Mechanism and Treatment Related to Oxidative Stress in Neonatal Hypoxic-Ischemic Encephalopathy

Qin, Xingping; Cheng, Jing; Zhong, Yi; Mahgoub, Omer Kamal; Akter, Farhana; Fan, Yanqin; Aldughaim, Mohammed S.; Xie, Qiurong; Qin, Lingxia; Gu, Lijuan; Jian, Zhihong; Xiong, Xiaoxing; Liu, Renzhong

doi:10.3389/fnmol.2019.00088

Cited by 67 publications

(61 citation statements)

References 127 publications

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“…The current therapeutic strategies for neonatal oxidative stress treatment include mitochondrial therapy, stem cell transplantation, inhibitors and scavengers of free radicals, excitatory amino acid antagonists, hyperbaric oxygen (HBO) therapy and hypothermic treatments [ 18 ]. Compounds such as metformin [ 19 ], coenzyme Q10 [ 20 ] and mitoquinone [ 21 ], which directly regulate mitochondrial functions, seem to be promising.…”

Section: Introductionmentioning

confidence: 99%

N-Acetylaspartylglutamate (NAAG) Pretreatment Reduces Hypoxic-Ischemic Brain Damage and Oxidative Stress in Neonatal Rats

2020

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N-acetylaspartylglutamate (NAAG), the most abundant peptide transmitter in the mammalian nervous system, activates mGluR3 at presynaptic sites, inhibiting the release of glutamate, and acts on mGluR3 on astrocytes, stimulating the release of neuroprotective growth factors (TGF-β). NAAG can also affect N-methyl-d-aspartate (NMDA) receptors in both synaptic and extrasynaptic regions. NAAG reduces neurodegeneration in a neonatal rat model of hypoxia-ischemia (HI), although the exact mechanism is not fully recognized. In the present study, the effect of NAAG application 24 or 1 h before experimental birth asphyxia on oxidative stress markers and the potential mechanisms of neuroprotection on 7-day old rats was investigated. The intraperitoneal application of NAAG at either time point before HI significantly reduced the weight deficit of the ischemic brain hemisphere, radical oxygen species (ROS) content and activity of antioxidant enzymes, and increased the concentration of reduced glutathione (GSH). No additional increase in the TGF-β concentration was observed after NAAG application. The fast metabolism of NAAG and the decrease in TGF-β concentration that resulted from NAAG pretreatment, performed up to 24 h before HI, excluded the involvement mGluR3 in neuroprotection. The observed effect may be explained by the activation of NMDA receptors induced by NAAG pretreatment 24 h before HI. Inhibition of the NAAG effect by memantine supports this conclusion. NAAG preconditioning 1 h before HI results in a mixture of mGluR3 and NMDA receptor activation. Preconditioning with NAAG induces the antioxidative defense system triggered by mild excitotoxicity in neurons. Moreover, this response to NAAG pretreatment is consistent with the commonly accepted mechanism of preconditioning. However, this theory requires further investigation.

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Section: Introductionmentioning

confidence: 99%

N-Acetylaspartylglutamate (NAAG) Pretreatment Reduces Hypoxic-Ischemic Brain Damage and Oxidative Stress in Neonatal Rats

2020

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“…Oxidative stress could interact with the inflammatory system after HI injury, activating microglia and astrocytes, which produce a mass of inflammatory cytokines, such as IL‐1α, IL‐1β, IL‐6, and TNF‐α. These inflammatory cytokines would induce neuronal apoptosis and exacerbate the damage of brain tissue (Qin et al., 2019). Consistently, our results showed that the contents of pro‐inflammatory cytokines were increased in the brain of mice subjected to HI injury.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxic‐ischemic (HI) brain injury in neonates is a serious complication that happens before or around birth due to lack of blood flow and oxygen deprivation to the brain. It occurs in about 1.5/1000 live birth and accounts for 25% of neonatal death worldwide (Qin et al., 2019). Although over the past a few decades the morbidity and mortality rates after HI brain injury has markedly reduced, perinatal HI brain injury would result in irreversible and lifelong motor and cognitive disabilities that becomes a significant health problem in the world (Todd, Jantzie, & Cheung, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Although over the past a few decades the morbidity and mortality rates after HI brain injury has markedly reduced, perinatal HI brain injury would result in irreversible and lifelong motor and cognitive disabilities that becomes a significant health problem in the world (Todd, Jantzie, & Cheung, 2011). The pathophysiology of HI brain injury has been widely studied (Allen & Brandon, 2011; Qin et al., 2019) and inflammation and oxidative stress are shown to play critical roles in this process.…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective role of Nrf2 on hypoxic‐ischemic brain injury in neonatal mice

