Myricitrin attenuates hypoxic-ischemia-induced brain injury in neonatal rats by mitigating oxidative stress and nuclear factor erythroid 2-related factor 2/hemeoxygenase-1/antioxidant response element signaling pathway

Background: Neonatal hypoxic ischemia (HI) is an overwhelming infantile neurological disability causing extreme morbidity and mortality with limited therapies available. Objectives: In this study, we aimed to explore the neuroprotective efficacy of myricitrin and elucidate the mechanism of action of myricitrin through the regulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1)/antioxidant response element (ARE)-signaling pathways in neonatal rats. Materials and Methods: Seven-day-old neonatal rats were divided into four groups. Sham group served as the control group. After inducing HI through standard operation procedure, two groups of neonatal rats were intraperitoneally administered with 20 and 40 mg/kg bw of myricitrin twice a day for up to 1 week. At the end of the experiment, we assessed the brain infract area, edema, and motor coordination activity by using Rota Rod test. Furthermore, we measured the level of antioxidant enzymes and oxidative stress markers in the brain tissue samples. Real-time quantitative polymerase chain reaction was conducted to detect the inflammatory molecules expression including HO-1 being the activator of Nrf2 where further mediates the transcriptional activation of ARE. Subsequently, the hypothesis was further confirmed by the immunosorbent assay and Western blot analysis. Results: Myricitrin administration ameliorated HI-induced increase in infract volume and edema of the brain, as well as improved neurobehavioral impairments. Interestingly, myricitrin significantly reduced the level of nuclear factor kappa B (NF-κB) p65 and reduced the levels of nuclear fraction of Nrf2-ARE and cytosolic fraction of HO-1 enzyme activation. Conclusion: In summary, myricitrin improved the antioxidant defense mechanism and ameliorated the oxidative stress-associated neurological damage via modulating Nrf2/ARE-dependent HO-1 pathway in neonatal rats.