Exercise training amplifies SIRT1/Nrf2/antioxidant/testosterone pathway after long-time tramadol toxicity in rat testicles; insights into miR-126-3p and miR-181a induced roles

Abstract

A long-time consumption of the tramadol (TRA) is shown to negatively affect spermatogenesis development through inducing oxidative stress and suppressing testicular endocrine status. Therefore, by focusing on miRNAs-related roles in the SIRT1/Nrf2/antioxidant/Testosterone-related pathway, the effects of exercise training protocols (ETPs) with different intensities on the TRA-reduced antioxidant and endocrine capacities were investigated. Thus, 36 mature Wistar rats were divided into control and TRA-received groups. Following 60 days, 6 rats from TRA group euthanized (TRA), and the others subdivided into TRA (C.TRA), TRA+low-intensity (TRA+LICT), TRA+moderate-intensity (TA+MICT), and TRA+high-intensity continuous (TRA+HICT) ETP-induced groups (N = 6/group, ETPs were induced for 60 days after stopping TRA consumption). Next, the SIRT1, Nrf2, SOD1, HO-1, miR-126-3p, and miR-181a expression levels were evaluated. The sperm count, testosterone levels, testicular total antioxidant status (TAC), total oxidant status (TOS), superoxide dismutase (SOD) levels, protein carbonyl groups (PCGs), Thiobarbituric acid reactive substances (TBARS), glutathione peroxidase (GPX) and glutathione reductase (GR), oxidative DNA damage were investigated. The TRA group exhibited a significant (p < 0.05) disruption in testicular antioxidant (TAC↓, TOS↑, SOD1↓, SOD enzyme↓, GPX↓, GR↑, TBARS↓, PCGs↑, and HO-1↓) and endocrine (testosterone↓) capacities, a reduction in SIRT1, Nrf2, miR-126-3p, and increment in miR-181a expression levels, a reduction in sperm count and increment in the sperm and testicular oxidative DNA damage. However, The ETPs (mainly LICT) could significantly decrease the TRA-induced molecular and histological alterations 60 days after stopping TRA consumption. In conclusion, ETPs (mainly LICT) through upregulating miR-126-3p and suppressing miR-181a expression levels could promote the SIRT1/Nrf2/antioxidant/Testosterone-related pathway in the testicular tissue.

Keywords: Exercise training; Oxidative DNA damage; Oxidative stress; Spermatogenesis; Testosterone; Tramadol.