Therapeutics for neonatal brain injury
University of California, San Francisco, United States Pharmacology [?] Therapeutics
(Impact Factor: 9.72).
10/2008; 120(1):43-53. DOI: 10.1016/j.pharmthera.2008.07.003
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.
Available from: Felipe Goñi de Cerio
- "Despite important progress in obstetric and neonatal care during the last decades, perinatal HI is still one of the most important causes of neonatal brain injury and its associated adverse developmental outcome [8,11,12]. The severity, intensity and timing of asphyxia, as well as a selective ischemic vulnerability and the immaturity of the brain, determine the extension and the degree of severity of the ensuing damage and long-term neurodevelopmental impairment [13,14,15,16]. "
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ABSTRACT: Hypoxic-ischemic (HI) brain injury is one of the main causes of disabilities in term-born infants. It is the result of a deprivation of oxygen and glucose in the neural tissue. As one of the most important causes of brain damage in the newborn period, the neonatal HI event is a devastating condition that can lead to long-term neurological deficits or even death. The pattern of this injury occurs in two phases, the first one is a primary energy failure related to the HI event and the second phase is an energy failure that takes place some hours later. Injuries that occur in response to these events are often manifested as severe cognitive and motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of HI injury, there is an increasing need to find effective therapies as new opportunities for the reduction of brain damage and its long term effects. Some of these therapies are focused on prevention of the production of reactive oxygen species, anti-inflammatory effects, anti-apoptotic interventions and in a later stage, the stimulation of neurotrophic properties in the neonatal brain which could be targeted to promote neuronal and oligodendrocyte regeneration.
Available from: Mariela Chertoff
- "Presently, optimal management of H/I brain injury involves prompt resuscitation, careful supportive care, and treatment of seizures. Although hypothermia is a promising new therapy, and recent studies suggested that head or whole-body cooling administered within 6 hours of birth reduces the incidence of death or moderate/severe disability at 12 to 22 months , there is undeniable need for the identification of new therapeutic targets for the implementation of clinical trials to address treatment of H/I encephalopathy . Accordingly, epidemiological and experimental data have allowed researchers to identify a number of potential targets for neuroprotective strategies. "
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ABSTRACT: Understanding the evolution of neonatal hypoxic/ischemic is essential for novel neuroprotective approaches. We describe the neuropathology and glial/inflammatory response, from 3 hours to 100 days, after carotid occlusion and hypoxia (8% O
, 55 minutes) to the C57/BL6 P7 mouse. Massive tissue injury and atrophy in the ipsilateral (IL) hippocampus, corpus callosum, and caudate-putamen are consistently shown. Astrogliosis peaks at 14 days, but glial scar is still evident at day 100. Microgliosis peaks at 3–7 days and decreases by day 14. Both glial responses start at 3 hours in the corpus callosum and hippocampal fissure, to progressively cover the degenerating CA field. Neutrophils increase in the ventricles and hippocampal vasculature, showing also parenchymal extravasation at 7 days. Remarkably, delayed milder atrophy is also seen in the contralateral (CL) hippocampus and corpus callosum, areas showing astrogliosis and microgliosis during the first 72 hours. This detailed and long-term cellular response characterization of the ipsilateral and contralateral hemisphere after H/I may help in the design of better therapeutic strategies.
Available from: Xiyong Fan
- "Despite important progress in obstetric and neonatal care during the last decades, perinatal hypoxia-ischemia (HI) or birth asphyxia is still one of the most important causes of neonatal brain injury and the associated adverse developmental outcome [1, 2]. Currently, treatment options for post-asphyxial reperfusion/reoxygenation injury of the brain are largely supportive with prompt recognition and treatment of seizures, normalization of blood glucose levels, optimizing blood gases and blood pressure . "
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ABSTRACT: Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentrated on prevention of the production of reactive oxygen species or free radicals (xanthine-oxidase-, nitric oxide synthase-, and prostaglandin inhibition), anti-inflammatory effects (erythropoietin, melatonin, Xenon) and anti-apoptotic interventions (nuclear factor kappa B- and c-jun N-terminal kinase inhibition); in a later stage stimulation of neurotrophic properties in the neonatal brain (erythropoietin, growth factors) can be targeted to promote neuronal and oligodendrocyte regeneration. Combination of pharmacological means of treatment with moderate hypothermia, which is accepted now as a meaningful therapy, is probably the next step in clinical treatment to fight post-asphyxial brain damage. Further studies should be directed at a more rational use of therapies by determining the optimal time and dose to inhibit the different potentially destructive molecular pathways or to enhance endogenous repair while at the same time avoiding adverse effects of the drugs used.
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