Perinatal brain injury frequently complicates preterm birth and leads to significant long-term morbidity. Cytokines and inflammatory cells are mediators in the common pathways associated with perinatal brain injury induced by a variety of insults, such as hypoxic-ischemic injury, reperfusion injury, toxin-mediated injury, and infection. This paper examines our current knowledge regarding cytokine-related perinatal brain injury and specifically discusses strategies for attenuating cytokine-mediated brain damage. 1. Introduction Preterm birth affects 12.5% of pregnancies in the United States [1, 2] and is the leading cause of neonatal morbidity and mortality, accounting for nearly half of the long-term neurologic morbidity in children [3]. The majority of premature infants in developed countries survive; however, 5–10% of survivors develop cerebral palsy (CP), and 40–50% develop cognitive and behavioral deficits [4, 5]. The prolonged vulnerability of the developing white and gray matter to excitotoxic, oxidative, and inflammatory forms of injury is a major factor in the pathogenesis of perinatal brain injury. While acute catastrophic brain injuries sometime occur (e.g., severe intraparenchymal hemorrhage), injury to white and gray matter regions is most often the cumulative result of metabolic, infectious and/or inflammatory, and hypoxic-ischemic insults over time [6]. For example, early respiratory compromise and systemic hypotension can precipitate glutamate, free radical, and cytokine toxicity to developing oligodendrocytes and neurons. The clinical course might be further complicated by late-onset or necrotizing enterocolitis (NEC). These sequential events result in different topographic patterns of injury based on developmental and genetic susceptibilities. Although there has been much focus on white matter injury (WMI) in premature infants, gray matter abnormalities in cortical and deep nuclear structures, and cerebellar injuries are also common and likely contribute to development of cognitive delay, psychomotor delay, and CP [7]. A variety of inciting events such as hypoxic-ischemia, infection, and/or inflammation, can stimulate a cascade of secondary responses, including fluid-electrolyte imbalance, regional blood flow alterations, calcium-mediated cellular injury, free-radical generation, oxidative and nitrosative stress, glutamate-induced excitotoxicity, disturbances in proinflammatory cytokine production, mitochondrion function, and apoptotic cell death [6, 8]. These disturbances result in activation of inflammatory cells involved in the
References
[1]
Outcomes IoMUCoUPBaAH, Preterm Birth: Causes, Consequences, and Prevention, National Academies Press, Washington, DC, USA, 2007.
[2]
T. J. Mathews, A. M. Mini？o, M. J. K. Osterman, D. M. Strobino, and B. Guyer, “Annual summary of vital statistics: 2008,” Pediatrics, vol. 127, no. 1, pp. 146–157, 2011.
[3]
M. C. McCormick, “The contribution of low birth weight to infant mortality and childhood morbidity,” New England Journal of Medicine, vol. 312, no. 2, pp. 82–90, 1985.
[4]
B. J. Stoll, N. I. Hansen, E. F. Bell et al., “Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network,” Pediatrics, vol. 126, no. 3, pp. 443–456, 2010.
[5]
R. A. Gargus, B. R. Vohr, J. E. Tyson et al., “Unimpaired outcomes for extremely low birth weight infants at 18 to 22 months,” Pediatrics, vol. 124, no. 1, pp. 112–121, 2009.
[6]
J. J. Volpe, “Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances,” The Lancet Neurology, vol. 8, no. 1, pp. 110–124, 2009.
[7]
H. C. Kinney, “The encephalopathy of prematurity: one pediatric neuropathologist's perspective,” Seminars in Pediatric Neurology, vol. 16, no. 4, pp. 179–190, 2009.
[8]
R. L. Haynes, R. D. Folkerth, R. J. Keefe et al., “Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia,” Journal of Neuropathology and Experimental Neurology, vol. 62, no. 5, pp. 441–450, 2003.
[9]
A. Foster-Barber, B. Dickens, and D. M. Ferriero, “Human perinatal asphyxia: correlation of neonatal cytokines with MRI and outcome,” Developmental Neuroscience, vol. 23, no. 3, pp. 213–218, 2001.
[10]
O. Dammann and T. M. O'Shea, “Cytokines and perinatal brain damage,” Clinics in Perinatology, vol. 35, no. 4, pp. 643–663, 2008.
[11]
M. A. Elovitz, A. G. Brown, K. Breen, L. Anton, M. Maubert, and I. Burd, “Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury,” International Journal of Developmental Neuroscience, vol. 29, no. 6, pp. 663–671, 2011.
[12]
S. Malaeb and O. Dammann, “Fetal inflammatory response and brain injury in the preterm newborn,” Journal of Child Neurology, vol. 24, no. 9, pp. 1119–1126, 2009.
