Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury

Kim, Minso; Степанова, Анна; Niatsetskaya, Zoya; Sosunov, Sergey A.; Arndt, Sabine; Murphy, Michael P.; Galkin, Alexander; Ten, Vadim S.

doi:10.1016/j.freeradbiomed.2018.06.040

Cited by 50 publications

(49 citation statements)

References 39 publications

(60 reference statements)

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“…The primary driver of such mitochondrial-derived reactive oxygen species (ROS) is an ischemic accumulation of the tricarboxylic acid (TCA) cycle metabolite succinate [ 3 , [11] , [12] , [13] ]. Data obtained from ischemic brain mitochondria have further suggested, that the flavin mononucleotide (FMN) site of complex I is responsible for the production of ROS via reverse electron transfer (RET), and that accumulation of succinate triggers release of FMN from mitochondrial complex I [ 2 , 14 , 15 ].…”

Section: Resultsmentioning

confidence: 99%

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Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation

et al. 2020

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Background Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine perfusion in clinical transplant models. Methods We investigated mitochondrial metabolism of isolated perfused rat livers before transplantation. Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation. Findings Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function. Interpretation Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation. Funding detailed information can be found in Acknowledgments.

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Section: Resultsmentioning

confidence: 99%

“…Current discoveries in the field of hepatic ischemia-reperfusion (I/R) point to mitochondrial-derived oxidative stress as key mechanism of tissue damage [1] , [2] , [3] . Optimization strategies for the treatment of ischemic organs may, therefore, depend on effective protection from mitochondrial injury.…”

Section: Introductionmentioning

confidence: 99%

Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation

et al. 2020

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“… 20 In another study, Kim et al. 21 reported that cerebral hypoxia–ischemia deactivated complex I. Curcumin can increase SOD levels and decrease MDA levels in hypoxic–ischemic brain injury in neonatal rats. 22 NSE levels are also an important factor in neurological function.…”

Section: Discussionmentioning

confidence: 96%

“…A previous study showed a three to four-fold increase in oxidative protein carbonylation in the cortex, perirhinal cortex, and hippocampus of injured male rats with HIE, and increased glutathione peroxidase was found in female rats with HIE. 20 In another study, Kim et al 21 reported that cerebral hypoxia-ischemia deactivated complex I. Curcumin can increase SOD levels and decrease MDA levels in hypoxic-ischemic brain injury in neonatal rats. 22 NSE levels are also an important factor in neurological function.…”

Section: Discussionmentioning

confidence: 96%

Efficacy of different treatment times of mild cerebral hypothermia on oxidative factors and neuroprotective effects in neonatal patients with moderate/severe hypoxic–ischemic encephalopathy

Yang

2020

J Int Med Res

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Objective To investigate the efficacy of different treatment times of mild cerebral hypothermia for treating moderate/severe hypoxic–ischemic encephalopathy (HIE) in neonatal patients and its effects on oxidative factors. Methods This prospective, randomized, controlled study included 92 neonatal patients with moderate/severe HIE and 30 controls. The patients with HIE received routine treatment, 48 hours of hypothermia, or 72 hours of hypothermia. Results Superoxide dismutase (SOD) values were significantly lower and malondialdehyde (MDA) and neuron-specific enolase (NSE) values were higher in patients with HIE than in controls before the study. After 24, 48, and 72 hours of treatment, SOD values in all patients with HIE gradually increased and MDA and NSE values gradually decreased. At 3, 7, and 10 days, the Neonatal Behavioral Neurological Assessment scores were highest in the mild hypothermia for 72 hours group than in the other groups. The Mental and Psychomotor Development Indices scores of the Bayley Scales were significantly higher in the mild hypothermia for 72 hours group than in the other groups. Conclusion Hypothermia treatment of 72 hours is better than 48 hours for improving oxidative conditions, reducing NSE values, and improving neurological behavior and development for neonates with moderate/severe HIE.

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“…Previous study has shown that secondary inflammation after HI has been shown to contributes to HI-induced brain injury (17). The toxic effects of inflammatory cytokines include both direct free radical release and indirect excitatory amino acid production (18).…”

Section: Discussionmentioning

confidence: 99%

The effects of carnosine pretreatment on the inflammatory response and the PI3K/Akt signaling pathway following hypoxia-ischemia in neonatal rats

Zhang

Xia

Huang

et al. 2019

Preprint

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An increasing number of studies have demonstrated that carnosine plays a neuroprotective role in many types of brain injury. We have previously shown that carnosine has both short-term and long-lasting neuroprotective effects in a hypoxia-ischemia(HI) rat model. In the mature brain, post-ischemia neuronal survival involves in activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, whether the activation of PI3K/Akt pathway also plays an important role in the immature brain still remain unclear.The goal of this study is to detect the effection of carnosine on inflammation response following HI, further evidencing neuroprotection of carnosine.We measured total Akt, phospho-Akt (p-AKT) and tumor necrosis factor receptor 1 (TNFR1) protein levels by western blot assay and tumor necrosis factor-α (TNF-α) and TNFR1 mRNA expression using real-time RT-PCR. We found the carnosine-pretreated group had statistically significant downregulation of TNF-α mRNA levels 24 h after HI (P < 0.05). Similar results were observed when we measured TNFR1 mRNA levels both 24h and 72h after HI (P < 0.05). And the TNFR1 protein expression after HI was markedly decreased at 24 and 72 h post-HI in the carnosine-pretreated rats(P < 0.05). Nevertheless, the rats pretreated with carnosine showed a 2 marked increase in p-Akt levels (P< 0.05). And the pro-apoptotic protein Bad was also examined using immunohistochemistry after 24 and 72 h of all groups. We found significantly fewer Bad-positive cells in the carnosine-pretreated group at each time point after HI (P < 0.05). These findings suggest that carnosine pretreatment inhibits the HI-induced inflammatory response, and neuroprotection mechanism of carnosine involved in activation of the PI3K/Akt signaling pathway.

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Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury

Cited by 50 publications

References 39 publications

Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation

Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation

Efficacy of different treatment times of mild cerebral hypothermia on oxidative factors and neuroprotective effects in neonatal patients with moderate/severe hypoxic–ischemic encephalopathy

The effects of carnosine pretreatment on the inflammatory response and the PI3K/Akt signaling pathway following hypoxia-ischemia in neonatal rats

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