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.
References
[1]
Kurinczuk, J.J.; White-Koning, M.; Badawi, N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum. Dev. 2010, 86, 329–338, doi:10.1016/j.earlhumdev.2010.05.010.
[2]
Lawn, J.E.; Cousens, S.; Zupan, J. Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: When? Where? Why? Lancet 2005, 365, 891–900.
[3]
Pierrat, V.; Haouari, N.; Liska, A.; Thomas, D.; Subtil, D.; Truffert, P. Groupe d’Etudes en Epidemiologie Perinatale. Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: Population based study. Arch. Dis. Child. Fetal Neonatal Ed. 2005, 90, F257–F261, doi:10.1136/adc.2003.047985.
[4]
Marlow, N.; Budge, H. Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy. Arch. Dis. Child. Fetal Neonatal Ed. 2005, 90, F193–F194, doi:10.1136/adc.2004.057059.
[5]
Cowan, F. Outcome after intrapartum asphyxia in term infants. Semin. Neonatol. 2000, 5, 127–140, doi:10.1053/siny.2000.0011.
[6]
Al-Macki, N.; Miller, S.P.; Hall, N.; Shevell, M. The spectrum of abnormal neurologic outcomes subsequent to term intrapartum asphyxia. Pediatr. Neurol. 2009, 41, 399–405, doi:10.1016/j.pediatrneurol.2009.06.001.
[7]
Barnett, A.; Mercuri, E.; Rutherford, M.; Haataja, L.; Frisone, M.F.; Henderson, S.; Cowan, F.; Dubowitz, L. Neurological and perceptual-motor outcome at 5–6 years of age in children with neonatal encephalopathy: Relationship with neonatal brain MRI. Neuropediatrics 2002, 33, 242–248, doi:10.1055/s-2002-36737.
[8]
Glass, H.C.; Ferriero, D.M. Treatment of hypoxic-ischemic encephalopathy in newborns. Curr. Treat. Options Neurol. 2007, 9, 414–423, doi:10.1007/s11940-007-0043-0.
[9]
Carl, G.; Reiger, I.; Evans, N. One-year neurodevelopmental outcome after moderate newborn hypoxic ischemic encephalopathy. J. Paediatr. Child Health 2004, 40, 217–220, doi:10.1111/j.1440-1754.2004.00341.x.
[10]
Du Plessis, A.J.; Volpe, J.J. Perinatal brain injury in the preterm and term newborn. Curr. Opin. Neurol. 2002, 15, 151–157, doi:10.1097/00019052-200204000-00005.
Fan, X.; Kavelaars, A.; Heijnen, C.J.; Groenendaal, F.; van Bel, F. Pharmacological neuroprotection after perinatal hypoxic-ischemic brain injury. Curr. Neuropharmacol. 2010, 8, 324–334, doi:10.2174/157015910793358150.
[13]
Ferriero, D. Neonatal brain injury. N. Engl. J. Med. 2004, 351, 1985–1995, doi:10.1056/NEJMra041996.
[14]
Walton, M.; Connor, B.; Lawlor, P.; Young, D.; Sirimanne, E.; Gluckman, P.; Cole, G.; Dragunow, M. Neuronal death and survival in two models of hypoxic-ischemic brain damage. Brain Res. Rev. 1999, 29, 137–168, doi:10.1016/S0165-0173(98)00053-8.
[15]
Sarnat, H.B.; Sarnat, M.S. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch. Neurol. 1976, 33, 696–705, doi:10.1001/archneur.1976.00500100030012.
[16]
Vannucci, R.C.; Vannucci, S.J. A model of perinatal hypoxic-ischemic brain damage. Ann. N. Y. Acad. Sci. 1997, 835, 234–249, doi:10.1111/j.1749-6632.1997.tb48634.x.
[17]
Yager, J.Y.; Thornhill, J.A. The effect of age on susceptibility to hypoxic-ischemic brain damage. Neurosci. Biobehav. Rev. 1997, 21, 167–174, doi:10.1016/S0149-7634(96)00006-1.
[18]
Shalak, L.F.; Laptook, A.R.; Velaphi, S.C.; Perlman, J.M. Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy. Pediatrics 2003, 111, 351–357, doi:10.1542/peds.111.2.351.
[19]
Sanders, R.D.; Manning, H.J.; Robertson, N.J.; Ma, D.; Edwards, A.D.; Hagberg, H.; Maze, M. Preconditioning and postinsult therapies for perinatal hypoxic-ischemic injury at term. Anesthesiology 2010, 113, 233–249, doi:10.1097/ALN.0b013e3181dc1b84.
[20]
Perlman, J.M. Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy. Pediatrics 2006, 117, 28–33, doi:10.1542/peds.2005-2425.
[21]
Volpe, J.J. Neurology of the Newborn, 5th ed.; Elsevier Health Sciences: New York, NY, USA, 2008.
[22]
Wyatt, J.S.; Edwards, A.D.; Azzopardi, D.; Reynolds, E.O. Magnetic resonance and near infrared spectroscopy for investigation of perinatal hypoxic-ischaemic brain injury. Arch. Dis. Child. 1989, 64, 953–963, doi:10.1136/adc.64.7_Spec_No.953.
[23]
Yager, J.Y.; Brucklacher, R.M.; Vannucci, R.C. Cerebral energy metabolism during hypoxia-ischemia and early recovery in immature rats. Am. J. Physiol. 1992, 262, 672–677.
[24]
Inder, T.E.; Huppi, P.S. In vivo studies of brain development by magnetic resonance techniques. Ment. Retard. Dev. Disabil. Res. Rev. 2000, 6, 59–67, doi:10.1002/(SICI)1098-2779(2000)6:1<59::AID-MRDD8>3.0.CO;2-E.
[25]
Girard, S.; Kadhim, H.; Larouche, A.; Roy, M.; Gobeil, F.; Sébire, G. Pro-inflammatory disequilibrium of the IL-1 beta/IL-1ra ratio in an experimental model of perinatal brain damages induced by lipopolysaccharide and hypoxia-ischemia. Cytokine 2008, 43, 54–62, doi:10.1016/j.cyto.2008.04.007.
[26]
Hilton, G.D.; Nunez, J.L.; Bambrick, L.; Thompson, S.M.; McCarthy, M.M. Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca2+ from intracellular stores and is prevented by estradiol. Eur. J. Neurosci. 2006, 24, 3008–3016, doi:10.1111/j.1460-9568.2006.05189.x.
