ppharmПедиатрическая фармакологияPediatric pharmacology1727-57762500-3089Издательство «ПедиатрЪ»10.15690/pf.v13i5.1641ppharm-1464Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWСовременные данные о патогенезе и лечении гипоксически-ишемических поражений головного мозга у новорожденныхRecent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newbornshttps://orcid.org/0000-0002-8540-3858КаркашадзеГ. А.KarkashadzeG. A.

кандидат медицинских наук, заведующий отделением когнитивной педиатрии НИИ педиатрии Адрес: 119991, Москва, Ломоносовский проспект, д. 2, стр. 1, тел.: +7 (495) 967-14-20

Moscow, Russian Federation

karkga@mail.ruАникинА. В.AnikinA. V.

Москва, Российская Федерация

Moscow, Russian Federation

ЗиминаЕ. П.ZiminaE. P.

Москва, Российская Федерация

Moscow, Russian Federation

https://orcid.org/0000-0001-5281-5074ДавыдоваИ. В.DavydovaI. V.

Москва, Российская Федерация

Moscow, Russian Federation

КаримоваХ. М.KarimovaKh. M.

Москва, Российская Федерация

Moscow, Russian Federation

ЗахарянМ. Э.ZakharyanM. E.

Москва, Российская Федерация

Moscow, Russian Federation

https://orcid.org/0000-0002-2209-7531Намазова-БарановаЛ. С.Namazova-BaranovaL. S.

Москва, Российская Федерация

Moscow, Russian Federation

МасловаО. И.MaslovaO. I.

Москва, Российская Федерация

Moscow, Russian Federation

ЯцыкГ. В.YatsykG. V.

Москва, Российская Федерация

Moscow, Russian Federation

ВалиеваС. И.ValievaS. I.

Москва, Российская Федерация

Moscow, Russian Federation

ГеворкянА. К.GevorkyanA. K.

Москва, Российская Федерация

Moscow, Russian Federation

Научный центр здоровья детейРоссияScientific Center of Children’s HealthRussian FederationНаучный центр здоровья детей Первый Московский государственный медицинский университет им. И.М. СеченоваРоссияScientific Center of Children’s Health I.M. Sechenov First Moscow State Medical UniversityRussian FederationРоссийский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияPirogov Russian National Research Medical UniversityRussian FederationНаучный центр здоровья детей Первый Московский государственный медицинский университет им. И.М. Сеченова Российский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияScientific Center of Children’s Health I.M. Sechenov First Moscow State Medical University Pirogov Russian National Research Medical UniversityRussian FederationНаучный центр здоровья детей Российский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияScientific Center of Children’s Health Pirogov Russian National Research Medical UniversityRussian Federation201616122016135452467Copyright © Каркашадзе Г.А., Аникин А.В., Зимина Е.П., Давыдова И.В., Каримова Х.М., Захарян М.Э., Намазова-Баранова Л.С., Маслова О.И., Яцык Г.В., Валиева С.И., Геворкян А.К., 20162016Каркашадзе Г.А., Аникин А.В., Зимина Е.П., Давыдова И.В., Каримова Х.М., Захарян М.Э., Намазова-Баранова Л.С., Маслова О.И., Яцык Г.В., Валиева С.И., Геворкян А.К.Karkashadze G.A., Anikin A.V., Zimina E.P., Davydova I.V., Karimova K.M., Zakharyan M.E., Namazova-Baranova L.S., Maslova O.I., Yatsyk G.V., Valieva S.I., Gevorkyan A.K.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pedpharma.ru/jour/article/view/1464

