Histochemical and immunohistochemical evaluation of possible protective and therapeutic effects of fluvastatin in doxorubicin induced rat testis damage model

Doxorubicin, which was first used clinically in 1967, is an anthracycline antibiotic commonly used in the treatment of solid tumors and hematological malignancies at the present time. This drug has mutagenic, carcinogenic and teratogenic effects as well as anti-neoplastic properties and its usage is restricted by acute and chronic side effects that occur in organs such as heart, kidney, liver, brain and testis. Findings from previous studies indicate that oxidative stress and lipid peroxidation occurring in germ cells due to the use of doxorubicin are major contributors to doxorubicin associated testicular injury, but the mechanisms responsible for doxorubicin-induced testicular damage have not yet been fully understood. Statins are the most effective cholesterol-lowering agents that competitively inhibit hydroxyl-methyl glutaryl coenzyme (HMG-CoA) reductase, the key enzyme for cholesterol biosynthesis. Fluvastatin, a totally synthetic statin, inhibits HMG-CoA reductase and blocks the conversion of HMG-CoA to mevalonate, a major sterol precursor molecule, including cholesterol. Fluvastatin has been shown to have antioxidant activity by clearing hydroxyl and superoxide radicals as well as cholesterol-lowering effects, and it has been shown that this drug may play a protective role by acting on the mTOR signaling pathway in obesity-induced testicular damage. In our study, it was aimed to evaluate and explain the possible protective and therapeutic effects of fluvastatin in doxorubicin-induced testicular injury model by histochemical, immunohistochemical, biochemical and real-time PCR analyses. The data obtained from our analyzes show that fluvastatin may have both protective and therapeutic effect in doxorubicin-induced testicular injury, particularly by regulating mTOR, Cx43 and MMP-9 protein and mRNA expressions, which play a crucial role in the regulation of the blood testis barrier. On the other hand, it has been observed that the use of this drug as a prophylactic agent provides more favorable results than the therapeutic use.