fk-866 and Reperfusion-Injury

Dynamin-related protein 1 (Drp1) mediates mitochondrial fission and triggers NLRP3 inflammasome activation. FK866 (a NAMPT inhibitor) exerts a neuroprotective effect in ischemia/reperfusion injury through the suppression of mitochondrial dysfunction. We explored the effects of FK866 on pyroptosis and inflammation mediated by Drp1 in a cardiac arrest/cardiopulmonary resuscitation (CA/CPR) rat model.. Healthy male Sprague-Dawley rats were subjected to 7 min CA by trans-esophageal electrical stimulation followed by CPR. The surviving rats were treated with FK866 (a selective inhibitor of NAMPT), Mdivi-1 (Drp1 inhibitor), FK866 + Mdivi-1, or vehicle and then underwent 24 h reperfusion. Hematoxylin and eosin staining and immunohistochemistry (to detect NSE) were used to evaluate brain injury. We performed immunofluorescent staining to analyze NLRP3 and GSDMD expression in microglia or astrocytes and western blot to determine expression of NLRP3, IL-1β, GSDMD, Drp1, and Mfn2. Transmission electron microscopy was used to observe mitochondria.. FK866 significantly decreased pathological damage to brain tissue, inhibited the activation of NLRP3 in microglia or astrocytes, downregulated the expression of NLRP3, IL-1β, GSDMD, p-Drp1 protein, upregulated Mfn2 and improve mitochondrial morphology.. Our results demonstrated that FK866 protects the brain against ischemia-reperfusion injury in rats after CA/CPR by inhibiting pyroptosis and inflammation mediated by Drp1.

Topics: Acrylamides; Animals; Anti-Inflammatory Agents; Brain; Cardiopulmonary Resuscitation; Disease Models, Animal; Dynamins; Inflammasomes; Inflammation Mediators; Male; Mitochondria; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Piperidines; Pyroptosis; Quinazolinones; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction

Emerging evidence reveals that nicotinamide phosphoribosyltransferase (NAMPT) has a significant role in the pathophysiology of the inflammatory process. NAMPT inhibition has a beneficial effect in the treatment of a variety of inflammatory diseases. However, it remains unclear whether NAMPT inhibition has an impact on ischemia-reperfusion (I/R)-induced acute lung injury. In this study, we examined whether NAMPT inhibition provided protection against I/R lung injury in rats.. Isolated perfused rat lungs were subjected to 40 min of ischemia followed by 60 min of reperfusion. The rats were randomly allotted to the control, control + FK866 (NAMPT inhibitor, 10 mg/kg), I/R, or I/R + FK866 groups (n = 6 per group). The effects of FK866 on human alveolar epithelial cells exposed to hypoxia-reoxygenation (H/R) were also investigated.. Treatment with FK866 significantly attenuated the increases in lung edema, pulmonary arterial pressure, lung injury scores, and TNF-α, CINC-1, and IL-6 concentrations in bronchoalveolar lavage fluid in the I/R group. Malondialdehyde levels, carbonyl contents and MPO-positive cells in lung tissue were also significantly reduced by FK866. Additionally, FK866 mitigated I/R-stimulated degradation of IκB-α, nuclear translocation of NF-κB, Akt phosphorylation, activation of mitogen-activated protein kinase, and downregulated MKP-1 activity in the injured lung tissue. Furthermore, FK866 increased Bcl-2 and decreased caspase-3 activity in the I/R rat lungs. Comparably, the in vitro experiments showed that FK866 also inhibited IL-8 production and NF-κB activation in human alveolar epithelial cells exposed to H/R.. Our findings suggest that NAMPT inhibition may be a novel therapeutic approach for I/R-induced lung injury. The protective effects involve the suppression of multiple signal pathways.

Topics: Acrylamides; Acute Lung Injury; Animals; Cytokines; Enzyme Activation; Lung; Male; Molecular Targeted Therapy; Nicotinamide Phosphoribosyltransferase; Piperidines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Treatment Outcome