[13]
C. A. Dinarello, “Proinflammatory cytokines,” Chest, vol. 118, no. 2, pp. 503–508, 2000.
[14]
V. Tayal and B. S. Kalra, “Cytokines and anti-cytokines as therapeutics - An update,” European Journal of Pharmacology, vol. 579, no. 1–3, pp. 1–12, 2008.
[15]
W. Rostène, M.-A. Dansereau, D. Godefroy et al., “Neurochemokines: a menage a trois providing new insights on the functions of chemokines in the central nervous system,” Journal of Neurochemistry, vol. 118, no. 5, pp. 680–694, 2011.
[16]
M. C. Morganti-Kossman, P. M. Lenzlinger, V. Hans et al., “Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue,” Molecular Psychiatry, vol. 2, no. 2, pp. 133–136, 1997.
[17]
G. Sebire, D. Emilie, C. Wallon et al., “In vitro production of IL-6, IL-1β, and tumor necrosis factor-α by human embryonic microglial and neural cells,” Journal of Immunology, vol. 150, no. 4, pp. 1517–1523, 1993.
[18]
S. C. Lee, W. Liu, D. W. Dickson, C. F. Brosnan, and J. W. Berman, “Cytokine production by human fetal microglia and astrocytes: differential induction by lipopolysaccharide and IL-1β,” Journal of Immunology, vol. 150, no. 7, pp. 2659–2667, 1993.
[19]
W. A. Banks, “Blood-brain barrier transport of cytokines: a mechanism for neuropathology,” Current Pharmaceutical Design, vol. 11, no. 8, pp. 973–984, 2005.
[20]
J. L. Wynn and O. Levy, “Role of innate host defenses in susceptibility to early-onset neonatal sepsis,” Clinics in Perinatology, vol. 37, no. 2, pp. 307–337, 2010.
[21]
O. Levy, “Innate immunity of the human newborn: distinct cytokine responses to LPS and other Toll-like receptor agonists,” Journal of Endotoxin Research, vol. 11, no. 2, pp. 113–116, 2005.
[22]
O. Levy, “Innate immunity of the newborn: basic mechanisms and clinical correlates,” Nature Reviews Immunology, vol. 7, no. 5, pp. 379–390, 2007.
[23]
O. Levy, M. Coughlin, B. N. Cronstein, R. M. Roy, A. Desai, and M. R. Wessels, “The adenosine system selectively inhibits TLR-mediated TNF-α production in the human newborn,” Journal of Immunology, vol. 177, no. 3, pp. 1956–1966, 2006.
[24]
B. Engelhardt and L. Sorokin, “The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction,” Seminars in Immunopathology, vol. 31, no. 4, pp. 497–511, 2009.
[25]
N. J. Abbott, L. R？nnb？ck, and E. Hansson, “Astrocyte-endothelial interactions at the blood-brain barrier,” Nature Reviews Neuroscience, vol. 7, no. 1, pp. 41–53, 2006.
[26]
Z. Redzic, “Molecular biology of the blood-brain and the blood-cerebrospinalfluid barriers: similarities and differences,” Cerebrospinal Fluid Research, vol. 8, article 3, 2011.
[27]
M. Khalil, J. Ronda, M. Weintraub, K. Jain, R. Silver, and A. J. Silverman, “Brain mast cell relationship to neurovasculature during development,” Brain Research, vol. 1171, no. 1, pp. 18–29, 2007.
[28]
N. R. Saunders, C. J. Ek, M. D. Habgood, and K. M. Dziegielewska, “Barriers in the brain: a renaissance?” Trends in Neurosciences, vol. 31, no. 6, pp. 279–286, 2008.
[29]
A. S. Lossinsky and R. R. Shivers, “Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review,” Histology and Histopathology, vol. 19, no. 2, pp. 535–564, 2004.
[30]
S. M. Stamatovic, R. F. Keep, and A. V. Andjelkovic, “Brain endothelial cell-cell junctions: how to “open” the blood brain barrier,” Current Neuropharmacology, vol. 6, no. 3, pp. 179–192, 2008.
[31]
N. R. Saunders, G. W. Knott, and K. M. Dziegielewska, “Barriers in the immature brain,” Cellular and Molecular Neurobiology, vol. 20, no. 1, pp. 29–40, 2000.
[32]
N. R. Saunders, M. D. Habgood, and K. M. Dziegielewska, “Barrier mechanisms in the brain, II. Immature brain,” Clinical and Experimental Pharmacology and Physiology, vol. 26, no. 2, pp. 85–91, 1999.
[33]
H. B. Stolp, K. M. Dziegielewska, C. J. Ek et al., “Breakdown of the blood-brain barrier to proteins in white matter of the developing brain following systemic inflammation,” Cell and Tissue Research, vol. 320, no. 3, pp. 369–378, 2005.
