NLRP3 Inflammasome: A New Pharmacological Target for Reducing Testicular Damage Associated with Varicocele

Abstract

Many bioactive natural compounds are being increasingly used for therapeutics and nutraceutical applications to counteract male infertility, particularly varicocele. The roles of selenium and Polydeoxyribonucleotide (PDRN) were investigated in an experimental model of varicocele, with particular regard to the role of NLRP3 inflammasome. Male rats underwent sham operation and were daily administered with vehicle, seleno-L-methionine (Se), PDRN, and with the association Se-PDRN. Another group of rats were operated for varicocele. After twenty-eight days, sham and varicocele rats were sacrificed and both testes were weighted and analyzed. All the other rats were challenged for one month with the same compounds. In varicocele animals, lower testosterone levels, testes weight, NLRP3 inflammasome, IL-1β and caspase-1 increased gene expression were demonstrated. TUNEL assay showed an increased number of apoptotic cells. Structural and ultrastructural damage to testes was also shown. PDRN alone significantly improved all considered parameters more than Se. The Se-PDRN association significantly improved all morphological parameters, significantly increased testosterone levels, and reduced NLRP3 inflammasome, caspase-1 and IL-1β expression and TUNEL-positive cell numbers. Our results suggest that NLRP3 inflammasome can be considered an interesting target in varicocele and that Se-PDRN may be a new medical approach in support to surgery.

Role of Oxidative Stress in Varicocele

“…Stimulating adenosine A2A receptor (A2AR) can induce the production of VEGF under the pathological condition of venous blood reflux. Some studies have shown that A2AR stimulation can be an interesting target to positively modulate harmful pathophysiological signals in experimental varicocele and improve the innate mechanism of new angiogenesis by supplying oxygen and metabolites to the testis to restore spermatogenesis ( Antonuccio et al, 2021 ). PDRN significantly increased Johnsen scores in varicocele rats and successfully improved histological damage, promoted the regeneration of new blood vessels, improve spermatogenesis, increased the content of the neuronal apoptosis inhibitory protein NAIP, and increased the survival rate of varicocele rats ( Hassanin et al, 2018 ).…”

“…Studies show that treatment of varicocele rats with PDRN for 1 month can significantly improve testosterone levels and decreased NLRP3 inflammasome, caspase-1, and IL-1 β expression and number of TUNEL positive cells ( Antonuccio et al, 2021 ). It improves the innate mechanism of new angiogenesis by providing compensatory oxygen and metabolites to testis, thus enhancing testis function and restoring spermatogenic function.…”

The NLRP3 inflammasome: molecular activation and regulation in spermatogenesis and male infertility; a systematic review

“…In the testis of mammalian, it has been shown that Sertoli cells, which function as non-professional tolerogenic APCs, have the ability to activate the inflammasome response via the TLR4/NOD/NFKB/Caspase-1/IL-1ß/IL-18 pathway [ 12 ]. Recently, it was reported that the NLRP3 inflammasome was activated in an experimental model of varicocele [ 13 – 16 ]. This suggests that activation of the NLRP3 inflammasome could be part or player of some infertility situations, as stated in previous reviews [ 17 , 18 ], via an inflammatory cytokine storm and, it is likely that this could explain COVID-19-induced infertility as recently hypothesized [ 19 ].…”

Lycopene improves testicular damage and sperm quality in experimentally induced varicocele: Relationship with apoptosis, hypoxia, and hyperthermia

“…Medical management, including the administration of antioxidants, can be a potential low‐risk solution to reduce OS and apoptosis in varicocele‐induced infertility (Garg & Kumar, 2016 ). Recently, the results of several studies on the effects of natural bio‐actives, such as lycopene, N‐palmitoylethanolamide (PEA), or polydeoxyribonucleotide (PDRN), on experimental varicocele have been promising (Antonuccio, Marini, et al., 2021 ; Antonuccio et al., 2020 ; Antonuccio, Micali, et al., 2021 ). So, the present study attempted to investigate the effects of lycopene, as a powerful antiradical compound in the carotenoid family, on sperm quality, testicular histopathology, and apoptosis, hypoxia, and heat‐shock protein gene expression in experimentally induced varicocele.…”