Dehydroepiandrosterone Prevents H₂O₂-Induced BRL-3A Cell Oxidative Damage through Activation of PI3K/Akt Pathways rather than MAPK Pathways

Abstract

Dehydroepiandrosterone (DHEA) is a popular dietary supplement that has well-known benefits in animals and humans, but there is not enough information about the mechanisms underlying its effects. The present study aimed at investigating these mechanisms through in vitro experiments on the effects of DHEA on rat liver BRL-3A cells exposed to oxidative stress through H2O2. The findings showed that DHEA increased the antioxidant enzyme activity, decreased ROS generation, and inhibited apoptosis in H2O2-treated cells. These effects of DHEA were not observed when the cells were pretreated with known antagonists of sex hormones (Trilostane, Flutamide, or Fulvestrant). Furthermore, treatment with estradiol and testosterone did not have the same protective effects as DHEA. Thus, the beneficial effects of DHEA were associated with mechanisms that were independent of steroid hormone pathways. With regard to the mechanism underlying the antiapoptotic effect of DHEA, pretreatment with DHEA was found to induce a significant decrease in the protein expression of Bax and caspase-3 and a significant increase in the protein expression of PI3K and p-Akt in H2O2-treated BRL-3A cells. These effects of DHEA were abolished when the cells were pretreated with the PI3K inhibitor LY294002. No changes were observed on the p-ERK1/2, p-p38, and p-JNK protein levels in H2O2-induced BRL-3A cells pretreated with DHEA. In conclusion, our data demonstrate that DHEA protects BRL-3A cells against H2O2-induced oxidative stress and apoptosis through mechanisms that do not involve its biotransformation into steroid hormones or the activation of sex hormone receptors. Importantly, the protective effect of DHEA on BRL-3A cells was mainly associated with PI3K/Akt signaling pathways, rather than MAPK signaling pathways.

Testosterone supplementation improves insulin responsiveness in HFD fed male T2DM mice and potentiates insulin signaling in the skeletal muscle and C2C12 myocyte cell line

“…In another study using BLA3A cells, it was reported that androgen had a protective effect on H 2 O 2 treated cells that experienced oxidative stress. This protective effect was mediated through the PI3K-AKT pathway and was reversed in the presence of flutamide [26]. Rossetti et al, 2017, summarized that castration of male mice reduced skeletal muscle P-AKT (Ser-473) and P-mTOR (Ser-2448) level, along with skeletal muscle protein synthesis and this effect was reversed upon exogenous administration of androgen to the to the castrated mice [27].…”

Antinociceptive properties of losmapimod in two acute pain models in rats: behavioural analysis, immunohistochemistry, dose response, and comparison with usual analgesic drugs

“…Information regarding the influence of sex hormones on the p38 MAPK pathway is controversial. 39 , 40 Choosing only male animals eliminated the potential effects of sex on our results while making the study more homogeneous. However, this remains a broad topic, and further studies wholly dedicated to it could be very useful.…”