Co-Administration of the Traditional Medicines Hachimi-Jio-Gan and Hochu-Ekki-To Can Reverse Busulfan-Induced Aspermatogenesis

Abstract

Busulfan is used as a chemotherapeutic drug to treat childhood and adult chronic myelogenous leukemia, and as an immunosuppressive agent before bone marrow transplantation. A key side effect of busulfan is the alteration of male reproductive function. Infertility caused by anti-cancer treatments has become a significant concern, but there are currently limited treatments for this condition. Recently, we demonstrated that Gosha-jinki-gan, a traditional Japanese medicine, completely reversed the spermatogenesis defects caused by cancer treatment in mice. Hochu-ekki-to and Hachimi-jio-gan are commonly used to treat male infertility, and Hachimi-jio-gan shares herbal ingredients with Gosha-jinki-gan. Therefore, in the present study, we administered Hachimi-jio-gan and Hochu-ekki-to alone or in combination to mice with severe aspermatogenesis caused by busulfan treatment. We performed testis weight measurements, quantitative histological assessments of the testes and the epididymis, and evaluated sperm counts and morphology. We also assessed the expression of immune mediators and macrophage markers. Treatment with a combination of both the medicines significantly reduced busulfan-induced testicular toxicity when compared to the lone treatment with either medicine. We demonstrated that treatment efficacy was related to a differential impact on testicular inflammation, and that the synergistic effect of co-administration completely reversed the busulfan-induced damage to the reproductive functions.

Effect of Gosha-Jinki-Gan on Levels of Specific mRNA Transcripts in Mouse Testes after Busulfan Treatment

“…The mice treated with BSF showed a significant decrease in body weight, testes weight, and epididymal spermatozoa counts at day 60 ( Figure 3 A(III)), which was more pronounced at day 120 ( Figure 1 A(III)) in agreement with our previous studies [ 9 , 14 ]. Furthermore, supplementation with TJ107 could lead to significant improvement in body weight but not complete recovery in groups IV and V ( Table 2 ).…”

“…We have previously demonstrated that TJ107 or administration of Hachimi-jio-gan (TJ7) and Hochu-ekki-to (TJ41) in combination were able to completely normalize testicular immunopathology and to promote recovery from severe aspermatogenesis after BSF treatment in mice [ 9 , 14 ]. We further showed that BSF treatment upregulated the expression of TNF-α , MCP-1 , TLR2 , and TLR4 in the testes, which was completely reversed by TJ107, or TJ7 and TJ41 coadministration [ 9 , 14 ]. This study is the first to examine whether TJ107 could recover spermatogenesis after 120 days by administering from the day of BSF injection.…”

“…In mice, we previously found testicular weight loss, seminiferous tubule atrophy, spermatogenic cell degeneration, and apoptosis 60 days after BSF treatment (40 mg/kg) [ 13 ]. As a result of the limited information on therapy for BSF-induced male infertility, we attempted to determine the effects of several oriental Japanese medicines, such as Gosha-jinki-gan, Hachimi-jio-gan, and Hochu-ekki-to, on BSF-induced infertility [ 9 , 14 ]. We demonstrated that Gosha-jinki-gan (TJ107) was able to completely normalize testicular immunopathology and to promote recovery from severe aspermatogenesis following BSF treatment in mice [ 9 ].…”

Prolonged space flight: Adverse health effects and treatment options with medicinal plants and natural products

“…In another study, Chinese herbal medicinal formulas Hachimi-jio-gan (Rehmanniae radix, Corni fructus, Dioscoreae rhizome, Alismatisrhizome, Hoelen, Moutan cortex, Cinnamon cortex, Aconiti tuber) (Table 1) (67) and Hochu-ekki-to (Astragali radix, Ginseng radix, Atractylode rhizome, Angelicae radix, Zizyphi fructus, Aurantii nobilispericarpium, Bupleuri radix, Glycyrrhizae radix, Cimicifugae rhizome, Zingiberis rhizome) (Table 2) (68) are been tested for zero gravity-induced problems. Results suggested that these formulations can decrease the level of ADH in the blood of astronauts in outer space (69).…”

Food-Derived High Arginine Peptides Promote Spermatogenesis Recovery in Busulfan Treated Mice

“…Mice were given a single round, intraperitoneal injection of either busulfan (35 mg/kg, Sigma, St. Louis, MO, United States) or DMSO (Sigma), according to previously described methods (Bucci and Meistrich, 1987;Qu et al, 2020). After 4 weeks, the testis weight, epididymal sperm count, and testis histology were evaluated and the phenotypes were checked.…”