[34]
C. J. Ek, K. M. Dziegielewska, H. Stolp, and N. R. Saunders, “Functional effectiveness of the blood-brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica),” Journal of Comparative Neurology, vol. 496, no. 1, pp. 13–26, 2006.
[35]
K. M. Dziegielewska, J. Ek, M. D. Habgood, and N. R. Saunders, “Development of the choroid plexus,” Microscopy Research and Technique, vol. 52, no. 1, pp. 5–20, 2001.
[36]
H. Hagberg and C. Mallard, “Effect of inflammation on central nervous system development and vulnerability,” Current Opinion in Neurology, vol. 18, no. 2, pp. 117–123, 2005.
[37]
O. Dammann and A. Leviton, “Inflammatory brain damage in preterm newborns—dry numbers, wet lab, and causal inferences,” Early Human Development, vol. 79, no. 1, pp. 1–15, 2004.
[38]
Y. Pang, Z. Cai, and P. G. Rhodes, “Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide,” Developmental Brain Research, vol. 140, no. 2, pp. 205–214, 2003.
[39]
S. Lehnard, C. Lachance, S. Patrizi et al., “The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS,” Journal of Neuroscience, vol. 22, no. 7, pp. 2478–2486, 2002.
[40]
K. C. Williams and W. F. Hickey, “Traffic of hematogenous cells through the central nervous system,” Current Topics in Microbiology and Immunology, vol. 202, pp. 221–245, 1995.
[41]
P. Megyeri, C. S. Abraham, P. Temesvari, J. Kovacs, T. Vas, and C. P. Speer, “Recombinant human tumor necrosis factor α constricts pial arterioles and increases blood-brain barrier permeability in newborn piglets,” Neuroscience Letters, vol. 148, no. 1-2, pp. 137–140, 1992.
[42]
V. J. Quagliarello, B. Wispelwey, W. J. Long, and W. M. Scheld, “Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat: characterization and comparison with tumor necrosis factor,” Journal of Clinical Investigation, vol. 87, no. 4, pp. 1360–1366, 1991.
[43]
P. Zeni, E. Doepker, U. S. Topphoff, S. Huewel, T. Tenenbaum, and H. J. Galla, “MMPs contribute to TNF-α-induced alteration of the blood-cerebrospinal fluid barrier in vitro,” American Journal of Physiology, vol. 293, no. 3, pp. C855–C864, 2007.
[44]
H. Xaio, W. A. Banks, M. L. Niehoff, and J. E. Morley, “Effect of LPS on the permeability of the blood-brain barrier to insulin,” Brain Research, vol. 896, no. 1-2, pp. 36–42, 2001.
[45]
B. Bauer, A. M. S. Hartz, and D. S. Miller, “Tumor necrosis factor α and endothelin-1 increase p-glycoprotein expression and transport activity at the blood-brain barrier,” Molecular Pharmacology, vol. 71, no. 3, pp. 667–675, 2007.
[46]
Z. Fabry, K. M. Fitzsimmons, J. A. Herlein, T. O. Moninger, M. B. Dobbs, and M. N. Hart, “Product ion of the cytokines interleukin 1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes,” Journal of Neuroimmunology, vol. 47, no. 1, pp. 23–34, 1993.
[47]
T. M. Reyes, Z. Fabry, and C. L. Coe, “Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli,” Brain Research, vol. 851, no. 1-2, pp. 215–220, 1999.
[48]
P. B. Eisenhauer, M. S. Jacewicz, K. J. Conn et al., “Escherichia coli Shiga toxin 1 and TNF-α induce cytokine release by human cerebral microvascular endothelial cells,” Microbial Pathogenesis, vol. 36, no. 4, pp. 189–196, 2004.
[49]
S. Verma, R. Nakaoke, S. Dohgu, and W. A. Banks, “Release of cytokines by brain endothelial cells: a polarized response to lipopolysaccharide,” Brain, Behavior, and Immunity, vol. 20, no. 5, pp. 449–455, 2006.
[50]
W. Pan, C. Cain, Y. Yu, and A. J. Kastin, “Receptor-mediated transport of LIF across blood-spinal cord barrier is upregulated after spinal cord injury,” Journal of Neuroimmunology, vol. 174, no. 1-2, pp. 119–125, 2006.
[51]
R. Koneru, D. Kobiler, S. Lehrer et al., “Macrophages play a key role in early blood brain barrier reformation after hypothermic brain injury,” Neuroscience Letters, vol. 501, no. 3, pp. 148–151, 2011.
[52]
K. Takeda and S. Akira, “Toll-like receptors,” Current Protocols in Immunology, vol. 14, unit 14.12, 2007.
[53]
R. Romero, S. Durum, C. A. Dinarello, E. Oyarzun, J. C. Hobbins, and M. D. Mitchell, “Interleukin-1 stimulates prostaglandin biosynthesis by human amnion,” Prostaglandins, vol. 37, no. 1, pp. 13–22, 1989.
