TBHQ Attenuates Neurotoxicity Induced by Methamphetamine in the VTA through the Nrf2/HO-1 and PI3K/AKT Signaling Pathways

Abstract

Methamphetamine (METH) leads to nervous system toxicity. Long-term exposure to METH results in damage to dopamine neurons in the ventral tegmental area (VTA), and depression-like behavior is a clinical symptom of this toxicity. The current study was designed to investigate whether the antioxidant tertiary butylhydroquinone (TBHQ) can alleviate neurotoxicity through both antioxidative stress and antiapoptotic signaling pathways in the VTA. Rats were randomly divided into a control group, a METH-treated group (METH group), and a METH+TBHQ-treated group (METH+TBHQ group). Intraperitoneal injections of METH at a dose of 10 mg/kg were administered to the rats in the METH and METH+TBHQ groups for one week, and METH was then administered at a dose that increased by 1 mg/kg per week until the sixth week, when the daily dosage reached 15 mg/kg. The rats in the METH+TBHQ group received 12.5 mg/kg TBHQ intragastrically. Chronic exposure to METH resulted in increased immobility times in the forced swimming test (FST) and tail suspension test (TST) and led to depression-like behavior. The production of reactive oxygen species (ROS) and apoptosis levels were increased in the VTA of animals in the METH-treated group. METH downregulated Nrf2, HO-1, PI3K, and AKT, key factors of oxidative stress, and the apoptosis signaling pathway. Moreover, METH increased the caspase-3 immunocontent. These changes were reversed by treatment with the antioxidant TBHQ. The results indicate that TBHQ can enhance Nrf2-induced antioxidative stress and PI3K-induced antiapoptotic effects, which can alleviate METH-induced ROS and apoptosis, and that the crosstalk between Nrf2 and PI3K/AKT is likely the key factor involved in the protective effect of TBHQ against METH-induced chronic nervous system toxicity.

Tert-butylhydroquinone mitigates Carbon Tetrachloride induced Hepatic Injury in mice

“…Activation of Nrf2/HO-1 showed protective effects in cardiovascular system and exhibits function in anti-inflammation, anti-apoptosis and anti-oxidative processes 35 . Moreover, activation of Nrf2/HO-1 could significantly mitigate neurotoxicity via reducing oxidative stress and inflammation 36 . In our study, we confirmed tBHQ could activate Nrf2 and increase HO-1 expression.…”

TBHQ-Overview of Multiple Mechanisms against Oxidative Stress for Attenuating Methamphetamine-Induced Neurotoxicity

“…Phosphatidylinositol 3-kinase (PI3K) is also involved in resisting methamphetamine-induced oxidative stress. PI3K works by activating protein kinase B (also known as AKT) [ 79 ]. PI3K/AKT has been reported as the upstream signaling pathway of Nrf2 in many papers [ 79 – 81 ].…”

“…PI3K has both Ser/Thr kinase activity and phosphatidylinositol kinase activity [ 87 ]. The Ser/Thr kinase activity of PI3K can activate its downstream target AKT [ 79 ]. PI3K/AKT signaling pathway can phosphorylate Ser/Thr residues, which is a key for Nrf2 activation [ 79 , 81 ].…”

“…The Ser/Thr kinase activity of PI3K can activate its downstream target AKT [ 79 ]. PI3K/AKT signaling pathway can phosphorylate Ser/Thr residues, which is a key for Nrf2 activation [ 79 , 81 ]. Under hyperoxia conditions, PI3K is inhibited.…”

“…Under hyperoxia conditions, PI3K is inhibited. In the presence of a large amount of ROS, Nrf2 and its downstream are inhibited through the PI3K/AKT signaling pathway [ 79 ]. Methamphetamine leads to the overactivation of astrocytes and generates ROS, thereby inhibiting the expression of Nrf2.…”