Roflumilast extenuates inflammation and oxidative stress in cadmium-induced hepatic and testicular injury in rats

Roflumilast (ROF), a highly selective phosphodiesterase-4 inhibitor, has proven anti-inflammatory and immunomodulatory effects on the pulmonary system. However, the protective effects of ROF on cadmium (Cd)induced hepatic and testicular injury has never been investigated. Adult male Sprague Dawley rats were acutely intoxicated with CdCl2 (3 mg/Kg, ip, qd, for 5 days). In treatment groups, ROF was administered in two doses (1.5 & 3 mg/Kg, po, qd, for 5 days) 2 h prior to CdCl2 intoxication. The results demonstrated that the therapeutic potential of ROF can extend beyond the pulmonary system. The histopathological manifestation of Cd in the liver and testes were evidently mitigated by ROF prophylaxis. This study unraveled the multi-faceted ROF protective mechanisms, these comprise (i) reviving normal liver and testicular architecture, (ii) lessen immune cell infiltration in injured tissues (iii) restoration of cellular oxidant status (GSH, SOD, NO and MDA), (iv) shielding proinflammatory signaling pathways (NF-kappa B, NLRP3, IL-1 beta axis), (v) dampening endoplasmic reticulum stress (IRE1), (vi) mitigating apoptotic injury (caspase-3), (vii) restoring the integrity of blood testes barrier (Cathepsin-D) and (viii) promoting the regenerative potentials of injured testes (SDF-1). In conclusion, ROF is a promising antiinflammatory and anti-oxidative candidate in Cd-induced hepatic and testicular injury.