Icariin is a prenylated flavonol glycoside isolated from Epimedium herb, and has been shown to be its main bioactive component. Recently, the antidepressant-like mechanism of icariin has been increasingly evaluated and demonstrated. However, there are few studies that have focused on the involvement of the phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase (AKT) signaling in mediating the perimenopausal depression effects of icariin. Perimenopausal depression is a chronic recurrent disease that leads to an increased risk of suicide, and poses a significant risk to public health. The aim of the present study was to explore the effect of icariin on the expression of the PI3K−AKT pathway related to proteins in a rat model of perimenopausal depression. Eighty percent of the left ovary and the entire right ovary were removed from the model rats. A perimenopausal depression model was created through 18 days of chronic unpredictable stimulation, followed by the gavage administration of target drugs for 30 consecutive days. We found that icariin administered at various doses significantly improved the apparent symptoms in the model rats, increased the organ indices of the uterus, spleen, and thymus, and improved the pathological changes in the ovaries. Moreover, icariin administration elevated the serum levels of female hormone estradiol (E2), testosterone (T), and interleukin (IL)-2, decreased those of follicle stimulating hormone (FSH) and luteotropic hormone (LH), promoted the expression levels of estrogen receptor (ER) and ERα in the hypothalamus, and increased those of serotonin (5-HT), dopamine (DA), and noradrenaline (NA) in the brain homogenate. Furthermore, icariin elevated the expression levels of AKT, phosphorylation-akt (p-AKT), PI3K (110 kDa), PI3K (85 kDa), and B-cell lymphoma 2 (Bcl-2) in the ovaries, and inhibited those of Bax. These results show that icariin administration rebalanced the disordered sex hormones in perimenopausal depression rats, regulated the secretion of neurotransmitters in the brain, boosted immune function, and improved the perimenopausal syndrome. The mechanism of action may be related to the regulation of the expression of PI3K−AKT pathway-related proteins.
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