O-1: Thraputic Effect of Silymarin, Celecoxib and Exogenous Testosterone on Varicocele-Induced Disorders; Possible Mechanisms
Varicocele (VCL) is characterized by a progressive disorder which is defined by tortuosity of the pampiniform plexus veins that exerts bilateral impacts. 50-60 percent of males with infertility problems are suffering from VCL. Considering VCL-induced massive problems in human fertilizing potential, investigating different aspects of VCL-induced derangements is gaining considerable attentions. Although, elevated oxidative stress, germinal cells apoptosis and nitrosative stress are reported as some of reasons for infertility in VCL patients, the exact mechanism(s) by which VCL reduces the fertilizing potential is unknown. Roles of cytokines in testicular endocrine status (steroidogenesis) and overexpression of potent pro-inflammatory activators are illustrated in patients with varicocele. Thus, taking together the inflammation, reduced endocrine status associated with various biochemical stresses are generally known for varicocele-induced apoptosis. However, the roles of proto-oncogenes, tumor suppressors, pro-apoptotic genes, testicular steroidogenesis, physiologic interactions of estrogen receptors and genes involved in aromatization are remained unknown. Due to conflicting outcomes of varicocelectomy, the medical/drug intervention as an important alternative gained increasing interest.
Materials and methods
Our previous data for this purpose showed that VCL by up-regulating inflammation ratio enhances oxidative stress and therefore it results in a significant reduction in testicular endocrine status. Moreover, the gene expression of E2F1 (gene involved in DNA fragmentation), protein biosynthesis of HSP70-2 (protein involved in protein, DNA and RNA assembling and reassembling) as well as ubiquitine (protein participating in post transcriptional regulation) were estimated in VCL alone-induced and silymarin co-treated animals. Our findings showed that silymarin (as an antioxidant and antinflammatory agent) ameliorated the inflammation, oxidative stress, E2F1 gene expression and DNA damage, while it did not considerably affect the endocrine status.
Thus, therapeutic properties of dexamethasone+ vitamin E in one study and testosterone+vitamin E in other research were assessed for estimating the possible major role of inflammation, oxidative stress and endocrine potential. Our lastly published data showed that simultaneous administration of testosterone with a potent antioxidant vitamin E more significantly up-regulated HSp70-2 expression, reduced mRNA damage and enhanced testosterone biosynthesis versus dexamethasone+vitamin E-received ones.
Considering dexamethasone-induced side effects, in our last running project we were tried to analyze the ameliorative/therapeutic effects of silymarin (100 mg/kg, potential antioxidant), celecoxib (10 mg/kg, anti-inflammatory drug) and exogenous testosterone (400 μg/kg, endocrine promoter) in experimentally-varicocelized rat models. For this purpose more especial and related parameters were analyzed. The mRNA levels of Bcl-2, p53, caspase III, caspase VIII, ERα, ERβ, cytochrome p450 (CYP19), iNOS and COXII were investigated by RT-PCR. The spermatogenesis and spermiogenesis cells series presenting Bcl-2, p53, ERα, ERβ, caspase III and caspase VIII proteins were stained immunohistochemically. Testicular total antioxidant capacity, malondialdehyde content and carbonyl groups were estimated biochemically. In conclusion, reduced endocrine status, enhanced inflammatory agents and elevated oxidative stress in VCLs, promote the apoptotic pathway at germinal cell level via affecting proto-oncogenes. However, co-administrating silymarin, celecoxib and testosterone ameliorated the VCL-induced derangements