Li-Min Zhang1, Dong-Xue Zhang2, Lan Fu3, Yan Li4, Xu-Peng Wang4, Man-Man Qi4, Chen-Chen Li4, Pan-Pan Song4, Xiao-Dong Wang4, Xiang-Jun Kong5. 1. Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China. Electronic address: azai2010@126.com. 2. Department of Gerontology, Cangzhou Central Hospital, Cangzhou, China. 3. Department of Radiodiagnosis, Cangzhou Central Hospital, Cangzhou, China. 4. Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China. 5. Central Laboratory, Cangzhou Central Hospital, Cangzhou, China.
Abstract
OBJECTIVE: Carbon monoxide (CO) releasing molecule (CORM)-3, a water-soluble CORM, has protective effects against inflammatory and ischemia/reperfusion injury. We determined the effect of CORM-3 against neuronal pyroptosis in a model of hemorrhagic shock and resuscitation (HSR) in rats via mitochondrial regulation. METHODS: Rats were treated with CORM-3 (4 mg/kg) in vitro after HSR. We measured cortical CO content 3-24 h after HSR; assessed neuronal pyroptosis, mitochondrial morphology, ROS production, and mitochondrial membrane potential at 12 h after HSR; and evaluated brain magnetic resonance imaging at 24 h after HSR and learning ability 30 days after HSR. We also measured soluble guanylate-cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway activity using a blocker of sGC, NS2028, and 125I-cGMP assay. RESULTS: Among rats that underwent HSR, CORM-3-treated rats had more CO in the cortical tissue than sham- and iCORM-3-treated rats. CORM-3-treated rats had significantly less neuronal pyroptosis in the cortical tissue; higher sGC activity and cGMP content; lower ROS production; better mitochondrial morphology, function, and membrane potential; and enhanced learning/memory ability than HSR-treated rats. However, these neuroprotective effects of CORM-3 were partially inhibited by NS2028. CONCLUSION: CORM-3 may alleviate neuronal pyroptosis and improve neurological recovery in HSR through mitochondrial regulation mediated by the sGC-cGMP pathway. Thus, CO administration could be a promising therapeutic strategy for hemorrhagic shock.
OBJECTIVE:Carbon monoxide (CO) releasing molecule (CORM)-3, a water-soluble CORM, has protective effects against inflammatory and ischemia/reperfusion injury. We determined the effect of CORM-3 against neuronal pyroptosis in a model of hemorrhagic shock and resuscitation (HSR) in rats via mitochondrial regulation. METHODS:Rats were treated with CORM-3 (4 mg/kg) in vitro after HSR. We measured cortical CO content 3-24 h after HSR; assessed neuronal pyroptosis, mitochondrial morphology, ROS production, and mitochondrial membrane potential at 12 h after HSR; and evaluated brain magnetic resonance imaging at 24 h after HSR and learning ability 30 days after HSR. We also measured soluble guanylate-cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway activity using a blocker of sGC, NS2028, and 125I-cGMP assay. RESULTS: Among rats that underwent HSR, CORM-3-treated rats had more CO in the cortical tissue than sham- and iCORM-3-treated rats. CORM-3-treated rats had significantly less neuronal pyroptosis in the cortical tissue; higher sGC activity and cGMP content; lower ROS production; better mitochondrial morphology, function, and membrane potential; and enhanced learning/memory ability than HSR-treated rats. However, these neuroprotective effects of CORM-3 were partially inhibited by NS2028. CONCLUSION: CORM-3 may alleviate neuronal pyroptosis and improve neurological recovery in HSR through mitochondrial regulation mediated by the sGC-cGMP pathway. Thus, CO administration could be a promising therapeutic strategy for hemorrhagic shock.