Efficacy of finerenone and/or roflumilast in alleviation of intestinal ischemic reperfusion injury via regulation of IL10/AMPK/VEGF/eNOS pathway in rats.

OBJECTIVES: Intestinal ischemia is a serious emergency that requires immediate management and surgical intervention. Finding an effective therapeutic strategy, in addition to surgical treatment, is essential to mitigate the harmful effects of intestinal ischemia-reperfusion (IIR)-induced tissue injury not only in the intestine itself but also in distant organs, especially the liver. This prompted us to evaluate, for the first time, the role of finerenone (FIN), a non-steroidal selective mineralocorticoid receptor antagonist, and/or roflumilast (ROF), a selective phosphodiesterase 4 inhibitor, in experimentally induced IIR injury in both hepatic and intestinal tissues, with a detailed study of various mechanisms. MATERIALS AND METHODS: Wistar rats were randomly assigned to 5 groups (N=10): Sham group, IIR group, FIN/ROF, FIN, and ROF-administered groups, with IIR induction. RESULTS: Interestingly, FIN/ROF significantly reduced elevated levels of liver function enzymes, tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), caspase-3 expression, and aldosterone. Furthermore, FIN/ROF could normalize the tissue level of interleukin 10 (IL-10), adenosine monophosphate-activated protein kinase (AMPK), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), antioxidant parameters, reduced glutathione (GSH), and total antioxidant capacity (TAC) with remarkable improvement in the histopathological features. CONCLUSION: FIN/ROF could mitigate IIR-induced hepatic and intestinal damage via FIN-mediated blockade of mineralocorticoid receptors and ROF-mediated inhibition of phosphodiesterase 4, and through antioxidant, anti-apoptotic, and anti-inflammatory properties with regulation of the IL-10/AMPK/VEGF/eNOS pathway. Thus, FIN/ROF is a potential medical treatment for IIR, in addition to surgery.