Enhancement of dopaminergic activity and region-specific activation of Nrf2-ARE pathway by intranasal supplements of testosterone propionate in aged male rats

• Antiaging effects of intranasal testosterone propionate (InTP) delivery was studied.
• InTP supplement ameliorated exploratory and motor behavioral deficits of aged male rats.
• Declined dopamine neurobiochemical indices were improved in aged male rats by InTP administration.
• InTP treatment activated Nrf2-ARE pathway in mesodopaminergic neurons of aged male rats.
• Activated Nrf2-ARE pathway was not found in the hippocampus of InTP-treated aged male rats.

The potential influence of intranasal testosterone propionate (InTP) supplements on mesodopaminergic system in aged male rats was investigated by analyzing the exploratory and motor behaviors as well as dopamine neurobiochemical indices. Meanwhile, oxidative stress parameters and pathway of nuclear factor erythroid 2-related factor 2 (Nrf2)-binding antioxidant response elements (Nrf2-ARE) were examined to check whether the Nrf2-ARE pathway was involved in the InTP-induced alteration of mesodopaminergic system in aged male rats. The exploratory and motor behavioral deficits, as well as the reduced expression of dopamine, tyrosine hydroxylase, and dopamine transporter, which indicated the declined activity of mesodopaminergic system, were ameliorated in rats administered with 12-week InTP. The results indicated that chronic InTP supplements could effectively influence the brain function activity in a way opposite to the effect of aging on the mesodopaminergic system of rats. The increased levels of Nrf2, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase-1 in the substantia nigra and ventral tegmental area, but not in the hippocampus of InTP-administered aged male rats, indicated that the ameliorative effect of InTP supplements on mesodopaminergic system might be related to the region-specific activation of the Nrf2-ARE pathway.