[27]
Kumar, A.; Mittal, R.; Khanna, H.D.; Basu, S. Free radical injury and blood-brain barrier permeability in hypoxic-ischemic encephalopathy. Pediatrics 2008, 122, 722–727, doi:10.1542/peds.2008-0269.
[28]
Cross, J.L.; Meloni, B.P.; Bakker, A.J.; Lee, S.; Knuckey, N.W. Modes of Neuronal Calcium Entry and Homeostasis following Cerebral Ischemia. Stroke Res. Treat. 2010, 2010, doi:10.4061/2010/316862.
[29]
McDonald, J.W.; Johnston, M.V. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Rev. 1990, 15, 41–70, doi:10.1016/0165-0173(90)90011-C.
[30]
Monyer, H.; Brunashev, N.; Laurie, D.J. Development and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1993, 12, 529–540, doi:10.1016/0896-6273(94)90210-0.
[31]
Van den Tweel, E.R.; Nijboer, C.; Kavelaars, A.; Heijnen, C.J.; Groenendaal, F.; van Bel, F. Expression of nitric oxide synthase isoforms and nitrotyrosine formation after hypoxia-ischemia in the neonatal rat brain. J. Neuroimmunol. 2005, 167, 64–71, doi:10.1016/j.jneuroim.2005.06.031.
[32]
Blomgren, K.; Hagberg, H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic. Biol. Med. 2006, 40, 388–397, doi:10.1016/j.freeradbiomed.2005.08.040.
[33]
Chang, Y.; Hsieh, C.Y.; Peng, Z.A.; Yen, T.L.; Hsiao, G.; Chou, D.S.; Chen, C.M.; Sheu, J.R. Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats. J. Biomed. Sci. 2009, 16, doi:10.1186/1423-0127-16-9.
[34]
Fabian, R.H.; Perez-Polo, J.R.; Kent, T.A. Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia. Am. J. Physiol. Heart. Circ. Physiol. 2008, 295, 1809–1814, doi:10.1152/ajpheart.00301.2007.
[35]
Suzuki, M.; Tabuchi, M.; Ikeda, M.; Tomita, T. Concurrent formation of peroxynitrite with the expression of inducible nitric oxide synthase in the brain during middle cerebral artery occlusion and reperfusion in rats. Brain Res. 2002, 951, 113–120, doi:10.1016/S0006-8993(02)03145-1.
[36]
Yang, L.; Sameshima, H.; Yamaguchi, M.; Ikenoue, T. Expression of inducible nitric oxide synthase and cyclooxygenase-2 mRNA in brain damage induced by lipopolysaccharide and intermittent hypoxia-ischemia in neonatal rats. J. Obstet. Gynaecol. Res. 2005, 31, 185–191, doi:10.1111/j.1341-8076.2005.00266.x.
[37]
Robertson, C.L.; Scafidi, S.; McKenna, M.C.; Fiskum, G. Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury. Exp. Neurol. 2009, 218, 371–380, doi:10.1016/j.expneurol.2009.04.030.
[38]
Hagberg, H.; Mallard, C.; Rousset, C.I.; Wang, X.Y. Apoptotic mechanisms in the immature brain: Involvement of mitochondria. J. Child Neurol. 2009, 24, 1141–1146, doi:10.1177/0883073809338212.
[39]
Leonardo, C.C.; Pennypacker, K.R. Neuroinflammation and MMPs: Potential therapeutic targets in neonatal hypoxic-ischemic injury. J. Neuroinflamm. 2009, 6, 13, doi:10.1186/1742-2094-6-13.
[40]
Nijboer, C.H.; Heijnen, C.J.; Groenendaal, F.; May, M.J.; van Bel, F.; Kavelaars, A. Strong neuroprotection by inhibition of NF-kappaB after neonatal hypoxia-ischemia involves apoptotic mechanisms but is independent of cytokines. Stroke 2008, 39, 2129–2137, doi:10.1161/STROKEAHA.107.504175.
[41]
Nijboer, C.H.; Heijnen, C.J.; Groenendaal, F.; May, M.J.; van Bel, F.; Kavelaars, A. A dual role of the NF-kappaB pathway in neonatal hypoxic-ischemic brain damage. Stroke 2008, 39, 2578–2586, doi:10.1161/STROKEAHA.108.516401.
Northington, F.J.; Ferriero, D.M.; Graham, E.M.; Traystman, R.J.; Martin, L.J. Early neurodegeneration after hypoxia-ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis. Neurobiol. Dis. 2001, 8, 207–219, doi:10.1006/nbdi.2000.0371.
[44]
Blomgren, K.; Leist, M.; Groc, L. Pathological apoptosis in the developing brain. Apoptosis 2007, 12, 993–1010, doi:10.1007/s10495-007-0754-4.
[45]
Wang, X.; Karlsson, J.O.; Zhu, C.; Bahr, B.A.; Hagberg, H.; Blomgren, K. Caspase-3 activation after neonatal rat cerebral hypoxia-ischemia. Biol. Neonate 2001, 79, 172–179, doi:10.1159/000047087.
[46]
Gill, R.; Soriano, M.; Blomgren, K.; Hagberg, H.; Wybrecht, R.; Miss, M.T.; Hoefer, S.; Adam, G.; Niederhauser, O.; Kemp, J.A.; Loetscher, H. Role of caspase-3 activation in cerebral ischemia- induced neurodegeneration in adult and neonatal brain. J. Cereb. Blood Flow. Metab. 2002, 22, 420–430.
[47]
Northington, F.J.; Zelaya, M.E.; O’Riordan, D.P.; Blomgren, K.; Flock, D.L.; Hagberg, H.; Ferriero, D.M.; Martin, L.J. Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. Neuroscience 2007, 149, 822–833, doi:10.1016/j.neuroscience.2007.06.060.
[48]
Lay, C.C.; Davis, M.F.; Chen-Bee, C.H.; Frostig, R.D. Mild sensory stimulation completely protects the adult rodent cortex from ischemic stroke. PLoS One 2010, 5, e11270.
[49]
Go？i-de-Cerio, F.; Alvarez, A.; Caballero, A.; Mielgo, V.E.; Alvarez, F.J.; Rey-Santano, M.C.; Gastiasoro, E.; Valls-i-Soler, A.; Bilbao, J.; Hilario, E. Early cell death in the brain of fetal preterm lambs after hypoxic-ischemic injury. Brain Res. 2007, 1151, 161–171, doi:10.1016/j.brainres.2007.03.013.
