Neonatal encephalopathy: pre-clinical studies in neuroprotection

Abstract

Neonatal encephalopathy resulting from HI (hypoxia-ischaemia) continues to be a significant cause of mortality and morbidity in infants and children, affecting 1-2/1000 live term births and up to 60% of pre-term births. In order to understand the pathophysiology of this insult, as well as design therapeutic interventions, it is important to establish a relevant animal model for pre-clinical studies. One of the most frequently used models of HI-induced brain damage in immature animals is the unilateral carotid ligation/hypoxia model, initially developed in our laboratory more than 30 years ago. The original model employed the postnatal day 7 rat, whose brain is representative of that of a late gestation, pre-term [32-36 weeks GA (gestational age)] human infant. We, and others, have employed this model to characterize the pathophysiological, biochemical/energetic and neuropathological events following HI, as well as the determination of the unique characteristics of the immature brain that define its vulnerability to, and outcome from, HI. In defining the cascade of events following HI, it has become possible to identify potential targets for intervention and neuroprotection. Currently, the only available therapeutic intervention for neonatal encephalopathy in the term asphyxiated infant is therapeutic hypothermia, although this must be initiated within 6 h of birth and is at best partially effective in moderately injured infants. Ongoing pre-clinical studies are necessary to determine the basis for the partial protection afforded by hypothermia as well as the design of adjunct therapies to improve the outcome. The present review highlights the importance of using a well-characterized and relevant animal model to continue to pursue translational research in neuroprotection for the infant brain.

Effects of Neonatal Hypoxic-Ischemic Injury and Hypothermic Neuroprotection on Neural Progenitor Cells in the Mouse Hippocampus

“…Moderate hypothermia has long been appreciated as a potential means of neuroprotection in neonatal HI [39,40,41,42]. This effect is operative in multiple cell types and brain regions, including in the hippocampus, where hypothermic treatment in a rat model of HI has been shown to attenuate neuron loss in the CA1 region [43].…”

Interdisciplinary Approach to Neurocritical Care in the Intensive Care Nursery

“…There are several agents "in the pipeline" that are being evaluated for neuroprotection or use in combination with therapeutic hypothermia or both, including growth factors (eg, erythropoietin), antioxidants (eg, melatonin and allopurinol), antiexcitotoxic agents (eg, topiramate, levetiracteam, and magnesium sulfate), mast cell stabilizers (eg, disodium chromoglycate), as well as xenon and stem cells, among others. [13][14][15][16] Education Neonatologists, especially those in academic units, large quaternary care centers, and stand-alone children's hospitals play an important role in the education of both trainees and staff in their respective units, as well as in the education of physician and staff at referral centers. Education is needed to help staff at those smaller hospitals identify patients who may benefit from neurocritical care.…”

Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups

“…A well-established Vannucci rat model of term neonatal HI encephalopathy [19,20,21,22,23,24], which combined a left common carotid artery ligation and a 2-hour exposure to hypoxia (8% oxygen) in 10-day-old (P10) rat pups, was used for the experiments, since this model is recognized to mimic the brain injuries observed in human term asphyxiated newborns [21,25,26,27]. Briefly, the 10-day-old male Long-Evans rat pups were weighed and then deeply anesthetized with an intraperitoneal injection of fentanyl (0.2 mg/kg) and midazolam (1 mg/kg) to the point of unresponsiveness to noxious stimulation.…”