggest that BRAE may exert anti-inflammatory and antioxidant effects on aging brain via the MAPK/NF-κB/Nrf2 pathways, as well as through the inhibition of dysbiosis.