Antioxidant Protects against Increases in Low Molecular Weight Hyaluronan and Inflammation in Asphyxiated Newborn Pigs Resuscitated with 100% Oxygen

Østerholt, Helene C. D.; Dannevig, Ingrid; Wyckoff, Myra H.; Liao, Jie; Akgul, Yucel; Ramgopal, Mrithyunjay; Mija, Dan; Cheong, Naeun; Longoria, Christopher; Mahendroo, Mala; Nakstad, Britt; Saugstad, Ola Didrik; Savani, Rashmin C.

doi:10.1371/journal.pone.0038839

Cited by 29 publications

(24 citation statements)

References 78 publications

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“…Interestingly, we now found a positive correlation between MPO, NAG, and ADA1 activities in the cerebral cortex. This finding supports that ADA, as MPO, NAG, is a marker of the inflammatory process [43][44][45][46][47].…”

Section: Discussionsupporting

confidence: 82%

Neuroinflammation after neonatal hypoxia–ischemia is associated with alterations in the purinergic system: adenosine deaminase 1 isoenzyme is the most predominant after insult

et al. 2015

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Hypoxic-ischemic (HI) injury perinatal brain is a major contributor to morbidity and mortality to infants and children. Adenosine may play a role in the pathophysiology of HI, since it modulates the inflammatory process and the release of several neurotransmitters. Thus, the aim of this study was to identify the isoforms of adenosine deaminase (ADA) responsible for the enzymatic activity as well as the adenosine kinase (ADK) and A1 adenosine receptor (A1R) expression in the cerebral cortex eight days after HI. Myeloperoxidase (MPO) and N-acetyl-glucosaminidase (NAG) were assessed as inflammation markers. ADA activity was analyzed, in the presence or absence of a specific ADA1 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine. The ADA1 activity (92.6%) was significantly higher than ADA2 (7.4%) activity in the cerebral cortex eight days after HI. A1Rs and ADK protein expression showed decreased 8 days after insult. Interestingly, the ADA1, MPO, and NAG activities were correlated positively. In view of this, we conclude that the inhibitor of ADA1, in in vitro conditions, was effective in decreasing the ADA activity, and that mainly ADA1 isoform is responsible for the increase in the ADA activity 8 days after HI insult. Therefore, HI neonatal was able to alter the ADK and A1R expression. Thus, due to the importance of adenosine signaling in the regulation of inflammatory and immune process and the crucial role of ADA in the postischemic homeostase of adenosine as well as during inflammatory process, we suggest that ADA1 inhibitors may play an important role in the regulation of events that follow the HI insult, favoring the increase in the adenosine in the sites of tissue injury. Together, these results highlight a role of the purinergic signaling cascade in the pathophysiology of HI neonatal.

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Section: Discussionsupporting

confidence: 82%

Neuroinflammation after neonatal hypoxia–ischemia is associated with alterations in the purinergic system: adenosine deaminase 1 isoenzyme is the most predominant after insult

et al. 2015

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“…In this study, we used an established pig model of perinatal hypoxia-reoxygenation to induce oxidative stress [7]. We investigated a potential protective effect of NACA on newborn piglets exposed to hypoxia and reoxygenation.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, our group showed previously that NAC attenuated the increase of oxidative stress in a neonatal pig model and reduced the levels of IL-1β [7]. Moreover, several investigators have displayed the many similar antioxidative effects of NAC and NACA [8,9].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated that N-acetylcysteine (NAC), a precursor of the endogenous antioxidant glutathione, has potential organ- and neuroprotective abilities when administered immediately after neonatal hypoxia-reoxygenation [5,6,7]. Recently, it has been revealed that NAC amide (NACA), an NAC derivate with higher bioavailability and enhanced antioxidant properties [8,9], may significantly mitigate the detrimental consequences of various toxic substances in different organs, including the lungs and kidneys [10,11,12].…”

Section: Introductionmentioning

confidence: 99%

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N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia

