Idebenone Orchestrates Anti-Inflammatory and Antioxidant Responses to Alleviate Brain Injury After Intracerebral Hemorrhage in Mice.

BACKGROUND

Intracerebral hemorrhage (ICH) is a critical form of stroke with limited treatment options, with secondary brain injury significantly affecting patient outcomes. This study investigated the neuroprotective benefits of idebenone (IDE) in ICH.

METHODS

An ICH model was established in mice and the temporal progression of oxidative stress and neuroinflammation was evaluated. IDE was then administered intraperitoneally for 3 consecutive days to evaluate its therapeutic effects. Tissue histology was examined after staining with hematoxylin-eosin and TdT-mediated dUTP nick end labeling (TUNEL), while oxidative stress was assessed by western blotting and measurement of malondialdehyde (MDA) levels and neuroinflammation was examined using immunostaining, western blotting, and enzyme-linked immunosorbent assay (ELISA).

RESULTS

Oxidative stress and neuroinflammation peaked at 3 days post-ICH, with elevated levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and significant microglial activation. IDE-treated mice had reduced hematoma volumes and improved neurological outcomes. IDE administration decreased Kelch-like ECH-associated protein 1 (Keap1) expression while increasing Nrf2 and NAD(P)H quinone oxidoreductase 1 (NQO1) levels, leading to reduced oxidative damage (p < 0.01, p < 0.05, and p < 0.05, respectively). Moreover, IDE attenuated microglial activation and neutrophil recruitment (p < 0.01, p < 0.01), reduced the levels of matrix metalloproteinase-9 (MMP-9), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels (p < 0.05, p < 0.05, and p < 0.05, respectively), and increased IL-10 expression (p < 0.01). IDE also preserved the integrity of the blood-brain barrier (BBB) and reduced brain edema.

CONCLUSIONS

The results demonstrated that IDE exerts neuroprotective effects in ICH through the mitigation of oxidative stress and neuroinflammation during the acute injury phase. IDE may be a viable therapeutic intervention for ICH.