[54]
M. D. Mitchell, D. J. Dudley, S. S. Edwin, and S. L. Schiller, “Interleukin-6 stimulates prostaglandin production by human amnion and decidual cells,” European Journal of Pharmacology, vol. 192, no. 1, pp. 189–191, 1991.
[55]
T. Taniguchi, N. Matsuzaki, T. Kameda et al., “The enhanced production of placental interleukin-1 during labor and intrauterine infection,” American Journal of Obstetrics and Gynecology, vol. 165, no. 1, pp. 131–137, 1991.
[56]
S. L. Hillier, S. S. Witkin, M. A. Krohn, D. H. Watts, N. B. Kiviat, and D. A. Eschenbach, “The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection,” Obstetrics and Gynecology, vol. 81, no. 6, pp. 941–948, 1993.
[57]
K. M. Adams Waldorf, C. E. Rubens, and M. G. Gravett, “Use of nonhuman primate models to investigate mechanisms of infection-associated preterm birth,” British Journal of Obstetrics and Gynaecology, vol. 118, no. 2, pp. 136–144, 2011.
[58]
R. Romero, D. T. Brody, E. Oyarzun et al., “Infection and labor—III. Interleukin-1: a signal for the onset of parturition,” American Journal of Obstetrics and Gynecology, vol. 160, no. 5, pp. 1117–1123, 1989.
[59]
R. Romero, C. Avila, U. Santhanam, and P. B. Sehgal, “Amniotic fluid interleukin 6 in preterm labor. Association with infection,” Journal of Clinical Investigation, vol. 85, no. 5, pp. 1392–1399, 1990.
[60]
R. Romero, M. Ceska, C. Avila, M. Mazor, E. Behnke, and I. Lindley, “Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition,” American Journal of Obstetrics and Gynecology, vol. 165, no. 4 I, pp. 813–820, 1991.
[61]
R. Romero, K. R. Manogue, M. D. Mitchell et al., “Infection and labor—IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor,” American Journal of Obstetrics and Gynecology, vol. 161, no. 2, pp. 336–341, 1989.
[62]
H. J. Kadhim, J. Duchateau, and G. Sébire, “Cytokines and brain injury: invited review,” Journal of Intensive Care Medicine, vol. 23, no. 4, pp. 236–249, 2008.
[63]
E. Molina-Holgado and F. Molina-Holgado, “Mending the broken brain: neuroimmune interactions in neurogenesis,” Journal of Neurochemistry, vol. 114, no. 5, pp. 1277–1290, 2010.
[64]
S. L. Bailey, P. A. Carpentier, E. J. McMahon, W. S. Begolka, and S. D. Miller, “Innate and adaptive immune responses of the central nervous system,” Critical Reviews in Immunology, vol. 26, no. 2, pp. 149–188, 2006.
[65]
J. M. Vela, E. Molina-Holgado, á. Arévalo-Martín, G. Almazán, and C. Guaza, “Interleukin-1 regulates proliferation and differentiation of oligodendrocyte progenitor cells,” Molecular and Cellular Neuroscience, vol. 20, no. 3, pp. 489–502, 2002.
[66]
M. Aschner, “Immune and inflammatory responses in the CNS: modulation by astrocytes,” Toxicology Letters, vol. 102-103, pp. 283–287, 1998.
[67]
H. Kadhim, B. Tabarki, G. Verellen, C. De Prez, A. M. Rona, and G. Sébire, “Inflammatory cytokines in the pathogenesis of periventricular leukomalacia,” Neurology, vol. 56, no. 10, pp. 1278–1284, 2001.
[68]
H. Hagberg, E. Gilland, E. Bona et al., “Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats,” Pediatric Research, vol. 40, no. 4, pp. 603–609, 1996.
[69]
V. Wee Yong, “Inflammation in neurological disorders: a help or a hindrance?” Neuroscientist, vol. 16, no. 4, pp. 408–420, 2010.
[70]
G. Favrais, Y. Van De Looij, B. Fleiss et al., “Systemic inflammation disrupts the developmental program of white matter,” Annals of Neurology, vol. 70, no. 4, pp. 550–565, 2011.
[71]
J. V. Welser-Alves, S. J. Crocker, and R. Milner, “A dual role for microglia in promoting tissue inhibitor of metalloproteinase (TIMP) expression in glial cells in response to neuroinflammatory stimuli,” Journal of Neuroinflammation, vol. 8, article 61, 2011.
[72]
A. Ould-Yahoui, E. Tremblay, O. Sbai et al., “A new role for TIMP-1 in modulating neurite outgrowth and morphology of cortical neurons,” PLoS ONE, vol. 4, no. 12, Article ID e8289, 2009.
