- •
There are many ways to achieve neuroprotection: preconditioning, salvaging, repair.
- •
Hypothermia is now standard of care for term hypoxic-ischemic encephalopathy so studies to investigate additional therapies will be added to that treatment.
- •
Strategies that target multiple mechanisms and consider age-appropriate mechanisms will be most beneficial.
Pharmacologic Neuroprotective Strategies in Neonatal Brain Injury
Section snippets
Key points
Mechanisms of brain injury: preterm versus term
The two most common causes of neonatal brain injury in the United States are extreme prematurity and hypoxic-ischemic encephalopathy (HIE). In the United States, 1 in 8 babies is born before term (37–40 weeks), and 1.44% of babies (56,000 per year) are born with a birth weight of 1250 g or less.1 These small, preterm babies are at high risk of death or neurodevelopmental impairment: approximately 20% die before hospital discharge, and 40% of survivors develop long-term intellectual or physical
The injury cascade
Although the cellular targets of HI are different depending on age and severity of insult, the basic cascade of injury occurs in a uniform way regardless of age and continues for a prolonged period of time. Cell death occurs in 2 main phases: primary death from hypoxia and energy depletion, followed by reperfusion and increased free radical (FR) formation, excitotoxicity, and nitric oxide production with secondary energy failure and delayed death (Fig. 1). A tertiary phase was recently
Antiexcitotoxic Agents
The earliest pharmacologic strategies to protect the newborn brain were designed to block the initial phases of injury, excitotoxicity, and oxidative stress. Many of these agents failed because it is impossible to block normal developmental processes, like glutamatergic signaling, without harming the brain. Therefore, therapies designed to block the NMDA receptor resulted in increased, rather than decreased, cell death.22 However, some agents, like magnesium sulfate, used to stop preterm labor,
Growth factors as neuroprotectants
Many growth factors have essential roles during fetal and postnatal brain development. Although the effects of some, such as brain-derived neurotrophic factor (BDNF), are largely restricted to the brain, others such as Epo, VEGF, granulocyte colony–stimulating factor (GCSF), and insulinlike growth factor 1 (IGF-1) have important somatic effects in addition to their roles in neurodevelopment. All of the factors listed earlier have been evaluated as neuroprotectant therapies for adult and
References (66)
- et al.
The ELGAN study of the brain and related disorders in extremely low gestational age newborns
Early Hum Dev
(2009) Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances
Lancet Neurol
(2009)- et al.
Global, regional, and national causes of child mortality in 2008: a systematic analysis
Lancet
(2010) - et al.
Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy
Early Hum Dev
(2010) - et al.
Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy?
Lancet Neurol
(2012) - et al.
Excitatory amino acids and taurine levels in cerebrospinal fluid of hypoxic ischemic encephalopathy in newborn
Clin Neurol Neurosurg
(1999) - et al.
Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?
Lancet Neurol
(2002) - et al.
Antenatal exposure to magnesium sulfate and neuroprotection in preterm infants
Obstet Gynecol Clin North Am
(2011) - et al.
General anesthesia versus monitored anesthesia care with remifentanil for assisted reproductive technologies: effect on pregnancy rate
J Clin Anesth
(2002) - et al.
Anti-oxidant strategies
Semin Fetal Neonatal Med
(2007)
Dose-dependent effects of erythropoietin in propofol anesthetized neonatal rats
Brain Res
Protective effects of erythropoietin against ethanol-induced apoptotic neurodegeneration and oxidative stress in the developing C57BL/6 mouse brain
Brain Res Dev Brain Res
Protective effect of erythropoietin on the oxidative damage of erythrocyte membrane by hydroxyl radical
Biochem Pharmacol
Erythropoietin promotes hippocampal neurogenesis in in vitro models of neonatal stroke
Neurobiol Dis
Neuroprotective properties and mechanisms of erythropoietin in in vitro and in vivo experimental models for hypoxia/ischemia
Brain Res Rev
Annual summary of vital statistics: 2010-2011
Pediatrics
Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network
Pediatrics
Unimpaired outcomes for extremely low birth weight infants at 18 to 22 months
Pediatrics
Neuroimaging of cortical development and brain connectivity in human newborns and animal models
J Anat
Maturation-dependent vulnerability of perinatal white matter in premature birth
Stroke
Perinatal infections and neurodevelopmental outcome in very preterm and very low-birth-weight infants: a meta-analysis
JAMA Pediatr
Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study
BMJ
Cerebral palsy in a term population: risk factors and neuroimaging findings
Pediatrics
Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain
Pediatr Res
Toll-like receptor 3 expression in glia and neurons alters in response to white matter injury in preterm infants
Dev Neurosci
Regulation of toll-like receptors in the choroid plexus in the immature brain after systemic inflammatory stimuli
Transl Stroke Res
Developmental factors regulating susceptibility to perinatal brain injury and seizures
Curr Opin Pediatr
Free radicals and brain damage in the newborn
Biol Neonate
Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults
Ann Neurol
Programmed necrosis: a prominent mechanism of cell death following neonatal brain injury
Neurol Res Int
Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation
J Am Soc Nephrol
Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia
PLoS One
Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia
J Cereb Blood Flow Metab
Cited by (0)
Disclosure Statement: Neither author has anything to disclose.