Tert-butylhydroquinone post-treatment attenuates neonatal hypoxic-ischemic brain damage in rats

Abstract

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.

Photobiomodulation Therapy Attenuates Hypoxic-Ischemic Injury in a Neonatal Rat Model

“…Evidence has accumulated, from our studies and others, which suggests that neonatal hypoxia-ischemia injury induces long-lasting oxidative stress, a process exacerbated by mitochondrial dysfunction (Odorcyk et al, 2017; Zhang et al, 2018). The positive effect of PBM treatment on mitochondrial function demonstrated above leads us to hypothesize that HI-triggered oxidative damage to cellular components in neonatal rats may be attenuated by PBM intervention.…”

LncRNA MIAT overexpression reduced neuron apoptosis in a neonatal rat model of hypoxic-ischemic injury through miR-211/GDNF

“…Treatment of levetiracetam reduced the number of apoptotic neurons thus to play a neuroprotective role in neonatal rats with HI injury [31]. Tert-butylhydroquinone post-treatment inhibited apoptosis and neuronal degeneration, suppressed inflammatory cytokines, and abated oxidative stress in the cerebral cortex of neonatal rat [32]. miR-592-5p overexpression decreased the apoptosis rate of hippocampal neuronal cells and protected against HI brain injuryinduced hippocampal neuronal injury [33].…”

Nrf2 Activation Provides Atheroprotection in Diabetic Mice Through Concerted Upregulation of Antioxidant, Anti-inflammatory, and Autophagy Mechanisms

“…Indeed, tBHQ treatment suppresses ischemia and reperfusion injury in brain ( Shih et al, 2005 ; Hou et al, 2018 ; Xu et al, 2018 ) and kidney ( Guerrero-Beltrán et al, 2012 ). Neuroprotective actions have been also reported in experimental models of traumatic brain injury ( Saykally et al, 2012 ; Chandran et al, 2017 ), Alzheimer’s disease ( Akhter et al, 2011 ), and neonatal hypoxic-ischemic brain damage ( Zhang et al, 2018 ). Moreover, tBHQ ameliorates overload-induced cardiac dysfunction by suppressing apoptosis and promoting autophagy ( Lin et al, 2014 ; Zhang et al, 2015 ), and also improves angiogenesis and heart function in a model of myocardial infarction ( Zhou et al, 2017 ).…”