[73]
C. S. Moore, R. Milner, A. Nishiyama et al., “Astrocytic tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes oligodendrocyte differentiation and enhances CNS myelination,” Journal of Neuroscience, vol. 31, no. 16, pp. 6247–6254, 2011.
[74]
P. Svedin, H. Hagberg, K. S？vman, C. Zhu, and C. Mallard, “Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia,” Journal of Neuroscience, vol. 27, no. 7, pp. 1511–1518, 2007.
[75]
R. L. Goldenberg, J. C. Hauth, and W. W. Andrews, “Intrauterine infection and preterm delivery,” New England Journal of Medicine, vol. 342, no. 20, pp. 1500–1507, 2000.
[76]
Y. W. Wu and J. M. Colford, “Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis,” Journal of the American Medical Association, vol. 284, no. 11, pp. 1417–1424, 2000.
[77]
J. G. Shatrov, S. C. M. Birch, L. T. Lam, J. A. Quinlivan, S. McIntyre, and G. L. Mendz, “Chorioamnionitis and cerebral palsy: a meta-analysis,” Obstetrics and Gynecology, vol. 116, no. 2, pp. 387–392, 2010.
[78]
V. M. Abrahams, P. Bole-Aldo, Y. M. Kim et al., “Divergent trophoblast responses to bacterial products mediated by TLRs,” Journal of Immunology, vol. 173, no. 7, pp. 4286–4296, 2004.
[79]
C. Mallard and H. Hagberg, “Inflammation-induced preconditioning in the immature brain,” Seminars in Fetal and Neonatal Medicine, vol. 12, no. 4, pp. 280–286, 2007.
[80]
B. H. Yoon, R. Romero, S. H. Yang, J. K. Jun, I. O. Kim, and J. H. Choi, “Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia,” American Journal of Obstetrics and Gynecology, vol. 174, no. 5, pp. 1433–1440, 1996.
[81]
O. Dammann and A. Leviton, “Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant,” Seminars in Pediatric Neurology, vol. 5, no. 3, pp. 190–201, 1998.
[82]
G. Oggé, R. Romero, D.-C. Lee et al., “Chronic chorioamnionitis displays distinct alterations of the amniotic fluid proteome,” Journal of Pathology, vol. 223, no. 4, pp. 553–565, 2011.
[83]
H. Martin, B. Olander, and M. Norman, “Reactive hyperemia and interleukin 6, interleukin 8, and tumor necrosis factor-alpha in the diagnosis of early-onset neonatal sepsis,” Pediatrics, vol. 108, no. 4, article E61, 2001.
[84]
P. C. Ng, K. Li, K. M. Chui et al., “IP-10 is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants,” Pediatric Research, vol. 61, no. 1, pp. 93–98, 2007.
[85]
S. R. Hintz, D. E. Kendrick, B. J. Stoll et al., “Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis,” Pediatrics, vol. 115, no. 3, pp. 696–703, 2005.
[86]
R. S. Procianoy and R. C. Silveira, “Association between high cytokine levels with white matter injury in preterm infants with sepsis,” Pediatric Critical Care Medicine. In press.
[87]
C. P. Speer, “Pulmonary inflammation and bronchopulmonary dysplasia,” Journal of Perinatology, vol. 26, no. 1, supplement, pp. S57–S62, 2006.
[88]
L. Gagliardi, R. Bellù, R. Zanini, and O. Dammann, “Bronchopulmonary dysplasia and brain white matter damage in the preterm infant: a complex relationship,” Paediatric and Perinatal Epidemiology, vol. 23, no. 6, pp. 582–590, 2009.
[89]
L. A. Koman, B. P. Smith, and J. S. Shilt, “Cerebral palsy,” Lancet, vol. 363, no. 9421, pp. 1619–1631, 2004.
[90]
R. M. McAdams and S. E. Juul, “Cerebral palsy: prevalence, predictability, and parental counseling,” NeoReviews, vol. 12, no. 10, pp. e564–e574, 2011.
[91]
S. A. Back, N. L. Luo, R. A. Mallinson et al., “Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes,” Annals of Neurology, vol. 58, no. 1, pp. 108–120, 2005.
[92]
W. Deng, J. Pleasure, and D. Pleasure, “Progress in periventricular leukomalacia,” Archives of Neurology, vol. 65, no. 10, pp. 1291–1295, 2008.
[93]
L. M. Nagae, A. H. Hoon, E. Stashinko et al., “Diffusion tensor imaging in children with periventricular leukomalacia: variability of injuries to white matter tracts,” American Journal of Neuroradiology, vol. 28, no. 7, pp. 1213–1222, 2007.
