Ginsenoside Rg1 alleviates chronic testicular damage caused by cranial irradiation through the SCF/PI3K/Akt/mTOR pathway in mice

To investigate whether Ginsenoside Rg1 can mitigate the adverse effects of cranial irradiation on distal reproductive function in mice and to explore the underlying mechanisms. Forty Male C57BL/6J mice were randomly divided to four groups(Control, IR, IR+Rg1, Rg1), IR+Rg1and Rg1group treated with intraperitoneal injections of Ginsenoside Rg1 for 30 d, followed by single-dose irradiation of 5 Gy X-ray irradiation (2 Gy/min) for the IR and IR+Rg1 group. After three months, testicles, whole brain, and serum samples were collected for analysis. Histological staining, transmission electron microscopy, sperm analysis, and immunofluorescence demonstrated that Ginsenoside Rg1 ameliorated structural and functional damage to the testicles, enhanced sperm count(IR: 20.70 ± 1.62 vs. IR+Rg1: 33.93 ± 2.20, t = -13.23, P < 0.05), and reduced sperm malformation rates(IR: 46.33 ± 2.18 vs. IR+Rg1: 39.00 ± 1.67, t = 7.33, P < 0.05). Further TUNEL and ELISA assays demonstrated that Rg1 inhibited testicular apoptosis(IR: 3.21 ± 0.28 vs. IR+Rg1: 1.81 ± 0.18, t = 1.40, P < 0.05)and modulated serum testosterone(IR: 4.47 ± 0.23 vs. IR+Rg1: 6.65 ± 0.09, t = -2.18, P < 0.05), GnRH(IR: 24.37 ± 0.92 vs. IR+Rg1: 32.98 ± 1.33, t = -8.61, P < 0.05), and FSH levels (IR: 1.41 ± 0.11 vs. IR+Rg1: 2.69 ± 0.21, t = -1.28, P < 0.05). Additionally, quantitative PCR and Western blot showed that Rg1 downregulated SCF, p-PI3K, p-Akt, and mTOR protein expressions in irradiated mice. Ginsenoside Rg1 potentially alleviate chronic testicular structural and functional damage by inhibiting germ cell apoptosis through the modulation of the HPG axis and the PI3K/Akt/mTOR pathway, suggesting that it is a potential therapeutic agent for reproductive disorders induced by cranial irradiation. • Cranial radiation induces chronic structural and functional damage to the testes in mice. • Rg1 inhibits apoptosis of distal reproductive cells caused by cranial radiation. • Rg1 activates SCF/C-kit signaling through the hypothalamic-pituitary-gonadal (HPG) axis. • Rg1 alleviates chronic testicular damage via the SCF/PI3K/Akt/mTOR pathway.