Postresuscitation N-acetylcysteine treatment reduces cerebral hydrogen peroxide in the hypoxic piglet brain
- 109 Downloads
Reactive oxygen species have been implicated in the pathogenesis of hypoxia–reoxygenation injury. However, little information is known regarding the temporal profile of cerebral hydrogen peroxide (HPO) production and its response to N-acetylcysteine (an antioxidant) administration during neonatal hypoxia–reoxygenation. Using an acute swine model of neonatal hypoxia–reoxygenation, we examined the short-term neuroprotective effects of N-acetylcysteine on cerebral HPO production and oxidative stress in the brain.
Controlled, block-randomized animal study.
University animal research laboratory.
Newborn piglets (1–3 days, 1.7–2.1 kg).
At 5 min after reoxygenation, piglets were given either saline or N-acetylcysteine (20 or 100 mg/kg/h) in a blinded, randomized fashion.
Measurements and results
Newborn piglets were block-randomized into a sham-operated group (without hypoxia–reoxygenation, n = 5) and three hypoxic–reoxygenated groups (2 h of normocapnic alveolar hypoxia followed by 2 h of reoxygenation, n = 7/group). Heart rate, mean arterial pressure, cortical HPO concentration, amino acid levels in cerebral microdialysate, and cerebral tissue glutathione and lipid hydroperoxide levels were examined. Hypoxic piglets were hypotensive and acidotic, and they recovered similarly in all hypoxic–reoxygenated groups. In hypoxic–reoxygenated control piglets, the cortical HPO concentration gradually increased during reoxygenation. Both doses of N-acetylcysteine abolished the increased HPO concentration and oxidized glutathione levels and tended to reduce the glutathione ratio and lipid hydroperoxide levels in the cerebral cortex (p = 0.08 and p = 0.1 vs. controls, respectively). N-acetylcysteine at 100 mg/kg/h also increased the cerebral extracellular taurine levels.
In newborn piglets with hypoxia–reoxygenation, postresuscitation administration of N-acetylcysteine reduces cerebral HPO production and oxidative stress, probably through a taurine-related mechanism.
KeywordsN-acetylcysteine Hypoxia–reoxygenation Neonates Oxidative stress Hydrogen peroxide
This project was funded by an operating grant from the Canadian Institutes of Health Research (MOP-CSB-53009) and a grant-in-aid from the George and Dorothy Davey Endowment for Brain Injury Research. P.Y.C. is an investigator with the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. L.L.J. is a recipient of a Canada Graduate Scholarship from the Natural Science and Engineering Research Council of Canada and a doctoral research award from the Alberta Heritage Foundation of Medical Research. There is no financial conflict of interest in this work.
- 11.Lee TF, Jantzie LL, Todd KG, Cheung P-Y (2007) Postresuscitation administration of N-acetylcysteine attenuates cerebral free radical generation during reoxygenation of hypoxic newborn piglets. E-PAS:618443.8 (abstract)Google Scholar
- 12.Ortalani O, Conti A, De Gaudio AR, Moraldi E, Cantini Q, Novelli G (2000) The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in patients with early septic shock. Am J Respir Crit Care Med 161:1907–1911Google Scholar
- 15.Richards JG, Todd KG, Emara M, Haase E, Cooper SL, Bigam DL, Cheung PY (2006) A dose-response study of graded reoxygenation on the carotid haemodynamics, matrix metalloproteinase-2 activities and amino acid concentrations in the brain of asphyxiated newborn piglets. Resuscitation 69:319–327PubMedCrossRefGoogle Scholar
- 16.Johnson ST, Bigam DL, Emara M, Obaid L, Slack G, Korbutt G, Korbutt G, Jewell LD, Van Aerde J, Cheung PY (2007) N-acetylcysteine improves the hemodynamics and oxidative stress in hypoxic newborn pigs reoxygenated with 100% oxygen. Shock 2007 Jun 17 [Epub ahead of print]Google Scholar
- 17.Jantzie LL, Rauw GA, Todd KG (2006) The effects of doxycycline administration on amino acid neurotransmitters in an animal model of neonatal hypoxia–ischemia. Neurochem Inter 49:771–728Google Scholar
- 32.Muhling J, Nickolaus KA, Halabi M, Fuchs M, Krull M, Engel J, Wolff M, Matejec R, Langefeld TW, Welters ID, Menges T, Dehne MG, Sablotzki A, Hempelmann G (2005) Alterations in neutrophil (PMN) free intracellular alpha-keto a profiles and immune functions induced by L-alanyl-L-glutamine, arginine or taurine. Amino Acids 29:289–300PubMedCrossRefGoogle Scholar