Background: Subarachnoid hemorrhage (SAH) is a cerebrovascular disease with high mortality and long-term neurological sequelae, largely driven by early brain injury, inflammation, neuronal apoptosis, and oxidative stress. Umbelliferone (7-hydroxycoumarin) exhibits notable antioxidant and anti-inflammatory properties. This study aimed to investigate the neuroprotective effect of umbelliferone in a mouse model of SAH and explore the underlying mechanisms. Materials and Methods: Following SAH induction, mice received the oral administration of umbelliferone (2.5, 5, or 10 mg/kg). Body weight, brain weight, and brain water content were measured to assess cerebral edema and neurological injury. Tight junction protein levels were quantified to assess blood brain barrier (BBB) integrity; meanwhile, antioxidant markers, inflammatory cytokines, and apoptosis-related parameters were also evaluated. Furthermore, mRNA expression levels in brain tissue were analyzed to elucidate the underlying molecular mechanisms. Results: Umbelliferone significantly improved body weight and enhanced brain weight (p < 0.001). Umbelliferone also altered the level of tight junction parameters (occludin, claudin-5, zonula occludens-1 (ZO-1)); oxidative stress parameters (glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), malonaldehyde (MDA)); mitogen-activated protein kinase (MAPK) parameters (phosphorylated c-Jun N-terminal kinase(p-JNK), phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated p38 MAPK (p-38)); inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18)); inflammatory parameters (cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), transforming growth factor-β (TGF-β)); apoptosis parameters (Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), caspase-3, Bax/Bcl-2 ratio). Umbelliferone also significantly (p < 0.001) altered the mRNA expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), basigin (BSG2), TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), claudin-5, occludin, phosphoinositide 3-kinase (PI3K), protein kinase B (AkT), toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4). Conclusion: Umbelliferone exerts neuroprotective effects against SAH in mice, at least in part, by modulating the TLR2/TLR4–NF-κB–MMP-9 and PI3K/Akt signaling pathways.
Zhao et al. (Thu,) studied this question.