[50]
McLendon, D.; Check, J.; Carteaux, P.; Michael, L.; Moehring, J.; Secrest, J.W.; Clark, S.E.; Cohen, H.; Klein, S.A.; Boyle, D.; et al. Implementation of potentially better practices for the prevention of brain hemorrhage and ischemic brain injury in very low birth weight infants. Pediatrics 2003, 111, 497–503.
[51]
Felderhoff-Mueser, U.; Buhrer, C. Clinical measures to preserve cerebral integrity in preterm infants. Early Hum. Dev. 2005, 81, 237–244, doi:10.1016/j.earlhumdev.2005.01.002.
[52]
Badr Zahr, L.K.; Purdy, I. Brain injury in the infant: The old, the new, and the uncertain. J. Perinat. Neonatal Nurs. 2006, 20, 163–175.
McGuire, W.; Fowlie, P.W.; Evans, D.J. Naloxone for preventing morbidity and mortality in newborn infants of greater than 34 weeks’ gestation with suspected perinatal asphyxia. Cochrane Database Syst. Rev. 2004, doi:10.1002/14651858.CD003955.
[55]
Kecskes, Z.; Healy, G.; Jensen, A. Fluid restriction for term infants with hypoxic-ischaemic encephalopathy following perinatal asphyxia. Cochrane Database Syst. Rev. 2005, doi:10.1002/14651858.CD004337.
[56]
Beveridge, C.J.; Wilkinson, A.R. Sodium bicarbonate infusion during resuscitation of infants at birth. Cochrane Database Syst. Rev. 2006, doi:10.1002/14651858.CD004864.
[57]
Evans, D.J.; Levene, M.I.; Tsakmakis, M. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst. Rev. 2007, doi:10.1002/ 14651858.CD001240.
[58]
Jacobs, S.; Hunt, R.; Tarnow-Mordi, W.; Inder, T.; Davis, P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Sys. Rev. 2007, doi:10.1002/14651858.CD003311.
[59]
Vannucci, R.; Towfighi, J.; Bucklacher, R.; Vannucci, S.J. Effect of extreme hypercapnia on hypoxic-ishcemic brain damage in the immature rat. Pediatr. Res. 2001, 49, 799–803, doi:10.1203/00006450-200106000-00015.
Thoresen, M.; Whitelaw, A. Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant. Curr. Opin. Neurol. 2005, 18, 111–116, doi:10.1097/01.wco.0000162850.44897.c6.
[62]
Perlman, J.M.; Wyllie, J.; Kattwinkel, J.; Atkins, D.L.; Chameides, L.; Goldsmith, J.P.; Guinsburg, R.; Hazinski, M.F.; Morley, C.; Richmond, S.; et al. Neonatal resuscitation: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Pediatrics 2010, 126, 1319–1344, doi:10.1542/peds.2010-2972B.
[63]
Shankaran, S.; Pappas, A.; McDonald, S.A.; Vohr, B.R.; Hintz, S.R.; Yolton, K.; Gustafson, K.E.; Leach, T.M.; Green, C.; Bara, R.; et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N. Engl. J. Med. 2012, 366, 2085–2092, doi:10.1056/NEJMoa1112066.
[64]
Varon, J.; Marik, P.E.; Einav, S. Therapeutic hypothermia: A state-of-the-art emergency medicine perspective. Am. J. Emerg. Med. 2012, 30, 800–810, doi:10.1016/j.ajem.2011.03.007.
[65]
Barrett, R.D.; Bennet, L.; Davidson, J.; Dean, J.M.; George, S.; Emerald, B.S.; Gunn, A.J. Destruction and reconstruction: Hypoxia and the developing brain. Birth Defects Res. C Embryo Today 2007, 81, 163–176, doi:10.1002/bdrc.20095.
[66]
Wagner, C.L.; Eicher, D.J.; Katikaneni, L.D. The use of hypothermia: A role in the treatment of neonatal asphyxia? Pediatr. Neurol. 1999, 21, 429–443, doi:10.1016/S0887-8994(99)00020-X.
Salazar-Reyes, H.; Varon, J. Hypoxic tisue damageand the protective effects of therapeutic hypothermia. Crit. Care Shock 2005, 8, 28–31.
[70]
Soto-Ruiz, K.M.; Varon, J. Resuscitation great. George W. Crile: A visionary mind in resuscitation. Resuscitation 2009, 80, 6–8, doi:10.1016/j.resuscitation.2008.09.008.
[71]
Hua, Y.; Hisano, K.; Morimoto, Y. Effect of mild and moderate hypothermia on hypoxic injury in nearly pure neuronal culture. J. Anesth. 2010, 5, 726–732.
[72]
Alzaga, A.G.; Cerdan, M.; Varon, J. Therapeutic hypothermia. Resuscitation 2006, 70, 369–380, doi:10.1016/j.resuscitation.2006.01.017.
[73]
Varon, J.; Acosta, P. Therapeutic hypothermia: Past, present, and future. Chest 2008, 133, 1267–1274, doi:10.1378/chest.07-2190.
[74]
Gluckman, P.D.; Wyatt, J.S.; Azzopardi, D.; Ballard, R.; Edwards, A.D.; Ferriero, D.M.; Polin, R.A.; Robertson, C.M.; Thoresen, M.; Whitelaw, A.; Gunn, A.J. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicentre randomized trial. Lancet 2005, 365, 663–670.
[75]
Shankaran, S.; Laptook, A.R.; Ehrenkranz, R.A.; Tyson, J.E.; McDonald, S.A.; Donovan, E.F.; Fanaroff, A.A.; Poole, W.K.; Wright, L.L.; Higgins, R.D.; et al. Whole body hypothermia for neonates with hypoxic-ischemic encephalopathy. N. Engl. J. Med. 2005, 353, 1574–1584, doi:10.1056/NEJMcps050929.
[76]
Lin, Z.; Yu, H.; Lin, J.; Chen, S.; Liang, Z.; Zhang, Z. Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: An experience from a single neonatal intensive care unit. J. Perinatol. 2006, 26, 180–184, doi:10.1038/sj.jp.7211412.
Shah, P.S.; Ohlsson, A.; Perlman, M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: A systemic review. Arch. Pediatr. Adolesc. Med. 2007, 161, 951–958, doi:10.1001/archpedi.161.10.951.
[79]
Pfister, R.H.; Soll, R.F. Hypothermia for the treatment of infants with hypoxic-ischemic encephalopathy. J. Perinatol. 2010, 30, 82–87, doi:10.1038/jp.2010.91.
