Targeting LPS‑induced Neuroinflammation with Puerarin: Mechanistic Insights into the TLR4/NF-κB/NLRP3/IL-1β Pathway

Puerarin (Pur), a famous isoflavonoid, can be used in the regulation of many biological and clinical conditions. However, its role in protecting against LPS-induced neuroinflammation is still unclear. This study supposed to assess the protective effect of Pur against LPS-induced hippocampal inflammation. The study included three groups of mice: Control group (n=6), LPS group (n=6), and LPS + Pur group. In the LPS group, there was a marked increase in the time to reach the target box (TTB) and WME and RME compared to control mice, indicating impaired spatial memory and learning. This was also reflected in the histological picture of hippocampal neuronal damage. Additionally, LPS induced a classic picture of hippocampal oxidative stress, evidenced by elevated MDA levels and depletion of GSH and GPx. Moreover, LPS caused neuroinflammation, as shown by increased protein levels of hippocampal TLR4 and NF-κB, along with the consequent secretion of IL-1β, TNF-α, IL-6. Furthermore, intraperitoneal injection of LPS significantly increased the levels of pyroptotic markers (NLRP3, caspase-1, IL-1β, IL-18, GSDMD) compared to normal mice. Meanwhile, oral intake of Pur improved the cognitive functions of LPS-treated mice by decreasing memory impairment parameters. These protective effects are attributed to its preservation of hippocampal neuron structure, its antioxidant properties, and its inhibition of LPS-activated TLR4/NF-κB and NLRP3/IL-1β pathways, thereby reducing hippocampal inflammation and pyroptosis. Overall, we can conclude that Pur has the ability to mitigate the negative impact of LPS on memory function in mice through its anti-inflammatory effects.