Hypothermia and Other Treatment Options for Neonatal Encephalopathy: An Executive Summary of the Eunice Kennedy Shriver NICHD Workshop

Higgins, Rosemary D.; Raju, Tonse N.K.; Edwards, A. David; Azzopardi, Denis; Bose, Carl; Clark, Reese H.; Ferriero, Donna M.; Guillet, Ronnie; Gunn, Alistair J.; Hagberg, Henrik; Hirtz, Deborah; Inder, Terrie E.; Jacobs, Susan E; Jenkins, Dorothea; Juul, Sandra E.; Laptook, Abbot R.; Lucey, Jerold F.; Maze, Mervyn; Palmer, Charles; Papile, Lu-Ann; Pfister, Robert H.; Robertson, Nicola J.; Rutherford, Mary A.; Shankaran, Seetha; Silverstein, Faye S.; Soll, Roger F.; Thoresen, Marianne; Walsh, William F.

doi:10.1016/j.jpeds.2011.08.004

Cited by 201 publications

(146 citation statements)

References 77 publications

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“…Unfortunately, in premature infants at risk, no neuroprotective agent has proven safe and effective so far. 3 Secreted from developing embryos, PreImplantation Factor (PIF) can be detected in the maternal circulation during pregnancy, 4,5 and its presence has been correlated with live birth. [5][6][7] PIF has been implicated in promoting embryo implantation through modulating maternal immune tolerance.…”

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confidence: 99%

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

et al. 2015

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A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

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confidence: 99%

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

et al. 2015

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“…It is increasingly recognized that the selection of appropriate animal models is critical to identify promising therapeutic agents and to reduce false negative outcomes [2]. The substantial translational advantages of studies in a large preclinical animal model are exemplified by pre-clinical studies in near term fetal sheep [3] that lead to the head cooling trials for neonatal encephalopathy, and the implementation of cerebral hypothermia protocols in neonatal intensive care units worldwide [4].…”

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The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

et al. 2012

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Despite advances in neonatal intensive care, survivors of premature birth remain highly susceptible to unique patterns of developmental brain injury that manifest as cerebral palsy and cognitive-learning disabilities. The developing brain is particularly susceptible to cerebral white matter injury related to hypoxia-ischemia. Cerebral white matter development in fetal sheep shares many anatomical and physiological similarities with humans. Thus, the fetal sheep has provided unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in models that replicate major features of acute and chronic human cerebral injury and have provided access to complex clinically relevant studies of cerebral blood flow and neuroimaging that are not feasible in smaller laboratory animals. Here, we focus on emerging insights and methodologies from studies in fetal sheep that have begun to define cellular and vascular factors that contribute to white matter injury. Recent advances include spatially defined measurements of cerebral blood flow in utero, the definition of cellular maturational factors that define the topography of injury and the application of high-field magnetic resonance imaging to define novel neuroimaging signatures for specific types of chronic white matter injury. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they provide powerful access to clinically relevant studies that provide a more integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

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“…Con el fin de maximizar el beneficio para los pacientes asfixiados que están en alto riesgo, es muy importante para nosotros seguir protocolos estándares, basado en la mejor evidencia científica disponible 41 . Debemos estar disponibles, una vez estandarizada la terapia integral del RN con EHI, a protocolos con tratamientos farmacológicos de neuroprotección que se adicionen a la hipotermia 42 .…”

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Consenso sobre manejo integral del neonato con encefalopatía hipóxico isquémica

et al. 2012

Rev. chil. pediatr.

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Consensus statement on integral management of the newborn with hypoxic-ischemic encephalopathyNeonatal encephalopathy secondary to birth asphyxia, the hypoxic ischemic encephalopathy, remains a major cause of postnatal death and neurological sequelae worldwide. supportive therapy has been the mainstay of treatment. Recently series of multicenter clinical trials show the benefits of therapeutic hypothermia in this high risk population. The International liaison Committee on Resuscitation (IlCOR) has recommended hypothermia as a standard of care and a beneficial therapy using the protocols followed in large clinical trials. Our objective was to develop a practical guide to be used at a national level in Chile, compatible with published protocols and standardized on an international basis, practical and compatible with the country's situation, and considering an integral management of the asphyxiated neonates, rescue and neuroprotective therapies. In summary, to establish rescue therapies, with the aim objective of support measures that promote cerebral and systemic oxygenation/perfusion, ensuring optimal cellular homeostasis, which are the basis of the rescue measures in asphyxiated neonates. Along with these rescue therapies, the objective is to perform the more beneficial neuroprotective therapy known today, hypothermia. Hypothermia should be conducted in a level 3 Neonatal Intensive Care unit, with multidisciplinary care and standardized protocols and also multidisciplinary follow-up and rehabilitation therapies.

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Hypothermia and Other Treatment Options for Neonatal Encephalopathy: An Executive Summary of the Eunice Kennedy Shriver NICHD Workshop

Cited by 201 publications

References 77 publications

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

Consenso sobre manejo integral del neonato con encefalopatía hipóxico isquémica

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