[80]
Marks, K.; Shany, E.; Shelef, I.; Golan, A.; Zmora, E. Hypothermia: A neuroprotective therapy for neonatal hypoxic ischemic encephalopathy. Isr. Med. Assoc. J. 2010, 12, 494–500.
[81]
Laptook, A.R. Use of therapeutic hypothermia for term infants with hypoxic-ischemic encephalopathy. Pediatr. Clin. North Am. 2009, 56, 601–616, doi:10.1016/j.pcl.2009.03.007.
[82]
Kelen, D.; Robertson, N.J. Experimental treatments for hypoxic ischaemic encephalopathy. Early Hum. Dev. 2010, 86, 369–377, doi:10.1016/j.earlhumdev.2010.05.011.
[83]
Marro, P.J.; Mishra, O.P.; Delivoria-Papadopoulos, M. Effect of allopurinol on brain adenosine levels during hypoxia in newborn piglets. Brain Res. 2006, 1073–1074, 444–450, doi:10.1016/j.brainres.2005.11.061.
Shadid, M.; Moison, R.; Steendijk, P.; Hiltermann, L.; Berger, H.M.; van Bel, F. The effect of antioxidative combination therapy on post hypoxic-ischemic perfusion, metabolism, and electrical activity of the newborn brain. Pediatr. Res. 1998, 44, 119–124, doi:10.1203/00006450-199807000-00019.
[86]
Betz, A.L. Identification of hypoxanthine transport and xanthine oxidase activity in brain capillaries. J. Neurochem. 1985, 44, 574–579, doi:10.1111/j.1471-4159.1985.tb05451.x.
[87]
Phillis, J.W.; Sen, S. Oxypurinol attenuates hydroxyl radical production during ischemia/reperfusion injury of the rat cerebral cortex: An ESR study. Brain Res. 1993, 628, 309–312, doi:10.1016/0006-8993(93)90970-X.
[88]
Moorhouse, P.C.; Grootveld, M.; Halliwell, B.; Quinlan, J.G.; Gutteridge, J.M. Allopurinol and oxypurinol are hydroxyl radical scavengers. FEBS Lett. 1987, 213, 23–28, doi:10.1016/0014-5793(87)81458-8.
[89]
Hudome, S.; Palmer, C.; Roberts, R.L.; Mauger, D.; Housman, C.; Towfighi, J. The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat. Pediatr. Res. 1997, 41, 607–616, doi:10.1203/00006450-199705000-00002.
[90]
Ko, K.M.; Godin, D.V. Inhibition of transition metal ion-catalysed ascorbate oxidation and lipid peroxidation by allopurinol and oxypurinol. Biochem. Pharmacol. 1990, 40, 803–809.
[91]
Peterson, D.A.; Kelly, B.; Gerrard, J.M. Allopurinol can act as an electron transferagent. Is this relevant during reperfusion injury? Biochem. Biophys. Res. Commun. 1986, 137, 76–79, doi:10.1016/0006-291X(86)91177-0.
[92]
Torrance, H.L.; Benders, M.J.; Derks, J.B.; Rademaker, C.M.; Bos, A.F.; van Den Berg, P.; Longini, M.; Buonocore, G.; Venegas, M.; Baquero, H.; et al. Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S-100B. Pediatrics 2009, 124, 350–357, doi:10.1542/peds.2008-2228.
[93]
Peeters-Scholte, C.; Braun, K.; Koster, J.; Kops, N.; Blomgren, K.; Buonocore, G.; van Buul-Offers, S.; Hagberg, H.; Nicolay, K.; van Bel, F.; Groenendaal, F. Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia. Pediatr. Res. 2003, 54, 516–522, doi:10.1203/01.PDR.0000081297.53793.C6.
[94]
Rodríguez-Yá？ez, M.; Castillo, J. Role of inflammatory markers in brain ischemia. Curr. Opin. Neurol. 2008, 21, 353–357, doi:10.1097/WCO.0b013e3282ffafbf.
[95]
Balduini, W.; Mazzoni, E.; Carloni, S.; De Simoni, M.G.; Perego, C.; Sironi, L.; Cimino, M. Prophylactic but not delayed administration of simvastatin protects against long-lasting cognitive and morphological consequences of neonatal hypoxic-ischemic brain injury, reduces interleukin-1beta and tumor necrosis factor-alpha mRNA induction, and does not affect endothelial nitric oxide synthase expression. Stroke 2003, 34, 2007–2012, doi:10.1161/01.STR.0000080677.24419.88.
[96]
Balduini, W.; de Angelis, V.; Mazzoni, E.; Cimino, M. Simvastatin protects against long-lasting behavioral and morphological consequences of neonatal hypoxic/ischemic brain injury. Stroke 2001, 32, 2185–2191.
Franks, N.; Dickinson, R.; de Sousa, S.; Hall, A.; Lieb, W. How does xenon produce anaesthesia? Nature 1998, 26, 324.
[99]
Perrone, S.; Stazzoni, G.; Tataranno, M.L.; Buonocore, G. New pharmacologic and therapeutic approaches for hypoxic-ischemic encephalopathy in the newborn. J. Matern. Fetal Neonatal Med. 2012, 25, 83–88.
[100]
Petzelt, C.P.; Kodirov, S.; Taschenberger, G.; Kox, W.J. Participation of the Ca2+-calmodulin-activated kinase in the control of metaphase-anaphase transition in human cells. Cell Biol. Int. 2001, 25, 403–409, doi:10.1006/cbir.2000.0646.
[101]
Ma, D.; Williamson, P.; Januszewski, A.; Nogaro, M.C.; Hossain, M.; Ong, L.; Shu, Y.; Franks, N.P.; Maze, M. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anaesthesiology 2007, 106, 746–753, doi:10.1097/01.anes.0000264762.48920.80.
[102]
Ma, D.; Lim, T.; Xu, J.; Tang, H.; Wan, Y.; Zhao, H.; Hossain, M.; Maxwell, P.H.; Maze, M. Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. J. Am. Soc. Nephrol. 2009, 20, 713–720, doi:10.1681/ASN.2008070712.
[103]
Ma, D.; Hossain, M.; Chow, A.; Arshad, M.; Battson, R.M.; Sanders, R.D.; Mehmet, H.; Edwards, A.D.; Franks, N.P.; Maze, M. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann. Neurol. 2005, 58, 182–193, doi:10.1002/ana.20547.
