Long-Term Neuroprotective Effect of Postischemic Hypothermia in a Neonatal Rat Model of Severe Hypoxic Ischemic Encephalopathy: A Comparative Study on the Duration and Depth of Hypothermia

Abstract

ABSTRACT:It is not known whether deeper or longer hypothermia (HT) can achieve better neuroprotection against hypoxic ischemic encephalopathy (HIE) in neonates. To compare the neuroprotective effects of different durations and temperatures of postischemic HT in neonatal rats with severe HIE, 7-d-old rats were subjected to the Rice-Vannucci model for 150 min hypoxia. Only the rats with identified brain lesions in diffusion-weighted MRI were assigned to normothermia (NT, 36°C/48 h) or four HT (HT-30°C/48 h; HT-30°C/24 h; HT-33°C/48 h; and HT-33°C/24 h) groups.1 H-magnetic resonance spectroscopy ( 1 H-MRS) and T2-weighted MRI were obtained serially, and functional studies were performed. HT groups showed significantly greater residual hemispheric volume and better rotarod and cylinder tests than did the NT group at 5 wk postischemia. HT groups also showed lower lactate-plus-lipid level in 1 H-MRS than did the NT group at 7 d postischemia. All of these outcome variables, however, did not differ among the 4 HT subgroups, despite a trend toward greater residual brain volume in the 48-h HT versus 24-h HT subgroups. In conclusion, neither reducing the target temperature from 33 to 30°C nor prolonging the duration from 24 to 48 h produced further improvements in neurologic outcomes in neonatal rat with HIE. (Pediatr Res 68: 303-308, 2010) H ypothermia (HT) is one of the most promising neuroprotective modalities against hypoxic ischemic encephalopathy (HIE) in neonatal brain (1). However, in neonates with severe HIE, little neuroprotection could be achieved using current HT protocols in which whole-body or head cooling is performed for 48 to 72 h by maintaining the core temperature within a range of 33.5 to 34.5°C (2-5). In animal studies, the efficacy of postischemic HT was also limited in the subgroup with severe ischemic injury (6,7). To treat severe HIE by HT, a recent review suggested a "deeper" and "more prolonged" cooling (8). However, no controlled clinical trials have tested this supposition and several experimental studies failed to clearly demonstrate an effect of postischemic HT protocols with different target temperatures or duration in a perinatal HIE model (9 -11).The 7-d-old rat with unilateral carotid artery ligation and subsequent exposure to 8% hypoxia is the most commonly used model to evaluate the efficacy of therapeutic interventions in the developing brain (12), and several studies have used this Rice-Vannucci model (RVM) to test the effects of HT (10,11,(13)(14)(15)(16)(17)(18)(19). However, an experimental design composed of a shorter duration of hypoxia, representing "mild" ischemic lesions, is not appropriate for evaluating the neuroprotective effect of HT against severe HIE. To date, few experimental studies have used the RVM with hypoxia exposure longer than 120 min (10,13,19), but none of these have reported the long-term neuroprotective effect of postischemic HT.The aim of this study was to investigate the long-term neuroprotective effect of various postischemic HT protocols with different t...

Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy

“…Using β-ketone as the standard and an Optium Xceed ® glucose strip (Abbott Diabetes Care, Maidenhead, UK), serial blood BHB and glucose levels were measured by the tail cut method just before and 1 h after each separate drug administration. Throughout the intervention period, rat pups were fed 3 times with 0.5 mL of a commercially available formula via a 22-G animal feeding tube [26].…”

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Hypothermia decreased the expression of heat shock proteins in neonatal rat model of hypoxic ischemic encephalopathy

“…Sevenday-old, male, Sprague-Dawley rats were subjected to the well-characterized Rice-Vannucci model of HIE (Rice et al 1981;Lee et al 2010). In brief, rats were anesthetized with isoflurane gas (induction, 4.0%; maintenance, 1.5%) in a 1:1 mixture of oxygen and nitrous oxide.…”

Neuroprotective Treatments after Perinatal Hypoxic-Ischemic Brain Injury Evaluated with Magnetic Resonance Spectroscopy

“…Lac levels in asphyxiated infants are reduced during hypothermia [29] , shortly after rewarming [30] , and in the subacute phase [31,32] . This may reflect the neuroprotective effect of hypothermia on mitochondria in the early phase after HI as well as its potential anti-inflammatory effects during the subacute phase (increased Lac levels at this time point are likely to be related to the presence of brain macrophages [microglia] [33,34] ).…”