sirolimus and Testicular-Diseases

This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress.. Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR.. There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05).. Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.

Topics: Animals; Autophagy; Cytoprotection; Diabetes Complications; Diabetes Mellitus, Experimental; Down-Regulation; Endoplasmic Reticulum Stress; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; Streptozocin; Testicular Diseases; Testis

Mammalian target of rapamycin (mTOR) inhibition has been associated with gonadal dysfunction. The aim of this study was to characterize the effect of sirolimus (SRL) on male gonadal function in an experimental model.. Male Wistar rats were treated with intraperitoneal administration of vehicle or SRL. Vehicle group was treated for 12 weeks. Rats treated with SRL were killed at 4, 8, and 12 weeks. A group of rats was treated with SRL for 4 weeks and then observed during 8 weeks to analyze the possible reversibility of the effect of mTOR inhibition. Body and testicular weight, testosterone, follicle-stimulating hormone level, and luteinizing hormone level were measured and testicular histology was analyzed including proliferation and apoptosis analysis.. Testicular weight was significantly lower in all SRL groups. After SRL withdrawal testicular weight had partially recovered. The expression of steroidogenic acute regulatory protein decreased during SRL treatment, which could explain the reduction of testosterone levels, because steroidogenic acute regulatory protein is crucial for testosterone synthesis. Spermatogenesis was blocked on the spermatogonial level by SRL treatment. Withdrawal of SRL treatment led to complete recovery.. mTOR inhibition in healthy animals produces sexual hormone dysfunction, seminiferous tubule dystrophy and spermatogenesis blockade. Furthermore, the spermatogenesis blockade produced by SRL is reversible.

Topics: Animals; Apoptosis; Cell Proliferation; Disease Models, Animal; Follow-Up Studies; Immunosuppressive Agents; Injections, Intraperitoneal; Male; Organ Size; Phosphoproteins; Rats; Rats, Wistar; Sirolimus; Spermatogenesis; Testicular Diseases; Testis; Testosterone; TOR Serine-Threonine Kinases