[104]
Dingley, J.; Tooley, J.; Porter, H.; Thoresen, M. Xenon provides short-term neuroprotection in neonatal rats when administered after hypoxia-ischemia. Stroke 2006, 37, 501–506, doi:10.1161/01.STR.0000198867.31134.ac.
[105]
Martin, J.L.; Ma, D.; Hossain, M.; Xu, J.; Sanders, R.D.; Franks, N.P.; Maze, M. Asynchronous administration of xenon and hypothermia significantly reduces brain infarction in the neonatal rat. Br. J. Anaesth. 2007, 98, 236–240, doi:10.1093/bja/ael340.
[106]
Thoresen, M.; Hobbs, C.E.; Wood, T.; Chakkarapani, E.; Dingley, J. Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia. J. Cereb. Blood Flow Metab. 2009, 4, 707–714.
[107]
Ryang, Y.M.; Fahlenkamp, A.V.; Rossaint, R.; Wesp, D.; Loetscher, P.D.; Beyer, C.; Coburn, M. Neuroprotective effects of argon in an in vivo model of transient middle cerebral artery occlusion in rats. Crit. Care Med. 2011, 39, 1448–1453, doi:10.1097/CCM.0b013e31821209be.
[108]
Ovbiagele, B.; Kidwell, C.S.; Starkman, S.; Saber, J.L. Neuroprotective agents for the treatment of acute ischemic stroke. Curr. Neurol. Neurosci. Rep. 2003, 3, 9–20, doi:10.1007/s11910-003-0031-z.
[109]
Spandou, E.; Soubasi, V.; Papoutsopoulou, S.; Augoustides-Savvopoulou, P.; Loizidis, T.; Pazaiti, A.; Karkavelas, G.; Guiba-Tziampiri, O. Neuroprotective effect of long-term MgSO4 administration after cerebral hypoxia-ischemia in newborn rats is related to the severity of brain damage. Reprod. Sci. 2007, 14, 667–677, doi:10.1177/1933719107305864.
[110]
Marret, S.; Gressens, P.; Gadisseux, J.F.; Evrard, P. Prevention by magnesium of excitotoxic neuronal death in the developing brain: An animal model for clinical intervention studies. Dev. Med. Child Neurol. 1995, 37, 473–484.
[111]
Imer, M.; Omay, B.; Uzunkol, A.; Erdem, T.; Sabanci, P.A.; Karasu, A.; Albayrak, S.B.; Sencer, A.; Hepgul, K.; Kaya, M. Effect of magnesium, MK-801 and combination of magnesium and MK-801 on blood-brain barrier permeability and brain edema after experimental traumatic diffuse brain injury. Neurol. Res. 2009, 31, 977–981, doi:10.1179/174313209X385617.
[112]
Enomoto, T.; Osugi, T.; Satoh, H.; McIntosh, T.K.; Nabeshima, T. Pre-Injury magnesium treatment prevents traumatic brain injury-induced hippocampal ERK activation, neuronal loss, and cognitive dysfunction in the radial-arm maze test. J. Neurotrauma 2005, 22, 783–792, doi:10.1089/neu.2005.22.783.
[113]
Türkyilmaz, C.; Türkyilmaz, Z.; Atalay, Y.; S？ylemezoglu, F.; Celasun, B. Magnesium pre-treatment reduces neuronal apoptosis in newborn rats in hypoxia-ischemia. Brain Res. 2002, 955, 133–137, doi:10.1016/S0006-8993(02)03395-4.
[114]
Go？i-de-Cerio, F.; Alvarez, A.; Alvarez, F.J.; Rey-Santano, M.C.; Alonso-Alconada, D.; Mielgo, V.E.; Gastiasoro, E.; Hilario, E. MgSO4 treatment preserves the ischemia-induced reduction in S-100 protein without modification of the expression of endothelial tight junction molecules. Histol. Histopathol. 2009, 24, 1129–1138.
[115]
Westermaier, T.; Zausinger, S.; Baethmann, A.; Schmid-Elsaesser, R. Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats. Acta Neurochir. 2005, 147, 525–532, doi:10.1007/s00701-005-0496-4.
[116]
Rouse, D.J.; Hirtz, D.G.; Thom, E. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N. Engl. J. Med. 2008, 359, 895–905, doi:10.1056/NEJMoa0801187.
[117]
Szemraj, J.; Sobolewska, B.; Gulczynska, E.; Wilczynski, J.; Zylinska, L. Magnesium sulfate effect on erythrocyte membranes of asphyxiated newborns. Clin. Biochem. 2005, 38, 457–464, doi:10.1016/j.clinbiochem.2005.02.005.
[118]
Groenendaal, F.; Rademaker, C.M.; Toet, M.C.; de Vries, L.S. Effects of magnesium sulphate on amplitude-integrated continuous EEG in asphyxiated term neonates. Acta Paediatr. 2002, 91, 1073–1077, doi:10.1111/j.1651-2227.2002.tb00102.x.
[119]
Khashaba, M.T.; Shouman, B.O.; Shaltout, A.A.; Al-Marsafawy, H.M.; Abdel-Aziz, M.M.; Patel, K.; Aly, H. Excitatory amino acids and magnesium sulfate in neonatal asphyxia. Brain Dev. 2006, 28, 375–379, doi:10.1016/j.braindev.2005.11.010.
[120]
Levene, M.; Blennow, M.; Whitelaw, A.; Hank？, E.; Fellman, V.; Hartley, R. Acute effects of two different doses of magnesium sulphate in infants with birth asphyxia. Arch. Dis. Child. Fetal Neonatal Ed. 1995, 73, F174–F177, doi:10.1136/fn.73.3.F174.
[121]
Temkin, N.; Anderson, G.D.; Winn, H.R.; Ellenbogen, R.G.; Britz, G.W.; Schuster, J.; Lucas, T.; Newell, D.W.; Mansfield, P.N.; Machamer, J.E.; et al. Magnesium sulfate for neuroprotection after traumatic brain injury: A randomised controlled trial. Lancet Neurol. 2007, 6, 29–38.
[122]
Alison, G.; Cahill, M.D.; Aaron, B.; Caughey, M.D. Magnesium for neuroprophylaxis: Fact or fiction? Am. J. Obstet. Gynecol. 2009, 200, 590–594, doi:10.1016/j.ajog.2009.04.003.
[123]
Elliott, J.P.; Lewis, D.F.; Morrison, J.C.; Garite, T.J. In defense of magnesium sulfate. Obstet. Gynecol. 2009, 113, 341–1348.