[94]
V. J. Ellison, T. J. Mocatta, C. C. Winterbourn, B. A. Darlow, J. J. Volpe, and T. E. Inder, “The relationship of CSF and plasma cytokine levels to cerebral white matter injury in the premature newborn,” Pediatric Research, vol. 57, no. 2, pp. 282–286, 2005.
[95]
H. C. Huang, C. L. Wang, L. T. Huang et al., “Association of cord blood cytokines with prematurity and cerebral palsy,” Early Human Development, vol. 77, no. 1-2, pp. 29–36, 2004.
[96]
W. A. Carlo, S. A. McDonald, J. E. Tyson et al., “Cytokines and neurodevelopmental outcomes in extremely low birth weight infants,” Journal of Pediatrics, vol. 159, no. 6, pp. 919–925, 2011.
[97]
B. H. Yoon, C. W. Park, and T. Chaiworapongsa, “Intrauterine infection and the development of cerebral palsy,” British Journal of Obstetrics and Gynaecology, vol. 110, no. 20, pp. 124–127, 2003.
[98]
S. Lehnardt, “Innate immunity and neuroinflammation in the CNS: the role of microglia in toll-like receptor-mediated neuronal injury,” Glia, vol. 58, no. 3, pp. 253–263, 2010.
[99]
W. Deng, “Neurobiology of injury to the developing brain,” Nature Reviews Neurology, vol. 6, no. 6, pp. 328–336, 2010.
[100]
Y. Pang, L. Campbell, B. Zheng, L. Fan, Z. Cai, and P. Rhodes, “Lipopolysaccharide-activated microglia induce death of oligodendrocyte progenitor cells and impede their development.,” Neuroscience, vol. 166, no. 2, pp. 464–475, 2010.
[101]
C. Y. Lin, Y. C. Chang, S. T. Wang, T. Y. Lee, C. F. Lin, and C. C. Huang, “Altered inflammatory responses in preterm children with cerebral palsy,” Annals of Neurology, vol. 68, no. 2, pp. 204–212, 2010.
[102]
L. F. Shalak and J. M. Perlman, “Infection markers and early signs of neonatal encephalopathy in the term infant,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 8, no. 1, pp. 14–19, 2002.
[103]
L. F. Shalak, A. R. Laptook, H. S. Jafri, O. Ramilo, and J. M. Perlman, “Clinical chorioamnionitis, elevated cytokines, and brain injury in term infants,” Pediatrics, vol. 110, no. 4, pp. 673–680, 2002.
[104]
K. B. Nelson, J. K. Grether, J. M. Dambrosia et al., “Neonatal cytokines and cerebral palsy in very preterm infants,” Pediatric Research, vol. 53, no. 4, pp. 600–607, 2003.
[105]
Y. W. Wu, G. J. Escobar, J. K. Grether, L. A. Croen, J. D. Greene, and T. B. Newman, “Chorioamnionitis and Cerebral Palsy in Term and Near-Term Infants,” Journal of the American Medical Association, vol. 290, no. 20, pp. 2677–2684, 2003.
[106]
B. Jacobsson and G. Hagberg, “Antenatal risk factors for cerebral palsy,” Best Practice and Research, vol. 18, no. 3, pp. 425–436, 2004.
[107]
J. J. Volpe, “Cerebral white matter injury of the premature infant—more common than you think,” Pediatrics, vol. 112, no. 1 I, pp. 176–180, 2003.
[108]
A. I. Bartha, A. Foster-Barber, S. P. Miller et al., “Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome,” Pediatric Research, vol. 56, no. 6, pp. 960–966, 2004.
[109]
K. S？vman, M. Blennow, K. Gustafson, E. Tarkowski, and H. Hagberg, “Cytokine response in cerebrospinal fluid after birth asphyxia,” Pediatric Research, vol. 43, no. 6, pp. 746–751, 1998.
[110]
B. H. Yoon, R. Romero, J. S. Park et al., “The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis,” American Journal of Obstetrics and Gynecology, vol. 183, no. 5, pp. 1124–1129, 2000.
[111]
A. Leviton, N. Paneth, M. L. Reuss et al., “Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants,” Pediatric Research, vol. 46, no. 5, pp. 566–575, 1999.
[112]
B. H. Yoon, R. Romero, J. S. Park et al., “Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years,” American Journal of Obstetrics and Gynecology, vol. 182, no. 3, pp. 675–681, 2000.
[113]
J. Correale and A. Villa, “The neuroprotective role of inflammation in nervous system Injuries,” Journal of Neurology, vol. 251, no. 11, pp. 1304–1316, 2004.
[114]
M. Djukic, C. S. Gibson, A. H. Maclennan et al., “Genetic susceptibility to viral exposure may increase the risk of cerebral palsy,” Australian and New Zealand Journal of Obstetrics and Gynaecology, vol. 49, no. 3, pp. 247–253, 2009.
