SOD mimic M40403 improves sperm fertilizing potential through activating NO/NRF2 signaling pathway

Global rise in male infertility give importance to find a new approach to increase fertility. Redox signaling emerged recently as important for spermatozoa functioning. Accordingly, we just showed great therapeutic potential of redox modulator SOD mimic M40403. Molecular mechanisms underlying beneficial effects of M40403 indicate NO involvement, but remain unsolved; we aimed to reveal this herein. Compared to the control, incubation of spermatozoa in Tyrodeu0027s medium for 3 h, decreased sperm motility, mitochondrial membrane potential (MMP), level of NO, expression of NO synthases (NOSs), and completely abolished nuclear localization of NF-E2-related nuclear factor 2 (Nrf2) that was followed by decrease in SODs, catalase and GPX expression. Treatment with M40403 decreased levels of O 2 •– , increased level of NO, restored expression of NOSs and MMP, and triggered marked nuclear translocation of Nrf2 followed by up-regulation of SODs, catalase and GPX and increase in sperm motility. In turn, M40403 + L-NAME treatment nullified all beneficial effects of M40403. These data reveal the redox based mechanisms of beneficial effects of M40403 SOD mimic in sperm cells, suggesting NO/Nrf2 signaling as a central pathway. Utilization of a redox modulator, M40403, as an inducer of Nrf2 is a promising pharmacological approach for the improvement of sperm fertilizing potential and beat infertility.