Гипоксически-ишемические поражения головного мозга у детей являются главным средовым (негенетическим) фактором формирования у них тяжелой неврологической патологии с последующей инвалидизацией. В качестве основного пути снижения тяжести неврологических осложнений ученые видят совершенствование лечебных подходов в острый период заболевания. Благодаря достижениям нейронауки в области изучения механизмов гипоксически-ишемических перинатальных повреждений (ГИПП) были определены три энергетические фазы развертывания патологических событий: первичная (до 6 ч с момента поражения), вторичная (от 6 до 24–48 ч от момента поражения) и отдаленная третичная (в течение нескольких недель-месяцев). При этом некроз, апоптоз, глутаматная эксайтотоксичность, окислительный стресс, воспаление, ангио- и нейрогенез составляют отдельные звенья процесса поражения. На основании новых данных о патогенезе заболевания ученые разных стран уже предложили современные методы лечения ГИПП препаратами эритропоэтина, аллопуринола, мелатонина, N-ацетилцистеина, сульфата магния, альбумина, -интерферона, а также при помощи управляемой гипотермии, ксенона, использования стволовых клеток и др. В статье представлен обзор новых данных о патогенезе и перспективных методах лечения ГИПП.

Hypoxic-ischemic brain lesions in children are the main environmental (non-genetic) factor in forming severe neurological pathology with subsequent disability. Scientists see the improvement of therapeutic approaches in acute phase of the disease as a main way to reduce the severity of neurologic complications. Due to the achievements in neuroscience in the field of perinatal hypoxicischemic injury mechanisms, three energy phases of pathologic events deployment were identified: primary (up to 6 hours from the lesion), secondary (6 to 24–48 h after the lesion) and distal tertiary (during few weeks, months). At the same time, necrosis, apoptosis, glutamate excitotoxicity, oxidative stress, inflammation, angiogenesis and neurogenesis make up separate links of destruction process. On the basis of new data on the pathogenesis of the disease, scientists from different countries have already offered modern treatment methods for perinatal hypoxic-ischemic injury with erythropoietin, allopurinol, melatonin, N-acetylcysteine, magnesium sulphate, albumin, -interferon, as well as with the help of controlled hypothermia, xenon, the use of stem cells, etc. This article presents a review of new data on pathogenesis and promising treatment methods for perinatal hypoxic-ischemic injuries.

