Effects of Postresuscitation N-Acetylcysteine on Cerebral Free Radical Production and Perfusion During Reoxygenation of Hypoxic Newborn Piglets

Abstract

ABSTRACT:Hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO) contribute to the pathogenesis of cerebral hypoxic-ischemic injury. We evaluated the neuroprotective effect of N-acetyl-L-cysteine (NAC, a free radical scavenger) against oxidative stress and perfusion in a model of neonatal hypoxia-reoxygenation (H-R). Piglets (1-3 d, 1.6 -2.3 kg) were randomized into a sham-operated group (without H-R) (n ϭ 5) and two H-R experimental groups (2 h normocapnic alveolar hypoxia followed by 4 h reoxygenation) (n ϭ 7/group). Five minutes after reoxygenation, piglets were given either i.v. saline (H-R controls) or NAC (30 mg/kg bolus then 20 mg/kg/h infusion) in a blinded-randomized fashion. Heart rate, mean arterial pressure, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H 2 O 2 and NO production (electrochemical sensor), cerebral tissue glutathione and nitrotyrosine levels (enzyme-linked immunosorbent assay) were examined. Hypoxic piglets were acidotic (pH 6.88 -6.90), which recovered similarly in the H-R groups (p Ͼ 0.05 versus shams). Postresuscitation NAC treatment significantly attenuated the increase in cortical H 2 O 2 , but not NO, concentration during reoxygenation, with lower cerebral oxidized glutathione levels. NAC-treated piglets had significantly higher carotid oxygen delivery and lower cerebral lactate levels than that of H-R controls with corresponding changes in carotid arterial flow and vascular resistance. In newborn piglets with H-R, postresuscitation administration of NAC reduced cerebral oxidative stress and improved cerebral perfusion. (Pediatr Res 64: 256-261, 2008)

Cerebral Amino Acid Profiles after Hypoxia-Reoxygenation and N-Acetylcysteine Treatment in the Newborn Piglet

“…However, in addition to being vulnerable to oxidative stress caused by HI, the immature CNS is also susceptible to oxidative stress caused by resuscitative respiratory support [32] . We previously investigated the effects of the antioxidant NAC in the swine model of neonatal H/R and showed that NAC improved systemic and cerebral hemodynamics [24,26] , re- duced oxidized glutathione and hydrogen peroxide [25,26] , and significantly protected other vital organs vulnerable to hypoxic injury. The present investigation builds on these findings and, to the best of our knowledge, we are the first to report that in the critical acute time period after H/R, administration of NAC maintains cerebral amino acid profiles.…”

“…Subsequently, we built on these findings to demonstrate that post-resuscitation administration of NAC reduces cerebral hydrogen peroxide and oxidized glutathione, improves carotid oxygen delivery and lowers cerebral lactate in neonatal H/R [25,26] . However, whether NAC maintains, restores or has no effect on brain amino acids after H/R is not yet known.…”

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

“…Ряд исследований рассматривает роль еще одного антиоксиданта в качестве нейропро-тектора при гипоксии-ишемии -противосвободнора-дикального агента N-ацетилцистеина (N-acetylcysteine, NAC) [155,156]. Его защитный эффект проявляется при введении как до, так и после гипоксии-ишемии, и счи-тается более выраженным, чем у других агентов, в том числе по сравнению с мелатонином [157].…”

Nevroprotektiv behandling ved fødselsasfyksi

“…N-acetyl cysteine is claimed to traverse the placenta and blood-brain barrier (31), can be safely used during pregnancy (32) and is a source of L-cysteine which is necessary for the formation of the endogenous antioxidant glutathione (31). Studies of neonatal pigs have shown that N-acetyl cysteine administered as an intravenous bolus of 150 mg/kg or 30 mg/kg ten or five minutes after the start of reoxygenation, followed by 100 mg/kg/hour or 20 mg/kg/hour reduces oxidative stress after hypoxia/ischaemia and improves systemic and cerebral haemodynamics (33,34).…”