Evaluation of the effect of Riociguat (BAY 63-2521) on testicular damage induced by lipopolysaccharide (LPS) in rats

Riociguat is a soluble guanylate cyclase stimulator for the treatment of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension. LPS is an important component of gram-negative bacteria and triggers the inflammatory response by promoting the secretion of various proinflammatory cytokines in the testes. In this study, we aimed to evaluate the histologic changes and processes such as testicular damage, oxidative stress and apoptosis that may be induced by riociguat and LPS administration on testicular tissue. Wistar albino rats were divided into 6 groups (n=8) as Control, LPS, Low Dose Riociguat (LDR), High Dose Riociguat (HDR), LPS+DDR and LPS+DR. Riociguat (1 and 10 mg/kg/day) was administered for 3 days and LPS (5 mg/kg/day) was administered as a single dose on day 3. Testicular tissues of rats were evaluated by histochemical (HE), immunohistochemical (Cas-3 and TNF-α), biochemical (TAS, TOS, OSI and GPx), genetic (Bax, Bcl-2 and HIF-1α) and spermiogram analyses. Our results suggest that riociguat may be protective against oxidative stress by strengthening antioxidant systems, but changes in TOS levels suggest that riociguat administration may act through antioxidant mechanisms rather than directly reducing oxidants. Riociguat showed positive effects in terms of sperm concentration, had no significant effect on sperm motility, increased the forward movement of spermatozoa, but did not change the number of motile spermatozoa in situ, while the effect of DDR on sperm motility was significant in increasing the proportion of forward moving spermatozoa, but limited in reducing immobile spermatozoa. It also improved the histopathologic changes induced by LPS. These results suggest that RIO may positively affect reproductive health by supporting testicular function. Riociguat suppresses HIF-1α activity at high doses, which may reduce the hypoxic state caused by inflammation in the testis, and when the apoptosis process is evaluated, TNF-α staining suggests that it prefers the extrinsic pathway, Bax increase and Bcl-2 decrease prefer the intrinsic pathway, and Cas-3 staining suggests that there may be a connection between the two pathways. As a result of this study, it was concluded that proinflammatory cytokines produced by LPS, which are important pathogenic mediators, have an inhibitory role in steroidogenesis through increased ROS production and that riociguat treatment may be effective in intrinsic and extrinsic apoptosis pathways in testes in conditions such as LPS-induced inflammation, testicular damage and oxidative stress. Keywords: Riociguat, Lipopolysaccharide (LPS), Toxicity, Testis, Rat