Ursolic Acid Alleviates Neuroinflammation after Intracerebral Hemorrhage by Mediating Microglial Pyroptosis via the NF-κB/NLRP3/GSDMD Pathway

Abstract

The neuroinflammatory response after intracerebral hemorrhage (ICH) causes a large amount of neuronal loss, and inhibiting the inflammatory response can improve the prognosis. In previous laboratory studies and clinical trials, ursolic acid (UA) inhibited the inflammatory response, but whether it can be administered to inhibit the neuroinflammatory response after cerebral hemorrhage is unknown. The aim of this study was to investigate the effects of ursolic acid after cerebral hemorrhage. Online databases were used to obtain potential therapeutic targets of ursolic acid for the treatment of cerebral hemorrhage, and possible mechanisms were analyzed by KEGG, GO, and molecular docking. A rat model of cerebral hemorrhage was established using collagenase, and an in vitro cerebral hemorrhage model was constructed by adding hemin to BV2 cell culture medium. Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), immunofluorescence, TUNEL staining, and calcein/PI staining were used to investigate the degree of microglial M1 polarization, changes in the levels of inflammatory factors, activation of the NF-κB pathway, and changes in the indicators of cellular death after ursolic acid treatment. In addition, phorbol 12-myristate 13-acetate (PMA) was used to activate the NF-κB pathway to verify that ursolic acid exerts its anti-neuroinflammatory effects by regulating the NF-κB/NLRP3/GSDMD pathway. Network pharmacology and bioinformatics analyses revealed that ursolic acid may exert its therapeutic effects on cerebral hemorrhage through multiple pathways. Together, in vivo and in vitro experiments showed that ursolic acid inhibited microglial M1 polarization and significantly reduced the levels of p-NF-κB, GSDMD-N, cleaved caspase-1, TNF-α, IL-6, and IL-1β, which were significantly inhibited by the use of PMA. Ursolic acid inhibits microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway to alleviate neuroinflammatory responses after cerebral hemorrhage.

Metabolomic Profiling and In Vivo Antiepileptic Effect of Zygophyllum album Aerial Parts and Roots Crude Extracts against Pentylenetetrazole-Induced Kindling in Mice

“…This is consistent with the current findings, which show that, when compared to the PTZ group, the groups pretreated with either the aerial part or the root extract of Z. album showed a significant inhibition in the NLRP3 inflammasome pathway and significantly downregulated NLRP3 , TXNIP and caspase-1 expression, along with reduced levels of IL-1β and IL-18. Indeed, NLRP3 inflammasome inactivation has been reported to be a potential mechanism of action of various compounds found in Z. album extract [ 71 , 72 , 73 , 74 , 75 ]. A better outcome has been observed with aerial part extract than the root extract.…”

Circular RNA DLGAP4 Inhibits Ischemic Stroke-Induced Microglia M1 Polarization and Proinflammatory Cytokine Production, Possibly through the NF-κB Pathway

“…These findings suggested that circ_DLGAP4 might inactivate the NF-κB pathway to inhibit OGD/R-induced microglia M1 polarization and proinflammatory cytokine production, but promote microglia M2 polarization and anti-inflammatory cytokine production. However, according to previous studies, PMA is an NF-κB pathway activator, as well as a microglia M1 polarization stimulator (Jin et al 2021;Kushwah et al 2022;Lei et al 2023). Therefore, the reversal of circ_DLGAP4' impact on microglia polarization and inflammatory cytokine production by PMA might not be exclusively attributed to the activation of the NF-κB pathway.…”

IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

“…NF-κB can promote the transcription of NLRP3, leading to the occurrence of pyroptosis [17]. NF-κB is involved in the pathophysiology of various central nervous system diseases, including epilepsy [18] and brain hemorrhage [19]. However, whether IRAK4 in epilepsy can act through the activation of the NF-κB/NLRP3 pathway is still unknown.…”