Hypoxic-ischemic (HI)
encephalopathy is a leading cause of dire mortality and morbidity in neonates. Unfortunately, no effective
therapies have been developed as of yet. Oxidative stress plays a critical role in pathogenesis and progression of neonatal HI. Previously, as a Nrf2 activator,
tert-butylhydroquinone (
TBHQ) has been demonstrated to exert neuroprotection on
brain trauma and
ischemic stroke models, as well as oxidative stress-induced cytotoxicity in neurons. It is, however, still unknown whether
TBHQ administration can protect against oxidative stress in neonatal HI
brain injury. This study was undertaken to determine the
neuroprotective effects and mechanisms of
TBHQ post-treatment on neonatal HI brain damage. Using a neonatal HI rat model, we demonstrated that
TBHQ markedly abated oxidative stress compared to the HI group, as evidenced by decreased oxidative stress indexes, enhanced Nrf2 nuclear accumulation and
DNA binding activity, and up-regulated expression of Nrf2 downstream antioxidative genes. Administration of
TBHQ likewise significantly suppressed reactive
gliosis and release of inflammatory
cytokines, and inhibited apoptosis and neuronal degeneration in the neonatal rat cerebral cortex. In addition,
infarct size and neuronal damage were attenuated distinctly. These beneficial effects were accompanied by improved neurological reflex and motor coordination as well as amelioration of spatial learning and
memory deficits. Overall, our results provide the first documentation of the beneficial effects of
TBHQ in neonatal HI model, in part conferred by activation of Nrf2 mediated antioxidative signaling pathways.