гипоксически-ишемические перинатальные поражения мозгановорожденныеперинатальные поражения мозгапатогенез гипоксически-ишемических перинатальных поражений мозгалечение гипоксически- ишемических перинатальных поражений мозгаperinatal hypoxic-ischemic brain injuryneonatesperinatal brain injuriespathogenesis of perinatal hypoxic-ischemic brain injurytreatment of perinatal hypoxic-ischemic brain injuryReferencesFatemi A, Wilson MA, Johnston MV. Hypoxic ischemic encephalopathy in the term infant. Clin Perinatol. 2009;36(4):835–858. doi: 10.1016/j.clp.2009.07.011.Fatemi A, Wilson MA, Johnston MV. Hypoxic ischemic encephalopathy in the term infant. Clin Perinatol. 2009;36(4):835–858. doi: 10.1016/j.clp.2009.07.011.Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev. 2001;7(1):56–64. doi: 10.1002/1098-2779(200102)7:1<56::aid-mrdd1008>3.0.co;2-a.Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev. 2001;7(1):56–64. doi: 10.1002/1098-2779(200102)7:1<56::aid-mrdd1008>3.0.co;2-a.Cotten CM, Shankaran S. Hypothermia for hypoxic-ischemic encephalopathy. Expert Rev Obstet Gynecol. 2010;5(2):227–239. doi: 10.1586/eog.10.7.Cotten CM, Shankaran S. Hypothermia for hypoxic-ischemic encephalopathy. Expert Rev Obstet Gynecol. 2010;5(2):227–239. doi: 10.1586/eog.10.7.Allen KA, Brandon DH. Hypoxic ischemic encephalopathy: pathophysiology and experimental treatments. Newborn Infant Nurs Rev. 2011;11(3):125–133. doi: 10.1053/j.nainr.2011.07.004.Allen KA, Brandon DH. Hypoxic ischemic encephalopathy: pathophysiology and experimental treatments. Newborn Infant Nurs Rev. 2011;11(3):125–133. doi: 10.1053/j.nainr.2011.07.004.Dixon BJ, Reis C, Ho WM, et al. Neuroprotective strategies after neonatal hypoxic ischemic encephalopathy. Int J Mol Sci. 2015;16(9):22368–22401. doi: 10.3390/ijms160922368.Dixon BJ, Reis C, Ho WM, et al. Neuroprotective strategies after neonatal hypoxic ischemic encephalopathy. Int J Mol Sci. 2015;16(9):22368–22401. doi: 10.3390/ijms160922368.Hassell KJ, Ezzati M, Alonso-Alconada D, et al. New horizons for newborn brain protection: enhancing endogenous neuroprotection. Arch Dis Child Fetal Neonatal Ed. 2015;100(6):F541–552. doi: 10.1136/archdischild-2014-306284.Hassell KJ, Ezzati M, Alonso-Alconada D, et al. New horizons for newborn brain protection: enhancing endogenous neuroprotection. Arch Dis Child Fetal Neonatal Ed. 2015;100(6):F541–552. doi: 10.1136/archdischild-2014-306284.Alvarez-Diaz A, Hilario E, de Cerio FG, et al. Hypoxic-ischemic injury in the immature brain- key vascular and cellular players. Neonatology. 2007;92(4):227–235. doi: 10.1159/000103741.Alvarez-Diaz A, Hilario E, de Cerio FG, et al. Hypoxic-ischemic injury in the immature brain- key vascular and cellular players. Neonatology. 2007;92(4):227–235. doi: 10.1159/000103741.Iwata O, Iwata S, Thornton JS, et al. Therapeutic time window duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets. Brain Res. 2007;1154:173–180. doi: 10.1016/j.brainres.2007.03.083.Iwata O, Iwata S, Thornton JS, et al. Therapeutic time window duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets. Brain Res. 2007;1154:173–180. doi: 10.1016/j.brainres.2007.03.083.Azzopardi D, Wyatt JS, Cady EB, et al. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1989;25(5): 445–451. doi: 10.1203/00006450-198905000-00004.Azzopardi D, Wyatt JS, Cady EB, et al. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1989;25(5): 445–451. doi: 10.1203/00006450-198905000-00004.Lorek A, Takei Y, Cady EB, et al. Delayed (secondary) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1994;36(6):699–706. doi: 10.1203/00006450-199412000-00003.Lorek A, Takei Y, Cady EB, et al. Delayed (secondary) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1994;36(6):699–706. doi: 10.1203/00006450-199412000-00003.Martin E, Buchli R, Ritter S, et al. Diagnostic and prognostic value of cerebral 31P magnetic resonance spectroscopy in neonates with perinatal asphyxia. Pediatr Res. 1996;40(5):749–758. doi: .10.1203/00006450-199611000-00015.Martin E, Buchli R, Ritter S, et al. Diagnostic and prognostic value of cerebral 31P magnetic resonance spectroscopy in neonates with perinatal asphyxia. Pediatr Res. 1996;40(5):749–758. doi: .10.1203/00006450-199611000-00015.Fleiss B, Gressens P. Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy. Lancet Neurol. 2012; 11(6):556–566. doi: 10.1016/s1474-4422(12)70058-3.Fleiss B, Gressens P. Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy. Lancet Neurol. 2012; 11(6):556–566. doi: 10.1016/s1474-4422(12)70058-3.Robertson NJ, Cox IJ, Cowan FM, et al. Cerebral intracellular lactic alkalosis persisting months after neonatal encephalopathy measured by magnetic resonance spectroscopy. Pediatr Res. 1999;46(3): 287–296. doi: 10.1203/00006450-199909000-00007.Robertson NJ, Cox IJ, Cowan FM, et al. Cerebral intracellular lactic alkalosis persisting months after neonatal encephalopathy measured by magnetic resonance spectroscopy. Pediatr Res. 1999;46(3): 287–296. doi: 10.1203/00006450-199909000-00007.Barkovich AJ, Westmark K, Partridge C, et al. Perinatal asphyxia: MR findings in the first 10 days. AJNR Am J Neuroradiol. 1995; 16(3):427–438.Barkovich AJ, Westmark K, Partridge C, et al. Perinatal asphyxia: MR findings in the first 10 days. AJNR Am J Neuroradiol. 1995; 16(3):427–438.Takeoka M, Soman TB, Yoshii A, et al. Diffusion-weighted images in neonatal cerebral hypoxic-ischemic injury. Pediatr Neurol. 2002;26(4):274–281. doi: 10.1016/s0887- 8994(01)00403-9.Takeoka M, Soman TB, Yoshii A, et al. Diffusion-weighted images in neonatal cerebral hypoxic-ischemic injury. Pediatr Neurol. 2002;26(4):274–281. doi: 10.1016/s0887- 8994(01)00403-9.Zhu W, Zhong W, Qi J, et al. Proton magnetic resonance spectroscopy in neonates with hypoxic-ischemic injury and its prognostic value. Transl Res. 2008;152(5):225–232. doi: 10.1016/j.trsl.2008.09.004.Zhu W, Zhong W, Qi J, et al. Proton magnetic resonance spectroscopy in neonates with hypoxic-ischemic injury and its prognostic value. Transl Res. 2008;152(5):225–232. doi: 10.1016/j.trsl.2008.09.004.Van Doormaal PJ, Meiners LC, ter Horst HJ, et al. The prognostic value of multivoxel magnetic resonance spectroscopy determined metabolite levels in white and grey matter brain tissue for adverse outcome in term newborns following perinatal asphyxia. Eur Radiol. 2012;22(4):772–778. doi: 10.1007/s00330-011-2315-z.Van Doormaal PJ, Meiners LC, ter Horst HJ, et al. The prognostic value of multivoxel magnetic resonance spectroscopy determined metabolite levels in white and grey matter brain tissue for adverse outcome in term newborns following perinatal asphyxia. Eur Radiol. 2012;22(4):772–778. doi: 10.1007/s00330-011-2315-z.Nakajima W, Ishida A, Lange MS, et al. Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci. 2000;20(21):7994–8004.Nakajima W, Ishida A, Lange MS, et al. Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci. 2000;20(21):7994–8004.Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Opin Pediatr. 2015;27(2):152–157. doi: 10.1097/mop.0000000000000199.Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Opin Pediatr. 2015;27(2):152–157. doi: 10.1097/mop.0000000000000199.Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 2015;169(4): 397–403. doi: 10.1001/jamapediatrics.2014.3269.Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 2015;169(4): 397–403. doi: 10.1001/jamapediatrics.2014.3269.Saliba E, Fakhri N, Debillon T. Establishing a hypothermia service for infants with suspected hypoxic-ischemic encephalopathy. Semin Fetal Neonatal Med. 2015;20(2):80–86. doi: 10.1016/j.siny.2015.01.008.Saliba E, Fakhri N, Debillon T. Establishing a hypothermia service for infants with suspected hypoxic-ischemic encephalopathy. Semin Fetal Neonatal Med. 2015;20(2):80–86. doi: 10.1016/j.siny.2015.01.008.Wallace BK, Foroutan S, O’Donnell ME. Ischemia-induced stimulation of Na-K-Cl cotransport in cerebral microvascular endothelial cells involves AMP kinase. Am J Physiol Cell Physiol. 