et al. 2016

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Background: Perinatal asphyxia and ensuing reoxygenation change the antioxidant capacity of cells and organs. Objectives: To analyze the neuroprotective effect of the antioxidant N-acetylcysteine amide (NACA) after perinatal hypoxia-reoxygenation with an emphasis on proinflammatory cytokines and the transcription factor NF-κB in the prefrontal cortex of neonatal pigs. Methods: Twenty-nine newborn pigs, aged 12-36 h, were subjected to global hypoxia and hypercapnia. One sham-operated group (n = 5) and 2 experimental groups (n = 12) were exposed to 8% oxygen, until the base excess was -20 mmol/l or the mean arterial blood pressure fell to <20 mm Hg (asphyxia with NACA or saline). The pigs were observed for 9.5 h after hypoxia. Samples of prefrontal cortex and plasma were analyzed. Results: Cortex: there was no significant difference in mRNA expression between the intervention groups regarding IL-1β, IL6, TNFα, MMP2, MMP9 or IL18. Pigs exposed to hypoxia-reoxygenation and treatment with NACA (NACA-pigs) had a significantly lower protein concentration of IL-1β than pigs treated with saline (placebo controls), i.e. 8.8 ± 3.9 versus 16.8 ± 10.5 pg/mg protein (p = 0.02). The activation of the transcription factor NF-κB (measured as the fold-change of phosphorylated p65^{Ser 536}), was reduced in the NACA-pigs when compared to the placebo controls (5.2 ± 4.3 vs. 16.0 ± 13.5; p = 0.02). No difference between the intervention groups regarding brain histopathology or in the levels of 8-oxoguanine measured in the prefrontal cortex were observed. Plasma: the NACA-pigs had a stronger reduction of TNFα in the first 30 min following asphyxia compared with the placebo controls, i.e. 36 (30-44) versus 24 (14-32)% (p = 0.01). Conclusion: The reduced levels of the pivotal inflammatory markers IL-1β and TNFα and the transcription factor NF-κB may indicate that NACA has possible neuroprotective effects after perinatal asphyxia.

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“…Vitamins A, E and N-acetyl-cysteine failed to reduce the occurrence of BPD in preterm newborns (175,185), and intravenous GSH did not improve acute respiratory outcomes in preterm baboons (160). In contrast to previous observations (6), a recent study in the animal model of hyperoxic resuscitation after perinatal asphyxia suggested a potential role for N-acetylcysteine in lung protection, as it was proved to reduce lung and systemic levels of OS and inflammatory markers (111). Moreover, pentoxifillyne, a phosphodiesterase inhibitor with immunomodulatory and antifibrotic features, has been investigated in the animal model of hyperoxia, and it was proved to reduce lung edema and neutrophils influx, while it increased lung activity of SOD, CAT, and GPx (9), in agreement with previous reports of reduced inflammatory cytokines in tracheal aspirates (173) and lung protection against mechanical ventilation-induced injury (81,158).…”

Section: Melatonin and Other Antioxidantsmentioning

confidence: 97%

The Role of Genetic Polymorphisms in Antioxidant Enzymes and Potential Antioxidant Therapies in Neonatal Lung Disease

Dani

Poggi

2014

Antioxidants & Redox Signaling

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Significance: Oxidative stress is involved in the development of newborn lung diseases, such as bronchopulmonary dysplasia and persistent pulmonary hypertension of the newborn. The activity of antioxidant enzymes (AOEs), which is impaired as a result of prematurity and oxidative injury, may be further affected by specific genetic polymorphisms or an unfavorable combination of more of them. Recent Advances: Genetic polymorphisms of superoxide dismutase and catalase were recently demonstrated to be protective or risk factors for the main complications of prematurity. A lot of research focused on the potential of different antioxidant strategies in the prevention and treatment of lung diseases of the newborn, providing promising results in experimental models. Critical Issues: The effect of different genetic polymorphisms on protein synthesis and activity has been poorly detailed in the newborn, hindering to derive conclusive results from the observed associations with adverse outcomes. Therapeutic strategies that aimed at enhancing the activity of AOEs were poorly studied in clinical settings and partially failed to produce clinical benefits. Future Directions: The clarification of the effects of genetic polymorphisms on the proteomics of the newborn is mandatory, as well as the assessment of a larger number of polymorphisms with a possible correlation with adverse outcome. Moreover, antioxidant treatments should be carefully translated to clinical settings, after further details on optimal doses, administration techniques, and adverse effects are provided. Finally, the study of genetic polymorphisms could help select a specific high-risk population, who may particularly benefit from targeted antioxidant strategies.

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Antioxidant Protects against Increases in Low Molecular Weight Hyaluronan and Inflammation in Asphyxiated Newborn Pigs Resuscitated with 100% Oxygen

Cited by 29 publications

References 78 publications

Neuroinflammation after neonatal hypoxia–ischemia is associated with alterations in the purinergic system: adenosine deaminase 1 isoenzyme is the most predominant after insult

Neuroinflammation after neonatal hypoxia–ischemia is associated with alterations in the purinergic system: adenosine deaminase 1 isoenzyme is the most predominant after insult

N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia

The Role of Genetic Polymorphisms in Antioxidant Enzymes and Potential Antioxidant Therapies in Neonatal Lung Disease

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