Sequential Upregulation of Superoxide Dismutase 2 and Heme Oxygenase 1 by tert-Butylhydroquinone Protects Mitochondria during Oxidative Stress

Abstract

Oxidative stress is linked to mitochondrial dysfunction in aging and neurodegenerative conditions. The transcription factor nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) regulates intracellular antioxidative capacity to combat oxidative stress. We examined the effect of tertbutylhydroquinone (tBHQ), an Nrf2-ARE signaling pathway inducer, on mitochondrial function during oxidative challenge in neurons. tBHQ prevented glutamate-induced cytotoxicity in an HT-22 neuronal cell line even with an 8-hour exposure delay. tBHQ blocked glutamate-induced intracellular reactive oxygen species (ROS) and mitochondrial superoxide accumulation. It also protected mitochondrial function under glutamate toxicity, including maintaining mitochondrial membrane potential, mitochondrial Ca 21 hemostasis, and mitochondrial respiration. Glutamate-activated, mitochondria-mediated apoptosis was inhibited by tBHQ as well. In rat primary cortical neurons, tBHQ protected cells from both glutamate and buthionine sulfoximine toxicity. We found that tBHQ scavenged ROS and induced a rapid upregulation of superoxide dismutase 2 (SOD2) expression and a delayed upregulation of heme oxygenase 1 (HO-1) expression. In HT-22 cells with a knockdown of SOD2 expression, delayed treatment with tBHQ failed to prevent glutamate-induced cell death. Briefly, tBHQ rescues mitochondrial function by sequentially increasing SOD2 and HO-1 expression during glutamate-mediated oxidative stress. This study is the first to demonstrate the role of tBHQ in preserving mitochondrial function during oxidative challenge and provides a clinically relevant argument for using tBHQ against acute neuron-compromising conditions.

Tert-butylhydroquinone compromises survival in murine experimental stroke

“…However, the mortality remained high. Further, we lowered the dose to 0.582 mg/kg, which has been shown to be protective in primary cortical neurons [15]. However, the mortality of tBHQ treatment group was still higher than control group (Figure 1B).…”

“…Two mice died before pMCAO surgery and four mice died during ischemic stroke (Figure 1B). According to our previous study in vitro , this dosage induced cytotoxicity in neurons [15]. Therefore, we reduced dosage to 3.34 mg/kg, a protective concentration against oxidative toxicity in the neuronal cell line [15].…”

“…Our previous data showed that tBHQ induces a rapid activation of Nrf2-ARE signaling pathway. However, activation of Nrf2-ARE signaling pathway is diminished with prolonged exposure of tBHQ [15]. A persistent accumulation of ROS during permanent occlusion may exceed the effective time window of tBHQ.…”

“…The dual antioxidative activities make tBHQ as a valuable candidate for the treatment of oxidative stress-induced neurodegeneration. Our previous study has shown that tBHQ exerts protection against oxidative stress-induced cytotoxicity in neurons though preserving mitochondrial function [15]. A published study reported that pretreatment with tBHQ reduced cortical damage and improved functional recovery up to 1 month after ischemia-reperfusion in rats [16].…”

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

“…Nrf2 may play a protective role against ischemia/reperfusion injury potentiating the antioxidant defenses, via activation of HO-1, NQO1, SODs, CAT, GPX genes as well as induction of GSH metabolism genes, protecting BBB integrity and counteracting inflammation. For these reasons, there is a growing interest in the development of therapies aimed to activate the Nrf2 pathway, and several food antioxidants, especially tert-Butylhydroquinone (tBHQ) [177] and resveratrol [178], have been tested as Nrf2 activators in stroke. Intriguingly, some Nrf2-regulating or -regulated miRs are related to stroke, representing putative therapeutic targets for modulating Nrf2 expression and/or potentiating antioxidant defenses after ischemic damage.…”