2011;301(2):C316–326. doi: 10.1152/ajpcell.00517.2010.Wallace BK, Foroutan S, O’Donnell ME. Ischemia-induced stimulation of Na-K-Cl cotransport in cerebral microvascular endothelial cells involves AMP kinase. Am J Physiol Cell Physiol. 2011;301(2):C316–326. doi: 10.1152/ajpcell.00517.2010.Chen YJ, Wallace BK, Yuen N, et al. Blood-brain barrier KCa3.1 channels: evidence for a role in brain Na uptake and edema in ischemic stroke. Stroke. 2015;46(1):237–244. doi: 10.1161/strokeaha.114.007445.Chen YJ, Wallace BK, Yuen N, et al. Blood-brain barrier KCa3.1 channels: evidence for a role in brain Na uptake and edema in ischemic stroke. Stroke. 2015;46(1):237–244. doi: 10.1161/strokeaha.114.007445.Brillault J, Lam TI, Rutkowsky JM, et al. Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells. Am J Physiol Cell Physiol. 2008;294(1):C88–96. doi: 10.1152/ajpcell.00148.2007.Brillault J, Lam TI, Rutkowsky JM, et al. Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells. Am J Physiol Cell Physiol. 2008;294(1):C88–96. doi: 10.1152/ajpcell.00148.2007.Hausmann R, Seidl S, Betz P. Hypoxic changes in Purkinje cells of the human cerebellum. Int J Legal Med. 2007;121(3):175–183. doi: 10.1007/s00414-006-0122-x.Hausmann R, Seidl S, Betz P. Hypoxic changes in Purkinje cells of the human cerebellum. Int J Legal Med. 2007;121(3):175–183. doi: 10.1007/s00414-006-0122-x.Bonfoco E, Krainc D, Ankarcrona M, et al. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A. 1995;92(16):7162–7166. doi: 10.1073/pnas.92.16.7162.Bonfoco E, Krainc D, Ankarcrona M, et al. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A. 1995;92(16):7162–7166. doi: 10.1073/pnas.92.16.7162.Sun X, Crawford R, Liu C, et al. Development-dependent regulation of molecular chaperones after hypoxia-ischemia. Neurobiol Dis. 2015;82:123–131. doi: 10.1016/j.nbd.2015.06.001.Sun X, Crawford R, Liu C, et al. Development-dependent regulation of molecular chaperones after hypoxia-ischemia. Neurobiol Dis. 2015;82:123–131. doi: 10.1016/j.nbd.2015.06.001.Blomgren K, Leist M, Groc L. Pathological apoptosis in the developing brain. Apoptosis. 2007;12(5):993–1010. doi: 10.1007/s10495-007-0754-4.Blomgren K, Leist M, Groc L. Pathological apoptosis in the developing brain. Apoptosis. 2007;12(5):993–1010. doi: 10.1007/s10495-007-0754-4.Portera-Cailliau C, Price DL, Martin LJ. Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum. J Comp Neurol. 1997;378(1):70–87. doi: 10.1002/(sici)1096-9861(19970203)378:1<10::aid-cne4>3.0.co;2-n.Portera-Cailliau C, Price DL, Martin LJ. Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum. J Comp Neurol. 1997;378(1):70–87. doi: 10.1002/(sici)1096-9861(19970203)378:1<10::aid-cne4>3.0.co;2-n.Northington FJ, Zelaya ME, O’Riordan DP, et al. 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(4):822–833. doi: 10.1016/j.neuroscience.2007.06.060.Northington FJ, Zelaya ME, O’Riordan DP, et al. 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(4):822–833. doi: 10.1016/j.neuroscience.2007.06.060.Baburamani AA, Hurling C, Stolp H, et al. Mitochondrial optic atrophy (OPA) 1 processing is altered in response to neonatal hypoxic- ischemic brain injury. Int J Mol Sci. 2015;16(9):22509–22526. doi: 10.3390/ijms160922509.Baburamani AA, Hurling C, Stolp H, et al. Mitochondrial optic atrophy (OPA) 1 processing is altered in response to neonatal hypoxic- ischemic brain injury. Int J Mol Sci. 2015;16(9):22509–22526. doi: 10.3390/ijms160922509.Blomgren K, Hagberg H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med. 2006;40(3):388–397. doi: 10.1016/j.freeradbiomed.2005.08.040.Blomgren K, Hagberg H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med. 2006;40(3):388–397. doi: 10.1016/j.freeradbiomed.2005.08.040.Wang X, Carlsson Y, Basso E, et al. Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury. J Neurosci. 