[124]
Costantine, M.M.; Drever, N. Antenatal exposure to magnesium sulfate and neuroprotection in preterm infants. Obstet. Gynecol. Clin. North Am. 2011, 38, 351–366, doi:10.1016/j.ogc.2011.02.019.
[125]
Zhu, H.; Meloni, B.P.; Bojarski, C.; Knuckey, M.W.; Knuckey, N.W. Post-ischemic modest hypothermia (35 degrees C) combined with intravenous magnesium is more effective at reducing CA1 neuronal death than either treatment used alone following global cerebral ischemia in rats. Exp. Neurol. 2005, 193, 361–368, doi:10.1016/j.expneurol.2005.01.022.
[126]
Chacón, A.; Lisott, E.; Eblen-Zajjur, A. Magnesium sulphate reduces cell volume in physiological conditions but not in the cytotoxic oedema during global brain ischemia. Brain Inj. 2006, 20, 1087–1091, doi:10.1080/02699050600910068.
[127]
Pazaiti, A.; Soubasi, V.; Spandou, E.; Karkavelas, G.; Georgiou, T.; Karalis, P.; Guiba-Tziampiri, O. Evaluation of long-lasting sensorimotor consequences following neonatal hypoxic-ischemic brain injury in rats: the neuroprotective role of MgSO4. Neonatology 2009, 95, 33–40, doi:10.1159/000151753.
[128]
Cetinkaya, M.; Alkan, T.; Ozyener, F.; Kafa, I.M.; Kurt, M.A.; Koksal, N. Possible neuroprotective effects of magnesium sulfate and melatonin as both pre- and post-treatment in a neonatal hypoxic-ischemic rat model. Neonatology 2010, 99, 302–310.
[129]
Solaroglu, A.; Suat Dede, F.; Gelisen, O.; Secilmis, O.; Dede, H. Neuroprotective effect of magnesium sulfate treatment on fetal brain in experimental intrauterine ischemia reperfusion injury. J. Matern. Fetal Neonatal Med. 2011, 24, 1259–1261, doi:10.3109/14767058.2011.572202.
[130]
Kang, S.W.; Choi, S.K.; Park, E.; Chae, S.J.; Choi, S.; Joo, H.J.; Lee, G.J.; Park, H.K. Neuroprotective effects of magnesium-sulfate on ischemic injury mediated by modulating the release of glutamate and reduced of hyperreperfusion. Brain Res. 2011, 1371, 121–128, doi:10.1016/j.brainres.2010.11.057.
[131]
Greenwood, K.; Cox, P.; Mehmet, H.; Penrice, J.; Amess, P.N.; Cady, E.B.; Wyatt, J.S.; Edwards, A.D. Magnesium sulfate treatment after transient hypoxia-ischemia in newborn piglet does not protect against cerebral damage. Pediatric Res. 2000, 48, 346–350, doi:10.1203/00006450-200009000-00014.
[132]
Gee, J.B.; Rorbett, R.J.; Perlman, J.; Laptook, A.R. The effects of systemic magnesium sulfate infusion on brain magnesium concentrations and energy state during hypoxia-ischemia in newborn miniswine. Pediatr. Res. 2004, 55, 93–100, doi:10.1203/01.PDR.0000099771.39629.E5.
[133]
Zhu, H.D.; Meloni, B.P.; Moore, S.R.; Majda, B.T.; Knuckey, N.W. Intravenous administration of magnesium is only neuroprotective following transient global ischemia when present with post-ischemic mild hypothermia. Brain Res. 2004, 1014, 53–60, doi:10.1016/j.brainres.2004.03.073.
[134]
Kalincik, T.; Maresova, D. Influence of magnesium sulphate on evoked activity of rat brain after exposure to short-term hypoxia. Physiol. Res. 2005, 54, 229–234.
[135]
Dribben, W.H.; Creeley, C.E.; Wang, H.H.; Smith, D.J.; Farber, N.B.; Olney, J.W. High dose magnesium sulfate exposure induces apoptotic cell death in the developing neonatal mouse brain. Neonatology 2009, 96, 23–32, doi:10.1159/000201327.
[136]
Yager, J.Y. Animal models of hypoxic-ischemic brain damage in the newborn. Semin. Pediatr. Neurol. 2004, 11, 31–46, doi:10.1016/j.spen.2004.01.006.
[137]
Mechoulam, R.; Panikashvili, D.; Shohami, E. Cannabinoids and brain injury: Therapeutic implications. Trends Mol. Med. 2002, 8, 58–61, doi:10.1016/S1471-4914(02)02276-1.
[138]
Amar, M.B. Cannabinoids in medicine: A review of their therapeutic potential. J. Ethnopharmacol. 2006, 105, 1–25, doi:10.1016/j.jep.2006.02.001.
[139]
Maresz, K.; Pryce, G.; Ponomarev, E.D.; Marsicano, G.; Croxford, J.L.; Shriver, L.P.; Ledent, C.; Cheng, X.; Carrier, E.J.; Mann, M.K.; et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB(1) on neurons and CB(2) on autoreactive T cells. Nat. Med. 2007, 13, 492–497.
[140]
Baker, D.; Pryce, G.; Croxford, J.L.; Brown, P.; Pertwee, R.G.; Makriyannis, A.; Khanolkar, A.; Layward, L.; Fezza, F.; Bisogno, T.; Di Marzo, V. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 2001, 15, 300–302.
[141]
Marsicano, G.; Goodenough, S.; Monory, K.; Hermann, H.; Eder, M.; Cannich, A.; Azad, S.C.; Cascio, M.G.; Gutiérrez, S.O.; van der Stelt, M.; et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 2003, 302, 84–88, doi:10.1126/science.1088208.
[142]
Chang, Y.H.; Lee, S.T.; Lin, W.W. Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: Involvement of eicosanoids. J. Cell. Biochem. 2001, 81, 715–723.
Parmentier-Batteur, S.; Jin, K.; Mao, X.O.; Xie, L.; Greenberg, D.A. Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J. Neurosci. 2002, 22, 9771–9775.
[145]
Freund, T.F.; Katona, I.; Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 2003, 83, 1017–1066.
[146]
Pacher, P.; Bátkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006, 58, 389–462, doi:10.1124/pr.58.3.2.
[147]
Hajos, N.; Ledent, C.; Freund, T.F. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 2001, 106, 1–4, doi:10.1016/S0306-4522(01)00287-1.
