Mol Neurobiol. 2026 Oct 29;63(1):999. doi: 10.1007/s12035-026-06289-7.
ABSTRACT
Intracerebral hemorrhage (ICH) is a devastating stroke with limited therapies. This study investigated the neuroprotective effects of farrerol after ICH and the contribution of Nrf2 signaling. ICH was induced by autologous blood injection in wild-type and Nrf2-knockout mice studied in separate cohorts. Complementary experiments used hemin-exposed HT-22 cells, with vehicle and sulforaphane controls included in the ML385 inhibition experiments. In wild-type mice, farrerol improved neurological function and reduced brain edema, neuronal injury, glial reactivity, and circulating pro-inflammatory cytokine levels. These improvements were accompanied by reduced hippocampal Keap1 abundance, increased Nrf2, HO-1, and NQO1 expression, and reduced TLR4/NF-κB pathway activation. Transcriptomic analysis suggested reduced NF-κB-related transcriptional activity, although this enrichment did not remain significant after multiple-testing correction. Farrerol did not significantly improve the assessed functional or inflammatory outcomes in Nrf2-knockout mice, although the separate-cohort design limits comparisons between genotypes. In HT-22 cells, farrerol improved viability, promoted Nrf2 nuclear accumulation, reduced Keap1 abundance, and increased HO-1 and NQO1 expression, alongside reductions in TLR4 expression and the p-p65/p65 ratio. Significant farrerol × ML385 interactions for cell viability, Nrf2 nuclear accumulation, and Keap1 abundance provided further support for Nrf2 involvement in cytoprotection. However, interactions for TLR4 expression and the p-p65/p65 ratio were not significant, leaving the contribution of Nrf2 to these signaling changes unresolved. Together, these findings demonstrate protective effects of farrerol after ICH in mice and support a contribution of Nrf2 to its cytoprotective activity, providing a basis for further preclinical investigation.
PMID:42955569 | DOI:10.1007/s12035-026-06289-7