[115]
D. Wu, Y.-F. Zou, X.-Y. Xu et al., “The association of genetic polymorphisms with cerebral palsy: a meta-analysis,” Developmental Medicine and Child Neurology, vol. 53, no. 3, pp. 217–225, 2011.
[116]
Y. W. Wu, L. A. Croen, A. R. Torres, J. Van De Water, J. K. Grether, and N. N. Hsu, “Interleukin-6 genotype and risk for cerebral palsy in term and near-term infants,” Annals of Neurology, vol. 66, no. 5, pp. 663–670, 2009.
[117]
M. D？rdelmann, J. Kerk, F. Dressler et al., “Interleukin-10 high producer allele and ultrasound-defined periventricular white matter abnormalities in preterm infants: a preliminary study,” Neuropediatrics, vol. 37, no. 3, pp. 130–136, 2006.
[118]
S. Thayyil, M. Chandrasekaran, A. Taylor et al., “Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis,” Pediatrics, vol. 125, no. 2, pp. e382–e395, 2010.
[119]
A. Leviton, K. Kuban, T. M. O'Shea et al., “The relationship between early concentrations of 25 blood proteins and cerebral white matter injury in preterm newborns: the ELGAN study,” Journal of Pediatrics, vol. 158, no. 6, pp. 897.e5–903.e5, 2011.
[120]
S. Shahrara, C. C. Park, V. Temkin, J. W. Jarvis, M. V. Volin, and R. M. Pope, “RANTES modulates TLR4-induced cytokine secretion in human peripheral blood monocytes,” Journal of Immunology, vol. 177, no. 8, pp. 5077–5087, 2006.
[121]
M. Digicaylioglu and S. A. Lipton, “Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades,” Nature, vol. 412, no. 6847, pp. 641–647, 2001.
[122]
N. Byts, A. Samoylenko, T. Fasshauer et al., “Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin,” Cell Death and Differentiation, vol. 15, no. 4, pp. 783–792, 2008.
[123]
L. Wang, M. Chopp, S. R. Gregg et al., “Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 7, pp. 1361–1368, 2008.
[124]
B. Viviani, S. Bartesaghi, E. Corsini et al., “Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor,” Journal of Neurochemistry, vol. 93, no. 2, pp. 412–421, 2005.
[125]
E. Spandou, Z. Papadopoulou, V. Soubasi et al., “Erythropoietin prevents long-term sensorimotor deficits and brain injury following neonatal hypoxia-ischemia in rats,” Brain Research, vol. 1045, no. 1-2, pp. 22–30, 2005.
[126]
S. Rees, N. Hale, R. De Matteo et al., “Erythropoietin is neuroprotective in a preterm ovine model of endotoxin-induced brain injury,” Journal of Neuropathology and Experimental Neurology, vol. 69, no. 3, pp. 306–319, 2010.
[127]
E. J. Demers, R. J. McPherson, and S. E. Juul, “Erythropoietin protects dopaminergic neurons and improves neurobehavioral outcomes in juvenile rats after neonatal hypoxia-ischemia,” Pediatric Research, vol. 58, no. 2, pp. 297–301, 2005.
[128]
B. A. Kellert, R. J. McPherson, and S. E. Juul, “A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats,” Pediatric Research, vol. 61, no. 4, pp. 451–455, 2007.
[129]
F. F. Gonzalez, R. Abel, C. R. Almli, D. Mu, M. Wendland, and D. M. Ferriero, “Erythropoietin sustains cognitive function and brain volume after neonatal stroke,” Developmental Neuroscience, vol. 31, no. 5, pp. 403–411, 2009.
[130]
M. Yamada, C. Burke, P. Colditz, D. W. Johnson, and G. C. Gobe, “Erythropoietin protects against apoptosis and increases expression of non-neuronal cell markers in the hypoxia-injured developing brain,” Journal of Pathology, vol. 224, no. 1, pp. 101–109, 2011.
[131]
S. Genc, K. Genc, A. Kumral, and H. Ozkan, “White matter protection by erythropoietin: an emerging matter in the treatment of neonatal hypoxic-ischemic brain injury,” Stroke, vol. 41, no. 11, article e595, 2010.
[132]
Y. Sun, J. W. Calvert, and J. H. Zhang, “Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration,” Stroke, vol. 36, no. 8, pp. 1672–1678, 2005.
[133]
S. E. Juul, R. P. Beyer, T. K. Bammler, R. J. Mcpherson, J. Wilkerson, and F. M. Farin, “Microarray analysis of high-dose recombinant erythropoietin treatment of unilateral brain injury in neonatal mouse hippocampus,” Pediatric Research, vol. 65, no. 5, pp. 485–492, 2009.