[148]
Breivogel, C.S.; Walker, J.M.; Huang, S.M.; Roy, M.B.; Childers, S.R. Cannabinoid signaling in rat cerebellar granule cells: G-protein activation, inhibition of glutamate release and endogenous cannabinoids. Neuropharmacology 2004, 47, 81–91, doi:10.1016/j.neuropharm.2004.02.017.
[149]
Hamrick, S.E.; Ferriero, D.M. The injury response in the term newborn brain. Can we neuroprotect? Curr. Opin. Neurol. 2003, 16, 147–154, doi:10.1097/00019052-200304000-00005.
[150]
Kim, S.H.; Won, S.J.; Mao, X.O.; Jin, K.; Greenberg, D.A. Molecular mechanisms of cannabinoid protection from neuronal excitotoxicity. Mol. Pharmacol. 2006, 69, 691–696.
[151]
Hampson, A.J.; Grimaldi, M.; Axelrod, J.; Wink, D. Cannabidiol and (？)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc. Natl. Acad. Sci. USA 1998, 95, 8268–8273, doi:10.1073/pnas.95.14.8268.
[152]
Marsicano, G.; Moosmann, B.; Hermann, H.; Lutz, B.; Behl, C. Neuroprotective properties of cannabinoids against oxidative stress: Role of the cannabinoid receptor CB1. J. Neurochem. 2002, 80, 448–456, doi:10.1046/j.0022-3042.2001.00716.x.
[153]
Lastres-Becker, I.; Fernández-Ruiz, J. An overview of Parkinson’s disease and the cannabinoid system and possible benefits of cannabinoid-based treatments. Curr. Med. Chem. 2006, 13, 3705–3718, doi:10.2174/092986706779026156.
[154]
Hillard, C.J. Endocannabinoids and vascular function. J. Pharmacol. Exp. Ther. 2000, 294, 27–32.
[155]
Golech, S.A.; McCarron, R.M.; Chen, Y.; Bembry, J.; Lenz, F.; Mechoulam, R.; Shohami, E.; Spatz, M. Human brain endothelium: Coexpression and function of vanilloid and endocannabinoid receptors. Brain Res. Mol. Brain Res. 2004, 132, 87–92, doi:10.1016/j.molbrainres.2004.08.025.
[156]
Fernandez-Ruiz, J.; Berrendero, F.; Hernandez, M.L.; Ramos, J.A. The endogenous cannabinoid system and brain development. Trends Neurosci. 2000, 23, 14–20, doi:10.1016/S0166-2236(99)01491-5.
[157]
Stella, N. Cannabinoid signaling in glial cells. Glia 2004, 48, 267–277, doi:10.1002/glia.20084.
[158]
Aguado, T.; Palazuelos, J.; Monory, K.; Stella, N.; Cravatt, B.; Lutz, B.; Marsicano, G.; Kokaia, Z.; Guzmán, M.; Galve-Roperh, I. The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. J. Neurosci. 2006, 26, 1551–1561, doi:10.1523/JNEUROSCI.3101-05.2006.
[159]
Sinor, A.D.; Irvin, S.M.; Greenberg, D.A. Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci. Lett. 2000, 278, 157–160, doi:10.1016/S0304-3940(99)00922-2.
[160]
Van der Stelt, M.; Veldhuis, W.B.; van Haaften, G.W.; Fezza, F.; Bisogno, T.; Bar, P.R.; Veldink, G.A.; Vliegenthart, J.F.; Di Marzo, V.; Nicolay, K. Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J. Neurosci. 2001, 21, 8765–8771.
[161]
Panikashvili, D.; Simeonidou, C.; Ben-Shabat, S.; Hanus, L.; Breuer, A.; Mechoulam, R.; Shohami, E. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 2001, 413, 527–531.
[162]
Lara-Celador, I.; Castro-Ortega, L.; Alvarez, A.; Go？i-de-Cerio, F.; Lacalle, J.; Hilario, E. Endocannabinoids reduce cerebral damage after hypoxic-ischemic injury in perinatal rats. Brain Res. 2012, 1474, 91–99, doi:10.1016/j.brainres.2012.07.045.
[163]
Chen, Y.C.; Tain, Y.L.; Sheen, J.M.; Huang, L.T. Melatonin utility in neonates and children. J. Formos. Med. Assoc. 2012, 111, 57–66, doi:10.1016/j.jfma.2011.11.024.
[164]
Carloni, S.; Buonocore, G.; Balduini, W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol. Dis. 2008, 32, 329–339, doi:10.1016/j.nbd.2008.07.022.
[165]
Reiter, R.J.; Tan, D.X.; Mayo, J.C.; Sainz, R.M.; Lopez-Burillo, S. Melatonin, longevity and health in the aged: An assessment. Free Radic. Res. 2002, 36, 1323–1329, doi:10.1080/1071576021000038504.
[166]
Sola, A.; Wen, T.C.; Hamrick, S.E.; Ferriero, D.M. Potential for protection and repair following injury to the developing brain: A role for erythropoietin. Pediatr. Res. 2005, 57, 110–117, doi:10.1203/01.PDR.0000159571.50758.39.
[167]
Chang, Y.S.; Mu, D.; Wendland, M.; Sheldon, R.A.; Vexler, Z.S.; McQuillen, P.S.; Ferriero, D.M. Eryhropoietin improves functional and histological outcome in neonatal stroke. Pediatr. Res. 2005, 59, 106–111.
[168]
Gonzalez, F.F.; McQuillen, P.; Mu, D.; Chang, Y.; Wendland, M.; Vexler, Z.; Ferriero, D.M. Erythropoietin enhaces long term neuropretection and neurogenesis in neonatal stroke. Dev. Neurosci. 2007, 29, 321–330, doi:10.1159/000105473.
[169]
Brion, L.P.; Bell, E.F.; Raghuveer, T.S. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst. Rev. 2003, doi:10.1002/14651858.CD003665.
[170]
Peeters-Scholte, C.; van den Tweel, E.; Ioroi, T.; Post, I.; Braun, K.; Veldhuis, W.; Nicolay, K.; Groenendaal, F.; van Bel, F. Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia. A hemodynamic and electrophysiological perspective. Exp. Brain Res. 2002, 147, 200–208, doi:10.1007/s00221-002-1182-x.
[171]
deLemos, R.A.; Roberts, R.J.; Coalson, J.J.; deLemos, J.A.; Null, D.M.; Gerstmann, D.R. Toxic effects associated with the administration of deferoxamine in the premature baboon with hyaline membrane disease. Am. J. Dis. Child. 1990, 144, 915–919.
