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Hypoglycemia and nitro-oxidative stress in the neonatal period

par Ghaddhab, Chiraz ;Lefevre, Nicolas ;Wayenberg, Jean-Louis ;Bottari, Serge P.
Référence Cell Membranes and Free Radical Research, 4, 2, page (202-208)
Publication Publié, 2012-05

Article révisé par les pairs

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Résumé :

Nitro-oxidative stress, i.e. peroxynitrite generation and subsequent nitration and/or oxidation of proteins, lipids and DNA are implicated in neuronal death. In animal models, peroxynitrite generation is increased by hypoglycemia, a condition that occurs frequently in low birth weight newborns. In order to detect systemic nitro-oxidative stress, we developed an assay to measure Plasma NitroAlbumin (PNA) concentration. and investigated its variations according to glycemia during the first days of life. PNA concentrations were measured at days 0, 1 and/or 4 of life in 119 newborns (26 small for gestational age term and 93 preterm infants). We investigated di!erences in PNA concentrations with regard respect to the occurrence and recurrence of hypoglycemia events (HG: glycemia < 2.5 mmol/l) PNA concentrations at days 0, 1 and 4 were significantly higher in both preterm and SGA term infants who developed at least one HG hypoglycemia than in normoglycemic patients (p = 0.001, 0.001 and 0.04, respectively). PNA concentration at D1 increased with the number of hypoglycemic events and was correlated to the area under curve of glycemia measured 12-24 hours before sampling. We conclude that hypoglycemia during the first 24 hours of life is associated with increased albumin nitration in newborns. This fact suggests that a significant nitrooxidative stress occurs promptly after hypoglycemia and this in turn implying a risk of end-organ damage due to protein nitration, lipid peroxidation and DNA damage. Evidence of nitrooxidative stress in hypoglycemic neonates may open new and exciting perspectives in neuroprotection. Neonatal hypoglycemia is a very challenging issue because of its potential harmful e!ects on the immature brain. In fact, newborns, especially low birth weight (< 2500 grams) infants, are extremely sensitive to conditions that a!ect glucose homeostasis during the transition from intra- to extrauterine life (Ward- Platt and Deshpande, 2005). Neonatal glucose metabolism is characterized by increased glucose utilization, failure of gluconeogenesis, and reduced fat and glycogen stores (Hawdon and Ward- Platt, 1993). Therefore low blood glucose values are frequently observed during the first days of life. Moreover as newborns are unable to oxidize fatty acids into ketone bodies (Stanley et al., 1979), glucose is an essential primary fuel for the brain. Therefore hypoglycemia may be particularly harmful during the early postnatal period. Neonatal hypoglycemia often occurs during the first hours of life in low birth weight infants. This episode may be unique or recurrent during the first days of life (Gutberlet and Cornblath, 1976). If asymptomatic early transient hypoglycemia is often considered to be benign (American Academy of Pediatrics, 1993) or even physiological (Deshpande and Ward-Platt, 2005), recurrent neonatal hypoglycemia has been associated with developmental delay (Lucas et al., 1988; Duvanel et al., 1999) and specific brain lesions on MRI magnetic resonance imaging (Spar et al., 1994 ; Filan et al., 2006; Yalnizoglu et al., 2007). However the consequences of neonatal hypoglycemia on the developing brain neurological outcome are still a matter of intense debate. FollowDue to methodological weaknesses follow-up studies did not show undisputable evidence that neonatal hypoglycemia, unless severe and prolonged, impairs brain development (Williams, 1997; Cornblatt and Schwartz, 1999; Cowett, 1999). Therefore monitoring, prevention and treatment of neonatal hypoglycemia remain largely empirical (Hay et al., 2009). In factdeed, even the level of glycemia which is safe for the premature newborn is still a matter of debatediscussed (Kalhan and Peter-Wohl, 2000; Cornblath et al., 2000; Inder, 2008; Hay et al., 2008: Rozance and Hay, 2010). On the other hand, fear of hypoglycemia imposes regular monitoring, which means 3-4 hours interval punctures and invasive interventions such as continuous feeding or intravenous perfusion. Careful glucose monitoring exposes newborns to numerous painful procedures which that might in turn a!ect cerebral development (Fabrizi and Slater, 2012). An approach to evaluate the potential deleterious e!ects of hypoglycemia is to search for correlations between blood glucose concentrations and biological markers of local or systemic distress. As the brain is the most sensitive organ to hypoglycemia, the e!ects of low glucose have mainly been investigated on the central nervous system and in neuronal models. Hypoglycemic neuronal death has been reported to be triggered by di!erent mechanisms (Ferrand-Drake et al., 1999; Suh et al., 2007a) among which nitro-oxidative stress seems to be a key event (Suh et al., 2007b ; Haces et al., 2010). In neuronal cells in culture, glucose deprivation is followed by superoxide ion (O2.-) generation and Nitric Oxide (NO) synthase activation (Liu et al., 2003). Overproduction of O2.- and nitric oxideNO leads to the generation of peroxynitrite (ONOO-), a highly reactive nitrogen cytotoxic species (Ischiropoulos and Beckman, 2003). Peroxynitrite is responsible for protein nitration, lipid peroxidation and DNA damage, a process referred to as nitro-oxidative stress. Plasma protein nitration reflects an increased production of ONOO- and can therefore be used as clinical marker of nitro-oxidative stress (Wayenberg et al., 2009). We developed and clinically validated a sensitive double-sandwich ELISA that allowsing the quantitative determination of Plasma NitroAlbumin (PNA) concentrations in newborns (Wayenberg et al., 2009; Wayenberg et al., 2011). In this articlestudy, we investigated whether neonatal hypoglycemia is associated with albumin nitration in low birth weight infants.