Therapeutic effects of zanamivir against L-NAME-induced preeclampsia in mice and network pharmacology analysis.

Since structural and functional damage of endothelial glycocalyx was observed in preeclampsia patients, maintaining the glycocalyx integrity appears to be a potential strategy to treat preeclampsia. Neuraminidase, which degrades the endothelial glycocalyx by stripping sialic acid residues, represents a novel target to restore the integrity of glycocalyx and the normal function of endothelium. Therefore, this work studied the potential effects of zanamivir, a neuraminidase inhibitor, against preeclampsia using a mouse disease model and network pharmacology analysis. Preeclampsia model was established in pregnant CD-1 mice after daily administration of L-NAME from gestational day (GD)8 to GD17. The preeclampsia mice showed hallmarks of disease, including elevated blood pressure, increased urine total protein, and reduced litter size and pup weight. More importantly, zanamivir treatment led to reduction of hypertension, mitigation of proteinuria, and protection of fetus, suggesting its therapeutical effects against preeclampsia. The major mechanisms of zanamivir involved the preservation of glycocalyx integrity and improvement of systemic endothelial function by inhibiting neuraminidase. Further network pharmacology analysis identified 74 potential targets by which zanamivir exerts regulation of preeclampsia pathogenesis. PPI network and clustering, GO annotation, pathway and organ system & cell-type enrichment analysis also supported that regulation of blood pressure was the core biological action of zanamivir in treating preeclampsia. Taken together, the in vivo and in silico findings demonstrated the therapeutic effects of zanamivir against preeclampsia, particularly the regulation of hypertension, the importance of restoring glycocalyx integrity and endothelial function, and the potential of targeting neuraminidase when seeking novel therapies for preeclampsia.