Protective Effects of 3,4-Dihydropyrimidin-2(1 <i>H</i> )-one Derivatives on Oxidative Stress Injury following Subarachnoid Hemorrhage

)-one derivatives (DHPMs) against neural dysfunction and EBI in a murine SAH model, compared with edaravone (EDA). We hypothesized that DHPMs alleviate SAH-induced neurological damage, dysfunction, and apoptosis through scavenging excess reactive oxygen species (ROS) generated post-SAH, a mechanistic premise systematically validated through experimental analyses. We hypothesized that male C57BL/6 mice weighing between 22 g and 30 g were arbitrarily classified into one of seven cohorts: sham, SAH, SAH + vehicle, SAH + DHPMs 50 mg/kg, SAH + DHPMs 300 mg/kg, SAH + DHPMs 500 mg/kg, and SAH + EDA 10 mg/kg. The intravascular threading method was utilized to induce SAH in the mice. DHPMs were intraperitoneally administered at 50 mg/kg, 300 mg/kg, and 500 mg/kg 15 min after SAH, while EDA was intraperitoneally provided at 10 mg/kg. The modified Garcia score (MGS) and balance beam test (BBT) were employed for behavioral activity assessment at 24 h and 72 h post-SAH, with neurological scores recorded for mice. Subsequently, mice were euthanized to evaluate SAH grade and severity, followed by determination of the optimal drug dosage according to the group exhibiting the most significant behavioral improvement. We computed the brain water content using the dry and wet protocol 24 h post-SAH, while Evans blue was employed to assess BBB leakage. Using Western blot, we also detected pathway-associated proteins, inflammation-related proteins, apoptosis-related proteins, and tight junction (TJ) proteins at the protein level in experimental SAH in mice. Frozen brain tissue sections of mice were prepared for immunofluorescence (IF) staining to observe the changes of microglia, astrocytes, and neurons before and after SAH administration in mice. Our experiment found that the intervention of 300 mg/kg DHPMs after SAH could improve the neurological score of mice, similar to the effects observed with EDA 10 mg/kg intervention. Additionally, DHPMs intervention was found to reduce brain edema and BBB damage 24 h post-SAH, surpassing the efficacy of EDA. Furthermore, the administration of 300 mg/kg DHPMs was linked to augmented Nrf2, apoptosis proteins Bax, Caspase-3, CHOP-1, inflammation proteins interleukin (IL)-1β, IL-18, TJ proteins Occludin, claudin-5, and zonulaoccludens-1 (ZO-1) protein expressions, and diminished heme oxygenase 1 (HO-1) and apoptosis protein Bcl-2 protein expressions. We demonstrated that DHPMs have the potential to safeguard neurological function, mitigate brain edema and BBB disruption, and alleviate OS, inflammation, and apoptosis following SAH.