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      PD98059 Protects Cerebral Cortex Mitochondrial Structure and Function at 48 h Post-Resuscitation in a Rat Model of Cardiac Arrest

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          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.


          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.


          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.


          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.

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          Most cited references 18

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          Mitochondrial dynamics--mitochondrial fission and fusion in human diseases.

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            Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore.

            Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, postmitotic cells, in response to sublethal noxious stress, engage mechanisms that afford protection from subsequent insults. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. Cell protection that exhibits a memory (preconditioning) results from triggered mitochondrial swelling that causes enhanced substrate oxidation and ROS production, leading to redox activation of PKC, which inhibits glycogen synthase kinase-3beta (GSK-3beta). Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3beta, via protein kinase B/Akt and mTOR/p70(s6k) pathways, PKC pathways, or protein kinase A pathways. The convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection.
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              The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury.

              The mitochondrial permeability transition pore (MPTP) is a non-specific pore that opens in the inner mitochondrial membrane (IMM) when matrix [Ca(2+)] is high, especially when accompanied by oxidative stress, high [Pi] and adenine nucleotide depletion. Such conditions occur during ischaemia and subsequent reperfusion, when MPTP opening is known to occur and cause irreversible damage to the heart. Matrix cyclophilin D facilitates MPTP opening and is the target of its inhibition by cyclosporin A that is cardioprotective. Less certainty exists over the composition of the pore itself, with structural and/or regulatory roles proposed for the adenine nucleotide translocase, the phosphate carrier and the FoF1 ATP synthase. Here we critically review the supporting data for the role of each and suggest that they may interact with each other through their bound cardiolipin to form the ATP synthasome. We propose that under conditions favouring MPTP opening, calcium-triggered conformational changes in these proteins may perturb the interface between them generating the pore. Proteins associated with the outer mitochondrial membrane (OMM), such as members of the Bcl-2 family and hexokinase (HK), whilst not directly involved in pore formation, may regulate MPTP opening through interactions between OMM and IMM proteins at "contact sites". Recent evidence suggests that cardioprotective protocols such as preconditioning inhibit MPTP opening at reperfusion by preventing the loss of mitochondrial bound HK2 that stabilises these contact sites. Contact site breakage both sensitises the MPTP to [Ca(2+)] and facilitates cytochrome c loss from the intermembrane space leading to greater ROS production and further MPTP opening. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                12 March 2020
                : 14
                : 1107-1115
                [1 ]Integrated Internal Medicine, Affiliated Tumor Hospital of Guangxi Medical University , Nanning, Guangxi 530021, People’s Republic of China
                [2 ]Department of Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University , Nanning, Guangxi 530000, People’s Republic of China
                [3 ]Department of Physiology, Pre-Clinical Science, Guangxi Medical University , Nanning, Guangxi 530021, People’s Republic of China
                Author notes
                Correspondence: Lu Xie Department of Physiology, Pre-Clinical Science, Guangxi Medical University , 22 Shuangyong Road, Nanning530021, People’s Republic of ChinaTel +86 137 0788 5560 Email xielu8282@163.com
                © 2020 Zheng et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 2, References: 31, Pages: 9
                Original Research


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