Abstract
There is a controversy over the effects of testosterone supplements on dopaminergic function. Both neuroprotective and toxic effects of testosterone supplements are reported. The status of oxidative stress seems to explain the neuroprotective or toxic properties of testosterone. To determine the efficacy of testosterone supplements in different status of oxidative stress, the present studies analyzed the dopamine (DA)-related behaviors and neurochemical indices, as well as markers of nigrostriatal dopaminergic (NSDA) system in reserpine-treated aged male rats followed by testosterone propionate (TP) supplements. The status of oxidative stress of experimental animals was evaluated by analyzing oxidative stress parameters and nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway in substantia nigra (SN). Consistent with our previous studies, TP supplements to 21-month old aged male rats had the beneficial effects on NSDA system and DA-related behaviors and enhanced the antioxidative capabilities in SN. However, the beneficial effects of TP supplements on NSDA system and DA-related behaviors in aged male rats were reversed by reserpine pretreatment to them. Reserpine treatment induced the severe oxidative stress and reduced the expressions of Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the SN of aged male rats. The TP supplements to reserpine-pretreated aged male rats exacerbated the defects in NSDA system and DA-related behaviors, aggravated oxidative damages and downregulated the expression of Nrf2, HO-1 and NQO1 in the SN. These results suggested that the efficacy of TP supplements on impaired NSDA system was related to the status of oxidative stress in experimental rats.
Highlights
Oxidative stress is involved in the progression of aging and aging-related dysfunction (Hamilton et al, 2001; Kregel and Zhang, 2007; Wang and Michaelis, 2010), and induces the progressive and irreversible oxidative damages during dopaminergic neurodegeneration (Chen et al, 2008; Hwang, 2013)
The reduced DA and its metabolites, as well as the decreased tyrosine hydroxylase (TH) and DA transporter (DAT) in nigrostriatal dopaminergic (NSDA) system of aged male rats were significantly ameliorated by testosterone propionate (TP) supplements
Administration of TP to aged male rats enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1) in substantia nigra (SN)
Summary
Oxidative stress is involved in the progression of aging and aging-related dysfunction (Hamilton et al, 2001; Kregel and Zhang, 2007; Wang and Michaelis, 2010), and induces the progressive and irreversible oxidative damages during dopaminergic neurodegeneration (Chen et al, 2008; Hwang, 2013). Activated Nrf induces a series of antioxidant genes to protect cells against oxidative stress (Dou et al, 2016). The enhanced dopaminergic activity in aged rats by testosterone seems related to the ameliorated status of oxidative stress (Zhang et al, 2016). Testosterone supplements to aged male rats activate the Nrf2-ARE pathway and strengthen the antioxidant capability (Zhang et al, 2013, 2016). Androgens exert neuroprotective action against oxidative stress (Ahlbom et al, 1999; Meydan et al, 2010)
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