Increased Brain Levels of F2-Isoprostane Are an Early Marker of Behavioral Sequels in a Rat Model of Global Perinatal Asphyxia

Abstract

Perinatal asphyxia is a major cause of immediate and postponed brain damage in the newborn. It may be responsible for several delayed neurologic disorders and, in this respect, early markers of brain injury would be relevant for therapeutic intervention as well as for identification of infants at high risk for developmental disabilities. Biochemical measurements (brain F 2 -isoprostane levels) and behavioral tests (ultrasonic vocalization pattern on postnatal days (pnd) 5, 8, and 11, spontaneous motor behaviors on pnd 7 and 12, and homing response on pnd 10) were performed in a rat model of global perinatal asphyxia in the immature neonate. Caesarean section was performed in rats and the pups, still in uterus horns, were placed into a water bath at 37°C for either 10 or 20 min. Caesarean delivered pups were used as controls. Pups experiencing severe (20 min), in contrast to those undergoing the 10 min, asphyctic insult presented with detectable abnormalities including early (two hours after the insult) increase in brain F 2 -isoprostane (a direct marker of oxidative injury) without detectable changes in PGE 2 , COX-2 and iNOS levels, and delayed physical (reduced weight gain on pnd 5 and thereafter) and behavioral disturbances (alterations in ultrasound emission on pnd 11 and spontaneous motricity levels mainly). These findings suggest that increased brain F 2 -isoprostane levels shortly after the asphyctic insult are predictive of delayed behavioral disturbances in the newborn rat. The present 20-min asphyxia model might serve for the assessment of preventive and curative strategies to treat neurologic/behavioral disturbances associated with perinatal asphyxia. Perinatal asphyxia is a major cause of neonatal mortality and irreversible damage to the brain. Severe asphyxia may induce major deficits (cerebral palsy, dystonia, epilepsy) shortly after birth (1), while mild/moderate asphyxia episodes may result in cognitive/attentional disorders later on in development. A critical concept emerging from recent research is that of a "therapeutic window." namely a narrow period of time between the insult and the occurrence of CNS injury, during which adoption of neuroprotective strategies could be effective (2, 3). A primary aim for clinical research is to identify as early as possible reliable indexes of brain injury in the asphyctic newborns to apply potential therapeutic interventions at the optimal time and to identify those infants at high risk for developmental delays and disabilities (4).To date the major advances in the early prediction of hypoxic-ischemic insult have been attained by means of EEG and

Effects of Genetic Background, Gender, and Early Environmental Factors on Isolation-Induced Ultrasonic Calling in Mouse Pups: An Embryo-Transfer Study

“…The finding that early environmental factors can influence calling behavior is in accordance with studies on the effects of prenatal malnutrition (Tonkiss et al 2003), prenatal stress (Morgan et al 1999;Williams et al 1998), perinatal asphyxia (Calmandrei et al 2004) or pre-and postnatal exposure of various substances, like alcohol (Barron and Gilbertson 2005;Marino et al 2002;Tatolli et al 2001), cocaine (Hahn et al 2000), lead (De Marco et al 2005), aluminum (Alleva et al 1998), or carbon monoxide (Di Giovanni et al 1993) on ultrasonic calling in infant rodents. However, in the natural context, variations in maternal care might be of major importance.…”

Nitric Oxide Production in the Striatum and Cerebellum of a Rat Model of Preterm Global Perinatal Asphyxia

“…However, directly after PA, when the foetal circulation and metabolism is still maintained, there were no apparent changes in the activity or transcription of nNOS (Lubec et al 1999) or inducible NOS (Calamandrei et al 2004). Early intervention in NO production could have long-term therapeutic effects.…”

Preliminary case control study to establish the correlation between novel peroxidation biomarkers in cord serum and the severity of hypoxic ischemic encephalopathy

“…Actually, increased brain levels of 8-epi-PGF2a were found in asphyctic newborn rats 2 h after global perinatal asphyxia, and this biomarker could be predictive of delayed behavioral disturbances [22]. These biomarkers have several advantages, such as establishing a quantitative result and diagnosis to clinically undefined samples, and being potential long-term neurological damage biomarkers [14,22]. This fact can be explained by the molecular damage occurred under hypoxic episode depending on its intensity, duration, previous metabolic state, gestational age, and the degree of development of the antioxidant system, altogether these factors can induce a different response to a hypoxic episode.…”

“…When comparing cord serum samples, we found that 8-iso-15(R)-PGF2α and total isoprostanes had a highly significant correlation with severe postnatal metabolic acidosis. Actually, increased brain levels of 8-epi-PGF2a were found in asphyctic newborn rats 2 h after global perinatal asphyxia, and this biomarker could be predictive of delayed behavioral disturbances [22]. These biomarkers have several advantages, such as establishing a quantitative result and diagnosis to clinically undefined samples, and being potential long-term neurological damage biomarkers [14,22].…”