Methylated urolithin a attenuates lipopolysaccharide-induced memory impairment and behavioral disorders by inhibiting mitochondrial inflammation through the Drp1/HK1/NLRP3 pathway

This study explored the effects of methylated urolithin A (mUro A), on lipopolysaccharide (LPS)-induced cognitive impairment and anxiety- and depression-like behaviors, and their molecular mechanism. mUro A significantly mitigated cognitive dysfunction, anxiety- and depression-like behaviors. Furthermore, mUro A improved activities of antioxidative enzymes, regulated the release of inflammatory factors, inhibited the LPS-induced generation of Aβ 1 – 42 and restored the cholinergic system balance in the AD mouse brain. Additionally, mUro A markedly attenuated microglial activation by inhibiting the Drp1/HK1/NLRP3 pathway, thereby suppressing mitochondrial inflammation. This was evidenced by the downregulation of p-Drp1 (s616), VDACs, NLRP3, ASC, cleaved caspase 1, IL-18, and IL-1β, alongside the upregulation of HK1 expression. In conclusion, mUro A mitigates AD-associated cognitive deficits by inhibiting the Drp1/HK1/NLRP3 pathway and suppressing mitochondrial inflammation. • mUro A mitigated cognitive dysfunction, anxiety- and depression-like behaviors. • mUro A alleviated oxidative stress, regulated the release of inflammatory factors. • mUro A inhibited the generation of Aβ1–42 in LPS-induced mice. • mUro A mitigates AD cognitive deficits by inhibiting the Drp1/HK1/NLRP3 pathway.