Magnolin and Lanosterol in WenYangTongbi pill-mediated Foxs1-Nlrp3 axis suppression alleviates chronic sleep deprivation-induced cognitive impairment.

BACKGROUND

Chronic sleep deprivation (CSD) impairs cognitive function, yet current therapeutic options remain limited. Evidence suggests CSD induces cognitive deficits through both central and peripheral mechanisms. The WenYang Tongbi (WYT) pill, composed of five herbs and Hirudo nipponica Whitman, has the potential on both improving nerve injury and peripheral homeostasis. Here, we hypothesized that the WYT pill can ameliorate related cognitive impairment and investigate its mechanism through a CSD mouse model.

PURPOSE: This work was designed to evaluate the therapeutic potential of WYT against CSD-related cognitive deficits, and to reveal its pharmacological mechanisms.

METHODS

We assessed the effects of the WYT pill on CSD mice through behavioral tests and histological examination. Furthermore, we employed multi-omics analyses, ChIP-qPCR, dual-luciferase reporter assay, cell thermal shift assay, etc. to elucidate its pharmacological mechanisms.

RESULTS

WYT pill protected against CSD-induced cognitive impairment, reduced multiple nerve injuries and microglial pyroptosis in the prefrontal cortex (PFC). Mechanically, we found that WYT inhibits microglial pyroptosis through the Nlrp3/Caspase-1/Gsdmd pathways by inhibiting Foxs1, a transcription factor of Nlrp3. Magnolin and Lanosterol in WYT were identified as the main contributors, and were further verified in animal experiments. WYT also improved the multiple organ injury, disorder of blood metabolism, and restored the level of 1-methylhistidine. Supplement with 1-methylhistidine improve the peripheral disorder in CSD mice. Finally, 16S sequencing results showed that WYT restored the diversity of the gut microbiota.

CONCLUSION

The present study demonstrates that WYT improves CSD-induced cognitive impairment by inhibiting Foxs1-mediated microglial pyroptosis and restoring peripheral 1-methylhistidine levels.