Therapeutics for neonatal brain injury

Abstract

Neonatal brain injury is an important cause of death and neurodevelopmental delay. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to both early and late phases of cell damage and death. Therapies targeting these different pathways have shown potential in protecting the brain from ongoing injury. More recent therapies, such as growth factors, have demonstrated an ability to increase cell proliferation and repair over longer periods of time. Even though hypothermia, which decreases cerebral metabolism and possibly affects other mechanisms, may show some benefit in particular cases, no widely effective therapeutic interventions for human neonates exist. In this review, we summarize recent findings in neuroprotection and neurogenesis for the immature brain, including combination therapy to optimize repair.

Introduction

Injury to the brain during early development is a significant contributor to mortality and long-term morbidity. Perinatal brain injury is that which occurs immediately before or after delivery, while neonatal injury occurs during the perinatal period up through 4 weeks of age. Causes of early brain injury include stroke, birth trauma, metabolic or genetic disorders, status epilepticus, and a variety of asphyxial events resulting in hypoxia and ischemia (HI). HI often leads to periventricular white matter injury in premature infants, while term infants develop cortical/subcortical lesions (Gressens & Luton, 2004). Studies of perinatal stroke conservatively estimate an incidence of 1 in 4000 live births (Nelson & Lynch, 2004), whereas perinatal asphyxia resulting in encephalopathy, or hypoxic–ischemic encephalopathy, occurs in 3 to 5 in 1000 live births (Wu et al., 2004), with an increasing incidence in Western countries (Hagberg et al., 1996). While many die during the neonatal period, the majority of survivors exhibit neurological deficits that persist throughout life, such as epilepsy, cerebral palsy or mental retardation (Dilenge et al., 2001). No established therapeutic regimens exist, and treatment and care for the sequelae of early brain injury requires significant resources, often with little improvement in an individual patient's overall abilities and with long-term effects on their family and society (Ferriero, 2004).

There has long been a search for therapies that can either prevent injury progression or enhance repair of the immature brain, hopefully improving long-term motor and behavioral outcomes. Making this challenging is the fact that the neonatal and adult brain do not respond similarly to injury, with altered susceptibility to oxidative stress and excitotoxicity and differences in gene regulation during hypoxia (McQuillen & Ferriero, 2004). Damage occurs via multiple pathways, and repair occurs over a period of days to weeks, if not months (Geddes et al., 2001). Neuronal death during the newborn period appears to occur in two phases: primary neuronal death from cellular hypoxia and energy depletion, followed by reperfusion and increases in excitotoxicity, free radical formation, and nitric oxide production with secondary energy failure and delayed death (Perlman, 2006). While some therapies that manipulate these pathways show promise, not all neonates will benefit from treatment. Damage may be so severe or prolonged that repair may not be possible, or survivors may be particularly devastated (Gluckman et al., 2005). Genetic factors and gender effects may also affect susceptibility to damage (Harding et al., 2004, Kerk et al., 2006).

Optimizing therapy for neonatal brain injury will require capitalizing on multiple pathways which prevent cell death and enhance cell growth, differentiation, and long-term integration into neural networks. Classically, the term neuroprotection has been used, but should we only think about protecting neurons? Injury to other cell types, such as oligendrocytes and astrocytes, impedes development and results in long-term damage. By targeting the injury response, the goal is to utilize targeted pharmacotherapies to salvage cells that would otherwise die, protect cells from becoming injured or at risk for death by increasing tolerance, and also repairing injured cells and enhancing neurogenesis. These post-insult therapies include glutamate receptor antagonists, free radical blockers or scavengers, microglial affectors or cytokine inhibitors, altering the cell death cascade effects on apoptosis, or modifying cerebral metabolism with hypothermia. More recent evidence suggests that therapies may be combined to enhance these protective and reparative processes.

In addition to developing new approaches for neuroprotection, we need to quickly identify neonates that will benefit from treatment. A variety of clinical predictors have been used to identify those at risk for hypoxic brain injury. These include an Apgar score < 5 at 5 min, elevated cord blood or early arterial acidosis, and seizures or the presence of encephalopathy on examination (Miller et al., 2004). More recently, cerebral function monitoring using bedside amplitude integrated EEG has provided an efficient and fairly accurate means for identifying encephalopathy or prolonged seizure (Hellstrom-Westas & Rosen, 2006), but it does not replace full EEG (Shellhaas et al., 2007). Brain imaging, specifically magnetic resonance imaging (MRI) with newer techniques such as spectroscopy (MRS), diffusion weighted (DWI) and diffusion tensor imaging (DTI), and volumetric analyses provides the most accurate assessment of injury. These allow identification of severity and evolution of brain injury, with specific injury patterns being associated with poor outcomes, such as loss of gray/white differentiation, watershed injury, and thalamic or basal ganglia injury (Miller et al., 2005). However, early and sequential imaging in neonates is often not possible because of scanner availability or difficulty in transporting these critically ill patients. Biomarkers for inflammation and oxidative stress, or indicating injury to other organ systems, are currently being studied but are of equivocal value in identifying early neonatal brain injury. For example, some serum neuronal and glial proteins such as myelin basic protein, S100B, and neuron-specific enolase show promise in traumatic brain injury (Berger et al., 2007). Given all the available evidence, a combination of encephalopathic physical exam and seizures provide an indication of infants that may be at risk for brain injury (Miller et al., 2004). Early identification is vital to improve outcomes, as early therapy appears to be superior to late (Thoresen, 2000) and identification of those who may benefit from those who will not is increasingly important. This review will focus on newer developments in treating neonatal brain injury, as well as combination therapy that will potentially optimize long-term outcomes.