Associate editor: M. MouradianTherapeutics for neonatal brain injury
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.
Section snippets
Inhibition of excitotoxicity
Glutamate plays a key role in brain development, affecting progenitor cell differentiation, proliferation, migration and survival. Excitotoxicity refers to excessive glutamatergic activation that leads to cell injury and death (Olney, 2003). Glutamate accumulates in the brain after HI (Gucuyener et al., 1999) from a variety of causes, including vesicular release from axons (Kukley et al., 2007) and reversal of glutamate transporters (Fern and Moller, 2000, Rossi et al., 2000). Excitotoxicity
Antioxidants
Oxidative stress is an important component of early injury to the neonatal brain (Ferriero, 2001). Oxygen toxicity results from excess formation of free radicals (FR) (reactive oxygen species (ROS) and reactive nitrogen species (RNS)) from oxidative metabolism that occurs under pathological conditions (Fig. 1). FRs include superoxide anion (O2−), hydroxyl radical (OH), singlet oxygen (1O2) and hydrogen peroxide (H2O2) (Fridovich, 1997, Halliwell, 1999). FRs target lipids, protein and DNA,
Anti-inflammatory agents
Maternal infection is a known risk factor for white matter disease and poor outcomes, such as cerebral palsy (Dammann et al., 2002, Wu and Colford, 2000, Wu et al., 2003). The inflammatory response that accompanies infection plays a vital role in cell damage and loss, with cytokines possibly being the final mediators of both initial damage and later injury to penumbral tissue (Stirling et al., 2005). Local microglia are activated early and produce pro-inflammatory cytokines such as TNF-α, IL-1β
Cell death inhibitors
Apoptosis is critical for normal brain development, but it is also an important component of injury following neonatal HI and stroke (Northington et al., 2005) (Fig. 2). Activation of intrinsic or extrinsic apoptotic pathways leads to cleavage and activation of caspase-3, which is maximally produced in the neonatal period (Hu et al., 2000). Proapoptotic Bax is present in high concentrations during the first two postnatal weeks (Lok & Martin, 2002). While necrosis plays a major role in early
Preconditioning
Lessons about protection can be gleaned from the response to milder forms of injury. Preconditioned animals that are treated with sublethal stress are protected from subsequent insults that would otherwise be lethal (Bergeron et al., 2000, Sheldon et al., 2007). For example, P6 rats exposed to 8% hypoxia have reduced brain injury following HI that occurs 24 h after a preconditioning stimulus, with protection that persists 1–3 weeks later (Gidday et al., 1994, Vannucci et al., 1998). It is
Growth factors
EPO is a 34-kDa glycoprotein that was originally identified for its role in erythropoiesis, but has since been found to have a variety of other roles. The pleiotropic functions of this cytokine include modulation of the inflammatory and immune responses (Villa et al., 2003), vasogenic and proangiogenic effects through its interaction with VEGF (Chong et al., 2002, Wang et al., 2004a, Wang et al., 2004b), as well as effects on CNS development and repair. EPO and EPO receptor are expressed by a
Stem cell therapy
Neural stem cells (NSCs) are multi-potent precursors that self-renew and retain the ability to differentiate into a variety of neuronal and non-neuronal cell types in the CNS. They reside in neurogenic zones throughout life, such as the subventricular zone and subgranular zone of the dentate gyrus in rodent models, and help maintain cell turnover at baseline and replace injured cells by migrating to penumbral tissue after injury. NSC transplantation has shown potential as a therapeutic strategy
Hypothermia
A recent therapy gaining momentum is the use of therapeutic hypothermia for brain injury. It is postulated to work by modifying apoptosis and interrupting early necrosis (Edwards et al., 1995), reducing cerebral metabolic rate and the release of excitotoxins, NO, and FRs (Globus et al., 1995). Multiple animal models of perinatal brain injury demonstrate histological and functional benefit of early initiation of hypothermia (Gunn et al., 1998a, Gunn et al., 1997, Gunn et al., 1998b, Laptook et
Manipulating mechanisms: Combination therapy
Single therapy with many of the aforementioned interventions often results in only mild improvement. Anti-apoptotic therapies may prevent delayed cell death, but would not suppress early necrotic and excitotoxic injury. Since hypothermia has shown benefit in moderately encephalopathic newborns, it is rapidly becoming standard of care in many institutions. However, it does not completely protect or repair a brain that has been injured, so the search for adjuvant therapies continues. In addition,
Concluding remarks
The initiation and development of injury to the neonatal brain is complex, with multiple contributing mechanisms and pathways resulting in both early and delayed injury. Studies have focused on these different processes, including oxidative stress, inflammation, and excitotoxicity, which differ between the mature and immature brain. More recent evidence has focused on synthesizing therapies that attack these pathways from multiple vantage points, helping us to understand how brain injury occurs
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2017, Physiology and BehaviorCitation Excerpt :The resulting cognitive and behavioral problems became a huge burden for both the family and society [3,4]. Although there is no established intervention that fully treat HI induced perinatal brain injury, many potential therapies that may prevent injury progression and enhance repair are under investigation [5]. Erythropoietin (EPO) is a 34-kDa glycoprotein that was originally identified for its essential role in erythropoiesis.
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