[134]
M. Iwai, G. Cao, W. Yin, R. A. Stetler, J. Liu, and J. Chen, “Erythropoietin promotes neuronal replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in rats,” Stroke, vol. 38, no. 10, pp. 2795–2803, 2007.
[135]
F. F. Gonzalez, P. McQuillen, D. Mu et al., “Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke,” Developmental Neuroscience, vol. 29, no. 4-5, pp. 321–330, 2007.
[136]
M. Iwai, R. A. Stetler, J. Xing et al., “Enhanced oligodendrogenesis and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain injury,” Stroke, vol. 41, no. 5, pp. 1032–1037, 2010.
[137]
S. E. Juul, R. J. McPherson, L. A. Bauer, K. J. Ledbetter, C. A. Gleason, and D. E. Mayock, “A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety,” Pediatrics, vol. 122, no. 2, pp. 383–391, 2008.
[138]
J. C. Fauchère, C. Dame, R. Vonthein et al., “An approach to using recombinant erythropoietin for neuroprotection in very preterm infants,” Pediatrics, vol. 122, no. 2, pp. 375–382, 2008.
[139]
R. Hardeland, “Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance,” Endocrine, vol. 27, no. 2, pp. 119–130, 2005.
[140]
J. C. Mayo, R. M. Sainz, D. X. Tan et al., “Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages,” Journal of Neuroimmunology, vol. 165, no. 1-2, pp. 139–149, 2005.
[141]
F. Luchetti, B. Canonico, M. Betti et al., “Melatonin signaling and cell protection function,” FASEB Journal, vol. 24, no. 10, pp. 3603–3624, 2010.
[142]
L. C. Hutton, M. Abbass, H. Dickinson, Z. Ireland, and D. W. Walker, “Neuroprotective properties of melatonin in a model of birth asphyxia in the spiny mouse (Acomys cahirinus),” Developmental Neuroscience, vol. 31, no. 5, pp. 437–451, 2009.
[143]
A. K. Welin, P. Svedin, R. Lapatto et al., “Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion,” Pediatric Research, vol. 61, no. 2, pp. 153–158, 2007.
[144]
H. Wang, D. X. Xu, J. W. Lv, H. Ning, and W. Wei, “Melatonin attenuates lipopolysaccharide (LPS)-induced apoptotic liver damage in d-galactosamine-sensitized mice,” Toxicology, vol. 237, no. 1-3, pp. 49–57, 2007.
[145]
F. Fulia, E. Gitto, S. Cuzzocrea et al., “Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin,” Journal of Pineal Research, vol. 31, no. 4, pp. 343–349, 2001.
[146]
E. Gitto, M. Karbownik, R. J. Reiter et al., “Effects of melatonin treatment in septic newborns,” Pediatric Research, vol. 50, no. 6, pp. 756–760, 2001.
[147]
A. Murakami and H. Ohigashi, “Targeting NOX, INOS and COX-2 in inflammatory cells: chemoprevention using food phytochemicals,” International Journal of Cancer, vol. 121, no. 11, pp. 2357–2363, 2007.
[148]
Y. J. Surh, K. S. Chun, H. H. Cha et al., “Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-κB activation,” Mutation Research, vol. 480-481, pp. 243–268, 2001.
[149]
L. F. He, H. J. Chen, L. H. Qian, G. Y. Chen, and J. S. Buzby, “Curcumin protects pre-oligodendrocytes from activated microglia in vitro and in vivo,” Brain Research, vol. 1339, no. C, pp. 60–69, 2010.
[150]
E. C. A. Kaal and C. J. Vecht, “The management of brain edema in brain tumors,” Current Opinion in Oncology, vol. 16, no. 6, pp. 593–600, 2004.
[151]
P. K. Stys and S. A. Lipton, “White matter NMDA receptors: an unexpected new therapeutic target?” Trends in Pharmacological Sciences, vol. 28, no. 11, pp. 561–566, 2007.
[152]
Z. G. Xiong, X. M. Zhu, X. P. Chu et al., “Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels,” Cell, vol. 118, no. 6, pp. 687–698, 2004.
[153]
A. D. Edwards, P. Brocklehurst, A. J. Gunn et al., “Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data,” British Medical Journal, vol. 340, article c363, 2010.
[154]
B. Mesplès, R. H. Fontaine, V. Lelièvre, J.-M. Launay, and P. Gressens, “Neuronal TGF-β1 mediates IL-9/mast cell interaction and exacerbates excitotoxicity in newborn mice,” Neurobiology of Disease, vol. 18, no. 1, pp. 193–205, 2005.
[155]
Y. Jin, A. J. Silverman, and S. J. Vannucci, “Mast cell stabilization limits hypoxic-ischemic brain damage in the immature rat,” Developmental Neuroscience, vol. 29, no. 4-5, pp. 373–384, 2007.