[172]
Coopman, K.; Smith, L.D.; Wright, K.L.; Ward, S.G. Temporal variation in CB2R levels following T lymphocyte activation: evidence that cannabinoids modulate CXCL12-induced chemotaxis. Int. Immunopharmacol. 2007, 7, 360–371, doi:10.1016/j.intimp.2006.11.008.
[173]
Romero-Sandoval, E.A.; Horvath, R.; Landry, R.P.; DeLeo, J.A. Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation. Mol. Pain 2009, 5, 25, doi:10.1186/1744-8069-5-25.
[174]
Fernández-López, D.; Pradillo, J.M.; García-Yébenes, I.; Martínez-Orgado, J.A.; Moro, M.A.; Lizasoain, I. The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia-ischemia. Stroke 2010, 41, 2956–2964, doi:10.1161/STROKEAHA.110.599357.
[175]
Zhang, M.; Martin, B.R.; Adler, M.W.; Razdan, R.J.; Kong, W.; Ganea, D.; Tuma, R.F. Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke. J. Neuroimmun. Pharmacol. 2009, 4, 249–259.
[176]
Sekhon, B.; Jatana, M.; Giri, S.; Gilg, A.G.; Sekhon, C.; Singh, I.; Singh, A.K. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J. Neurosci. Res. 2004, 76, 519–527, doi:10.1002/jnr.20087.
[177]
Ahola, T.; Lapatto, R.; Raivio, K.O.; Selander, B.; Stigson, L.; Jonsson, B.; Jonsbo, F.; Esberg, G.; St？vring, S.; Kjartansson, S.; et al. N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial. J. Pediatr. 2003, 143, 713–719, doi:10.1067/S0022-3476(03)00419-0.
[178]
Jatana, M.; Singh, I.; Singh, A.; Jenkins, D. Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr. Res. 2006, 59, 684–689, doi:10.1203/01.pdr.0000215045.91122.44.
[179]
Esposito, E.; Cuzzocrea, S. Antiinflammatory activity of melatonin in central nervous system. Curr. Neuropharmacol. 2010, 8, 228–242, doi:10.2174/157015910792246155.
[180]
Deng, W.G.; Tang, S.T.; Tseng, H.P.; Wu, K.K. Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 2006, 108, 518–524, doi:10.1182/blood-2005-09-3691.
[181]
Welin, A.K.; Svedin, P.; Lapatto, R.; Sultan, B.; Hagberg, H.; Gressens, P.; Kjellmer, I.; Mallard, C. Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion. Pediatr. Res. 2007, 61, 153–158, doi:10.1203/01.pdr.0000252546.20451.1a.
[182]
Pandi-Perumal, S.R.; Srinivasan, V.; Maestroni, G.J.; Cardinali, D.P.; Poeggeler, B.; Hardeland, R. Melatonin: Natures most versatile biological signal? FEBS J. 2006, 273, 2813–2838, doi:10.1111/j.1742-4658.2006.05322.x.
[183]
Elmahdy, H.; El-Mashad, A.R.; El-Bahrawy, H.; El-Gohary, T.; El-Barbary, A.; Aly, H. Human recombinant erythropoietin in asphyxia neonatorum: Pilot trial. Pediatrics 2010, 125, 1135–1142, doi:10.1542/peds.2009-2268.
[184]
Wei, L.; Han, B.H.; Li, Y.; Keogh, C.L.; Holtzman, D.M.; Yu, S.P. Cell death mechanism and protective effect of erythropoietin after focal ischemia in the whisker-barrel cortex of neonatal rats. J. Pharmacol. Exp. Ther. 2006, 317, 109–116.
[185]
Sun, Y.; Calvert, J.W.; Zhang, J.H. Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration. Stroke 2005, 36, 1672–1678, doi:10.1161/01.STR.0000173406.04891.8c.
Slusarski, J.D.; McPherson, R.J.; Wallace, G.N.; Juul, S.E. High-dose erythropoietin does not exacerbate retinopathy of prematurity in rats. Pediatr. Res. 2009, 66, 625–630, doi:10.1203/PDR.0b013e3181bc33e6.
[188]
Iwai, M.; Stetler, R.A.; Xing, J.; Hu, X.; Gao, Y.; Zhang, W.; Chen, J.; Cao, G. Enhanced oligodendrogenesis and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain injury. Stroke 2010, 4, 1032–1037.
[189]
Nijboer, C.H.; Groenendaal, F.; Kavelaars, A.; Hagberg, H.H.; van Bel, F.; Heijnen, C.J. Gender-specific neuroprotection by 2-iminobiotin after hypoxia-ischemia in the neonatal rat via a nitric oxide independent pathway. J. Cereb. Blood Flow Metab. 2007, 27, 282–292.
[190]
Bartley, J.; Soltau, T.; Wimborne, H.; Kim, S.; Martin-Studdard, A.; Hess, D. BRDU-positive cells in the neonatal mouse hippocampus following hypoxic-ischemic brain injury. BMC Neurosci. 2005, 6, 15, doi:10.1186/1471-2202-6-15.
Ong, J.; Plane, J.M.; Parent, J.M.; Silverstein, F.S. Hypoxic-ischemic injury stimulates subventricular zone proliferation and neurogenesis in the neonatal rat. Pediatr. Res. 2005, 58, 600–606, doi:10.1203/01.PDR.0000179381.86809.02.
[193]
Van Velthoven, C.T.; Kavelaars, A.; van Bel, F. Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes. Brain Res. Rev. 2009, 61, 1–13, doi:10.1016/j.brainresrev.2009.03.003.
[194]
Wei, X.; Du, Z.; Zhao, L.; Feng, D.; Wei, G.; He, Y.; Tan, J.; Lee, W.H.; Hampel, H.; Dodel, R.; et al. IFATS collection: The conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells 2009, 27, 478–488, doi:10.1634/stemcells.2008-0333.
[195]
Rivera, F.J.; Sierralta, W.D.; Minguell, J.J.; Aigner, L. Adult hippocampus derived soluble factors induce a neuronal-like phenotype in mesenchymal stem cells. Neurosci. Lett. 2006, 406, 49–54, doi:10.1016/j.neulet.2006.07.049.
[196]
Van Velthoven, C.T.; Kavelaars, A.; van Bel, F.; Heijnen, C.J. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav. Immun. 2010, 24, 387–393, doi:10.1016/j.bbi.2009.10.017.
