J Pharmacol Sci. 2026 Oct;162(2):162-178. doi: 10.1016/j.jphs.2026.07.004. Epub 2026 Jul 23.
ABSTRACT
Friedelin (FD), a natural pentacyclic triterpene, exerts neuroprotective effects, but its role in cerebral ischemic stroke remains unknown. In this study, FD attenuated middle cerebral artery occlusion and reperfusion (MCAO/R)-induced neurological deficits, reduced infarct volume, and inhibited neuronal apoptosis in mice. Additionally, FD suppressed proinflammatory microglial phenotype and proinflammatory cytokine secretion in oxygen-glucose deprivation and reoxygenation (OGD/R)-exposed BV2 cells and in mice after MCAO/R. FD alleviated HT22 cell injury after exposure to conditioned medium from BV2 cells subjected to OGD/R. A mechanistic exploration using network pharmacology and the finding that FD concentration-dependently suppressed nitric oxide (NO) overproduction induced by the Toll-like receptor 4 (TLR4)-specific ligand ultrapure LPS, identified TLR4 as a potential target of FD. FD suppressed proinflammatory microglial phenotype, proinflammatory cytokine secretion and ferroptosis by reducing TLR4 protein expression in mice after MCAO/R and in OGD/R-exposed BV2 cells. Inhibiting ferroptosis in BV2 cells ameliorated OGD/R-induced proinflammatory microglial phenotype and proinflammatory cytokine secretion. Thus, FD alleviated cerebral ischemic injury by repressing proinflammatory microglial phenotype through the regulation of TLR4-induced ferroptosis.
PMID:42632749 | DOI:10.1016/j.jphs.2026.07.004