Drug Design, Development and Therapy (Mar 2020)
PD98059 Protects Cerebral Cortex Mitochondrial Structure and Function at 48 h Post-Resuscitation in a Rat Model of Cardiac Arrest
Abstract
Jun-Hui Zheng,1 Meng-Hua Chen,2 Zhao-Yin Fu,2 Nuo Li,2 Lu Xie3 1Integrated Internal Medicine, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 2Department of Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People’s Republic of China; 3Department of Physiology, Pre-Clinical Science, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaCorrespondence: Lu XieDepartment of Physiology, Pre-Clinical Science, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, People’s Republic of ChinaTel +86 137 0788 5560Email [email protected]: Mitochondria play a critical role as effectors and targets of brain injury in the post-resuscitation period. Although we found previously that the extracellular signal-regulated kinase (ERK)1/2 inhibitor PD98059 (PD) protects the brain against mitochondrial-mediated cell death at 24 h post-resuscitation in rats subjected to cardiac arrest/cardiopulmonary resuscitation (CA/CPR), it is not clear whether PD also exerts mitochondrial protective effect for a lasting time. Therefore, we examined the effect of PD on brain mitochondria at 48 h post-resuscitation to evaluate the time-effect of PD in the current study.Methods: Experimental rats were divided randomly into 5 groups: Sham, CA, dimethylsulfoxide (DMSO), 0.15mg/kg PD and 0.3mg/kg PD. Rats except for sham group were subjected to CA for 6 min followed by CPR. We detected survival rates and neurologic deficit scores, cerebral cortex mitochondrial function by evaluating adenosine triphosphate (ATP) levels, mitochondrial permeability transition pore (MPTP) opening, and the expression of mitofusin2 (Mfn2) and observing the ultrastructure by electron microscopy at 48 h post-resuscitation in a 6-min CA rat model.Results: PD improved survival rates and neurologic deficit scores, alleviated cerebral cortex mitochondrial damage by reducing MPTP opening and increasing Mfn2 production at 48 h post-resuscitation in a 6-min CA rat model.Conclusion: A single dose of PD improved 48 h post-resuscitation outcome and mitochondrial function, indicating the potential of the use of ERK inhibitors for the treatment of brain injury resulting from CA in the future.Keywords: cardiac arrest, extracellular signal-regulated kinase, mitochondria, mitofusin2, mitochondrial permeability transition pore
