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The option for term-born infants diagnosed with neonatal encephalopathy (NE) linked to hypoxia-ischemia (HI), (hypoxic-ischemic encephalopathy, HIE) is hypothermia (head alone, or whole-body cooling), which is only effective if commenced within 6 h of birth and requires specialized medical facilities ( 17, 18). The option for impending preterm birth is intrapartum use of magnesium sulfate preterm birth, but there are no postnatal therapies. At the present time, the treatment options for perinatally acquired brain damage are very limited. These disabilities include cerebral palsy, mild cognitive deficits, learning difficulties, epilepsy, and pervasive behavioral deficits such as autism spectrum disorders ( 16). These global problems in perinatology all too often result in death or life-time disabilities ( 13, 14), and account for around 2.4% of the total Global Burden of Disease ( 15). Perinatal brain damage arises from events such as fetal hypoxia, birth asphyxia, exposure to in utero and postnatal inflammation/infection (e.g., chorioamnionitis, sepsis), and/or preterm birth. We also interrogated gene expression databases to bring together the developmental and cell specific expression of MK and where possible PTN and their receptors. Both highlight the potential for the use of MK as a treatment for perinatal brain damage. In this review, we discuss the spatiotemporal expression of MK and some of its key receptors during neurodevelopment and the function of MK following injury-induced expression. However, the therapeutic potential of MK following injury to the developing CNS has yet to be explored. MK also promotes hypoxia-induced angiogenesis ( 11) and serves as a chemoattractant for leukocytes ( 12). Specifically, MK has been shown to ameliorate cell death, modulate glial reactivity, and enhance proliferation and migration of neural precursor cells ( 8, 10). Previous work has demonstrated the potential therapeutic efficacy of MK for repair and regeneration after ischemic brain damage ( 8) and in seizure ( 9), and drug addiction-related brain injuries ( 10). However, expression of MK in the adult is induced following many forms of injury, and in many forms of cancer ( 5), where it mediates hypoxic or inflammatory-driven cell response pathways ( 6, 7). PTN expression has a different pattern, increasing from birth and persisting into adulthood ( 3, 4). MK is called midkine because it was originally identified as a cyto kine highly expressed in mid-gestation in many organs of the mouse, particularly the kidneys, heart, and brain ( 1, 2).
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Midkine (MK) and pleiotrophin (PTN) are structurally and functionally related neurotrophic factors and are the only two members of the neurite growth-promoting factor family. The structural and functional development of the brain depends on neurotrophic factors that drive the growth, differentiation, and migration of neural precursor cells. This review discusses what is known of MK's expression and actions in the developing brain, areas for future research, and the potential for using MK as a therapeutic agent to ameliorate the effects of brain damage caused by insults such as birth-related hypoxia and inflammation. The potential for MK as a therapy for developmental brain injury is largely unknown. MK is upregulated in the adult central nervous system (CNS) after multiple types of experimental injury and has neuroprotective and neuroregenerative properties. Midkine (MK) is a small secreted heparin-binding protein highly expressed during embryonic/fetal development which, through interactions with multiple cell surface receptors promotes growth through effects on cell proliferation, migration, and differentiation. 4Neurodiderot, Inserm U1141, Universita de Paris, Paris, France.3The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia.2School of Health Sciences, Swinburne University of Technology, Melbourne, VIC, Australia.1Neurodevelopment in Health and Disease Research Program, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology (RMIT), Melbourne, VIC, Australia.Miller 3, Mary Tolcos 1, Bobbi Fleiss 1,4 † and David W. Emily Ross-Munro 1 †, Faith Kwa 1,2 †, Jenny Kreiner 1, Madhavi Khore 1, Suzanne L.