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

Abstract

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.

DHA reduces oxidative stress following hypoxia-ischemia in newborn piglets: a study of lipid peroxidation products in urine and plasma

“…Additional adjuvant strategies There are other treatments that have been tried out in addition to therapeutic hypothermia. These include noble gasses like Xenon and Argon, remote ischemic post-conditioning and the free-radical scavengers N-acetylcystein and N-acetylcystein amide [100][101][102][103][104][105] .…”

“…This was the first study that we know where DHA was administered in a large-animal model. We wanted to investigate the following in our well established piglet model: Preclinical models of hypoxic-ischemic injury involve a range from invitro studies of cell cultures 154 and brain slices 155 to animal models ranging from rodents 133,138 to larger lamb 156,157 and piglet models 59,89,103 and even to non-human primates 158 .…”

“…Anesthesia was maintained by a continuous infusion of fentanyl 50 μg/kg/hour and midazolam 0.25 mg/kg/h, yielding 1 ml/kg/hour for each drug. These modalities have been used extensively on newborn piglets in our research group 103,163,167,168 . The drugs have been thoroughly tested in newborn piglets 169,170 and we are aware of the alterations in cerebral blood flow that fentanyl 171 , phenobarbital 172 , and midazolam 173 exert.…”

Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide

“…Our group has recently described anti-inflammatory and possible neuroprotective effects of the antioxidant N-acetylcysteine amide (NACA) after neonatal hypoxia-reoxygenation in a neonatal pig model. Further, NACA reduced the levels of the proinflammatory cytokine IL-1 β and the transcription factor NF- κ B in the prefrontal cortex of the brain after neonatal hypoxia-reoxygenation [ 6 ]. The substance NACA has many similarities with N-acetylcysteine, which has been used as an antioxidant precursor to glutathione in the treatment of paracetamol overdose for more than 30 years [ 7 ].…”

N-Acetylcysteine Amide (NACA) Reduces Cell Death after Oxidative Stress in a Porcine Embryonic Kidney Cell Line

“…Recently, we have published a study demonstrating that NACA displayed antiinflammatory properties after exposure to oxidative stress in an established neonatal piglet model, imitating perinatal asphyxia [2]. Our piglet model has been established for many years and several authors have shown a significant increase in markers of oxidative stress after the inflicted asphyxia [3].…”