Combination of Systemic Hypothermia and N-acetylcysteine Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

Abstract

Hypoxic ischemic (HI) injury in neonates may have devastating, long-term consequences. Recently completed clinical trials in HI neonates indicate that hypothermia within 6 h of birth results in modest improvement in the combined outcome of death or severe disability. The aim of this study was to investigate the effects of combining hypothermia and N-acetylcysteine (NAC) on brain injury, neonatal reflexes and myelination after neonatal HI. Sevenday-old rats were subjected to right common carotid artery ligation and hypoxia (8% oxygen) for 2 h. Systemic hypothermia (30 ϩ 0.5°C) was induced immediately after the period of HI and was maintained for 2 h. NAC (50 mg/kg) was administered by intraperitoneal injection daily until sacrifice. Brain infarct volumes were significantly reduced at 48 h post-HI in the hypothermia plus NAC group (21.5 Ϯ 3.84 mm3) compared with vehicle (240.85 Ϯ 4.08 mm 3 ). Neonatal reflexes were also significantly improved by combination therapy at days 1 and 7. There was a significant loss of right hemispheric brain volume in the untreated group at 2 and 4 wk after HI insult. Brain volumes were preserved in hypothermia plus NAC group and were not significantly different when compared with the sham group. Similarly, increased myelin expression was seen in brain sections from hypothermia plus NAC group, when stained for Luxol Fast Blue (LFB), Myelin Basic Protein (MBP) and Proteolipid protein (PLP). These results indicate that hypothermia plus NAC combination therapy improves infarct volume, myelin expression and functional outcomes after focal HI injury. H ypoxic ischemic (HI) injury in neonates occurs in termneonates at a frequency of 1-4 per 1,000 live births (1) and may result in reduced potential for motor and cognitive development (2,3). Hypothermia improves survival and neurologic outcomes in neonatal animal models of severe HI injury (4 -7), and in recently completed clinical trials of HI neonates when instituted within 6 h of birth (8 -11). Animal data shows that initiation of hypothermia between 6 and 12 h after HI reduces cerebral injury (12,13), perhaps moderating secondary injury cascades during a time when cellular recovery is still possible. However, some inflammatory mediators are merely delayed by hypothermia treatment (14), indicating that hypothermia may be most helpful in extending the therapeutic window after HI injury.Therefore, the combination of hypothermia with other pharmacologic interventions may allow for significant improvements in outcome, which are not possible when the therapies are used separately. There have been limited reports of hypothermia treatment with other pharmacologic interventions. Systemic hypothermia and a pan-caspase inhibitor, bocaspartyl-(OMe)-fluoromethyl-ketone (BAF), produced a strong protective effect against neuronal cell damage in the ipsilateral hippocampal CA1 region of the developing rat brain, along with a reduction in caspase-3 activity (15). The combination of MK-801 and hypothermia also protected animals against HI injury ...

Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: Attenuation by N-acetyl cysteine

“…NAC is probably one of the most widely investigated agents that serves as a precursor of glutathione and has both antioxidant and anti-inflammatory properties. NAC has been shown to attenuate inflammation in various disease models such as ischemia-reperfusion injury in brain (Sekhon et al, 2003;Khan et al, 2004), lethal endotoxemia (Victor et al, 2003), animal model of multiple sclerosis (Lehmann et al, 1994;Stanislaus et al, 2005), and hypoxic-ischemic brain injury in neonatal brains (Jatana et al, 2006;Wang et al, 2007). In addition, we and others have reported the attenuation of brain white matter injury by NAC in the systemic maternal infection model of PVL (Cai et al, 2000;).…”

Effects of N-acetylcysteine on neurocognitive functions after coronary artery bypass graft surgery

“…[7][8][9][10] Çalışmamızda KABG ameliyatı geçiren hastalarda NAC'nin nörolojik komplikasyonlar üzerine olumlu etkileri araştırıldı. Daha önce yapılan çalışmalarla paralel olarak NAC uygulanmayan kontrol grubunda ameliyat sonrası nörokognitif fonksiyon testlerinde ameliyat öncesi olanlara göre anlamlı skor düşüşleri olduğu görüldü.…”

“…[5,6] Santral sinir sistemi üze-rine olumlu etkileri özellikle birçok deneyde hayvanlar üzerinde araştırılmış, iskemi sonrası reperfüzyonla oluşan beyin enfarkt alanlarını azalttığı ve nörolojik iyileşmeyi hızlandırdığı gösterilmiştir. [7][8][9][10] Bu çalışmada, koroner arter baypas greft (KABG) ameliyatı geçiren, NAC uygulanan ve uygulanmayan hastalarda ameliyat öncesi ve sonrası nörokognitif fonksiyonlar karşılaştırıldı. Bu çalışmada, çeşitli organ sistemlerindeki reperfüzyon hasarına olumlu etkileri gösterilmiş olan NAC'nin KABG ameliyatı sonrası nörokognitif fonksiyonlar üzerine olumlu etkileri ve nörolojik hasarı önleyip önleyemeyeceği araştırıldı.…”

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury

“…Other therapies are centered on diminishing brain damage arising from free radicals, thus employing antioxidant molecules such as allopurinol which inhibits xantine oxidase [40,41] , and N-acetylcysteine which increases the intracellular level of glutathione and reduces apoptosis and inflammation [42][43][44][45] , to sequester free radicals. Other antioxidant-related drugs commonly used include erythropoietin, which has antiapoptotic and angiogenic properties [46] and provides neuroprotection and neurogenesis in neonatal rats [47,48] , and melatonin, which reduces brain damage and development of later sequelae [49,50] .…”