Long-term supplementation of dehydroepiandrosterone improved depressive-like behaviors by increasing BDNF expression in the hippocampus in ovariectomized rats

Abstract

Objective: Dehydroepiandrosterone (DHEA), a precursor of estrogen, partially exhibits its biological effect after conversion to estrogen. Its biological significance in perimenopausal depressive disorder or postpartum depression remains unknown. Here, we observed the effects of long-term supplementation of DHEA on depression-like behaviors in ovariectomized rats.

Methods: We established the model as one of sex hormone deficiency in female rats by bilateral ovariectomy. We observed the effects of 13.3 mg/kg DHEA or 0.27 mg/kg estradiol were given daily by gavage for 12 weeks on lipid metabolism, glucose tolerance, and depression-like behaviors in ovariectomized rats. Furthermore, the expression of brain-derived neurotrophic factor (BDNF) and its signaling molecule in the hippocampus was analyzed.

Results: The 12-week supplementation of DHEA or estradiol significantly alleviated weight gain and improved the glucose tolerance in the ovariectomized rats. Moreover, Long-term supplement of DHEA or estradiol significantly increased sucrose preference and locomotion activities, and reduced immobility duration of the ovariectomized rats in the water. Both DHEA and estradiol treatments increased the expression of BDNF, phosphorylation of ERK and CREB, and ERβ, but not that of ERα in the hippocampus of the ovariectomized rats.

Conclusions: Overall, chronic treatment with DHEA improved depression-like behaviors in ovariectomized rats, suggesting that it may be useful for the treatment of sex hormone deficiency such as perimenopausal depressive disorder or postpartum depression.

Keywords: Brain-derived neurotrophic factor; Dehydroepiandrosterone; Depression; Estrogen receptors; Gynecology; Health sciences; Hippocampus; Neuroscience; Nutrient availability; Perimenopausal depressive disorder; Pharmacology.

Figure 1

Effects of DHEA treatment on body weight, glucose tolerance in the OVX rats. Oral glucose tolerance test (OGTT) curve (A), the corresponding area under the curve (AUC) (B), and body weight (C) among the four groups. Chronic treatment with DHEA or E2 reduced the AUC of OGTT and body weight gain in the OVX rats. Data were shown as the mean ± SEM (n = 8). ∗P < 0.05 compared to the sham group; ^#P < 0.05 compared to the OVX group.

Figure 2

Effects of DHEA treatment on blood lipids in the OVX rats. The figure presented the Level of triglycerides (TG) (A), total cholesterol (TC) (B), HDL-C (C), and LDL-C (D) in rats. The TG, TC, and LDL-C levels were higher in the OVX group than in the sham rats. The LDL-C level was reversed in the E2 group, but not in DHEA treated group. Data were shown as the mean ± SEM (n = 8). ∗P < 0.05 compared to the sham group; ^#P < 0.05 compared to the OVX group.

Figure 3

Effects of DHEA treatment on the depressive-like behaviors. Sucrose preference index in the sucrose preference test (A), line crossing numbers (B), and rearing numbers (C) in the open field test; immobility time (D) in the forced swimming test. Long-term supplement of DHEA or E2 could reversed the depressive-like behaviors in the OVX rats. Data were shown as the mean ± SEM (n = 8). ∗P < 0.05 compared to the sham group; ^#P < 0.05 compared to the OVX group.

Figure 4

Effects of DHEA on the ERK/CREB/BDNF signaling pathway in the hippocampus. The representative bands and their relative expression histogram of Phosphorylation level of ERK (A), phosphorylation level of CREB (B), and BDNF(C) in the hippocampus are shown. DHEA or E2 treatment increased the expression of p-ERK, p-CREB, and BDNF in the hippocampus. Data were shown as the mean ± SEM (n = 4). ∗P < 0.05 compared to the sham group; ^#P < 0.05 compared to the OVX group.

Figure 5

Effects of DHEA on the expression of ERβ and ERα in the hippocampus. The representative bands and their relative expression histogram of ERβ (A) and ERα (B) in hippocampus are shown. After 12 weeks of E2 and DHEA administration, the expression of ERβ was upregulated significantly. Data were shown as the mean ± SEM (n = 4). ∗P < 0.05 compared to the sham group; ^#P < 0.05 compared to the OVX group.