Zhang

Dou

Yang

2020

Synapse

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Inflammation and oxidative stress play a key role in mediating the pathophysiology of hypoxic‐ischemic (HI) brain injury. Nrf2 is a transcriptional factor that contributes to the innate defense of the body against oxidative stress and inflammation. The current study investigated the effect of Nrf2 in neonatal HI brain injury using Nrf2−/− mice. Nrf2−/− and wild‐type Nrf2+/+ mice on a C57BL/6J background at postnatal day 9 underwent unilateral common carotid artery ligation, followed by hypoxia. Brain damage was determined by infarct size measurement. Apoptosis was evaluated by measuring the expression of Bax and Bcl‐2. The levels of inflammatory cytokines and mediators involved in oxidative stress were measured. Nrf2 knockout exacerbated HI injury‐induced brain infarct and cell apoptosis in the brain. Nrf2−/− mice showed increased inflammatory cytokines and MDA, and reduced activities of antioxidant enzymes including CAT, GSH‐Px, and SOD. Nrf2−/− mice showed reduced HO‐1 expression after HI injury compared with wild‐type mice. This study supported a protective effect of Nrf2 in neonatal HI brain injury.

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“…After ischemic brain injury, the overproduction of ROS not only directly damaged neurons and resulted in neuronal apoptosis but also indirectly caused neuronal degeneration by regulating mitochondrial pathways, DNA repair enzymes, and transcription factors [ 10 ]. Among many factors involved in the pathogenesis of neonatal HIE [ 11 ], OS plays a crucial role in the neuronal degeneration and apoptosis [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Rh-CSF1 Attenuates Oxidative Stress and Neuronal Apoptosis via the CSF1R/PLCG2/PKA/UCP2 Signaling Pathway in a Rat Model of Neonatal HIE

Xiao

Liu

Doycheva

et al. 2020

Oxidative Medicine and Cellular Longevity

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Oxidative stress (OS) and neuronal apoptosis are major pathological processes after hypoxic-ischemic encephalopathy (HIE). Colony stimulating factor 1 (CSF1), binding to CSF1 receptor (CSF1R), has been shown to reduce neuronal loss after hypoxic-ischemia- (HI-) induced brain injury. In the present study, we hypothesized that CSF1 could alleviate OS-induced neuronal degeneration and apoptosis through the CSF1R/PLCG2/PKA/UCP2 signaling pathway in a rat model of HI. A total of 127 ten-day old Sprague Dawley rat pups were used. HI was induced by right common carotid artery ligation with subsequent exposure to hypoxia for 2.5 h. Exogenous recombinant human CSF1 (rh-CSF1) was administered intranasally at 1 h and 24 h after HI. The CSF1R inhibitor, BLZ945, or phospholipase C-gamma 2 (PLCG2) inhibitor, U73122, was injected intraperitoneally at 1 h before HI induction. Brain infarct volume measurement, cliff avoidance test, righting reflex test, double immunofluorescence staining, western blot assessment, 8-OHdG and MitoSOX staining, Fluoro-Jade C staining, and TUNEL staining were used. Our results indicated that the expressions of endogenous CSF1, CSF1R, p-CSF1R, p-PLCG2, p-PKA, and uncoupling protein2 (UCP2) were increased after HI. CSF1 and CSF1R were expressed in neurons and astrocytes. Rh-CSF1 treatment significantly attenuated neurological deficits, infarct volume, OS, neuronal apoptosis, and degeneration at 48 h after HI. Moreover, activation of CSF1R by rh-CSF1 significantly increased the brain tissue expressions of p-PLCG2, p-PKA, UCP2, and Bcl2/Bax ratio, but reduced the expression of cleaved caspase-3. The neuroprotective effects of rh-CSF1 were abolished by BLZ945 or U73122. These results suggested that rh-CSF1 treatment attenuated OS-induced neuronal degeneration and apoptosis after HI, at least in part, through the CSF1R/PLCG2/PKA/UCP2 signaling pathway. Rh-CSF1 may serve as therapeutic strategy against brain damage in patients with HIE.

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Mechanism and Treatment Related to Oxidative Stress in Neonatal Hypoxic-Ischemic Encephalopathy

Cited by 67 publications

References 127 publications

N-Acetylaspartylglutamate (NAAG) Pretreatment Reduces Hypoxic-Ischemic Brain Damage and Oxidative Stress in Neonatal Rats

N-Acetylaspartylglutamate (NAAG) Pretreatment Reduces Hypoxic-Ischemic Brain Damage and Oxidative Stress in Neonatal Rats

Neuroprotective role of Nrf2 on hypoxic‐ischemic brain injury in neonatal mice

Rh-CSF1 Attenuates Oxidative Stress and Neuronal Apoptosis via the CSF1R/PLCG2/PKA/UCP2 Signaling Pathway in a Rat Model of Neonatal HIE

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