2009;29(8):2588–2596. doi: 10.1523/jneurosci.5832-08.2009.Wang X, Carlsson Y, Basso E, et al. Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury. J Neurosci. 2009;29(8):2588–2596. doi: 10.1523/jneurosci.5832-08.2009.Cao G, Xing J, Xiao X, et al. Critical role of calpain I in mitochondrial release of apoptosis- inducing factor in ischemic neuronal injury. J Neurosci. 2007;27(35):9278–9293. doi: 10.1523/jneurosci.2826-07.2007.Cao G, Xing J, Xiao X, et al. Critical role of calpain I in mitochondrial release of apoptosis- inducing factor in ischemic neuronal injury. J Neurosci. 2007;27(35):9278–9293. doi: 10.1523/jneurosci.2826-07.2007.Wang X, Karlsson JO, Zhu C, et al. Caspase-3 activation after neonatal rat cerebral hypoxia-ischemia. Biol Neonate. 2001; 79(3–4):172–179. doi: 10.1159/000047087.Wang X, Karlsson JO, Zhu C, et al. Caspase-3 activation after neonatal rat cerebral hypoxia-ischemia. Biol Neonate. 2001; 79(3–4):172–179. doi: 10.1159/000047087.Rossiter JP, Anderson LL, Yang F, Cole GM. Caspase-3 activation and caspase-like proteolytic activity in human perinatal hypoxicischemic brain injury. Acta Neuropathol. 2002;103(1):66–73. doi: 10.1007/s004010100432.Rossiter JP, Anderson LL, Yang F, Cole GM. Caspase-3 activation and caspase-like proteolytic activity in human perinatal hypoxicischemic brain injury. Acta Neuropathol. 2002;103(1):66–73. doi: 10.1007/s004010100432.Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009;30(2):180–192. doi: 10.1016/j.immuni.2009.01.001.Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009;30(2):180–192. doi: 10.1016/j.immuni.2009.01.001.Andrabi SA, Dawson TM, Dawson VL. Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann N Y Acad Sci. 2008; 1147:233–241. doi: 10.1196/annals.1427.014.Andrabi SA, Dawson TM, Dawson VL. Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann N Y Acad Sci. 2008; 1147:233–241. doi: 10.1196/annals.1427.014.Mandir AS, Poitras MF, Berliner AR, et al. NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. J Neurosci. 2000;20(21):8005–8011.Mandir AS, Poitras MF, Berliner AR, et al. NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. J Neurosci. 2000;20(21):8005–8011.Ducrocq S, Benjelloun N, Plotkine M, et al. Poly(ADP-ribose) synthase inhibition reduces ischemic injury and inflammation in neonatal rat brain. J Neurochem. 2000;74(6):2504– 2511. doi: 10.1046/j.1471-4159.2000.0742504.x.Ducrocq S, Benjelloun N, Plotkine M, et al. Poly(ADP-ribose) synthase inhibition reduces ischemic injury and inflammation in neonatal rat brain. J Neurochem. 2000;74(6):2504– 2511. doi: 10.1046/j.1471-4159.2000.0742504.x.Hagberg H, Wilson MA, Matsushita H, et al. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J Neurochem. 2004;90(5):1068– 1075. doi: 10.1111/j.1471-4159.2004.02547.x.Hagberg H, Wilson MA, Matsushita H, et al. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J Neurochem. 2004;90(5):1068– 1075. doi: 10.1111/j.1471-4159.2004.02547.x.McCullough LD, Zeng Z, Blizzard KK, et al. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab. 2005;25(4): 502–512. doi: 10.1038/sj.jcbfm.9600059.McCullough LD, Zeng Z, Blizzard KK, et al. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab. 2005;25(4): 502–512. doi: 10.1038/sj.jcbfm.9600059.Li H, Pin S, Zeng Z, et al. Sex differences in cell death. Ann Neurol. 2005;58(2):317–321. doi: 10.1002/ana.20538.Li H, Pin S, Zeng Z, et al. Sex differences in cell death. Ann Neurol. 2005;58(2):317–321. doi: 10.1002/ana.20538.Du L, Hickey RW, Bayir H, et al. Starving neurons show sex difference in autophagy. J Biol Chem. 2009;284(4):2383–2396. doi: 10.1074/jbc.m804396200.Du L, Hickey RW, Bayir H, et al. Starving neurons show sex difference in autophagy. J Biol Chem. 2009;284(4):2383–2396. doi: 10.1074/jbc.m804396200.Thompson DK, Warfield SK, Carlin JB, et al. Perinatal risk factors altering regional brain structure in the preterm infant. Brain. 2007;130(3):667–677. doi: 10.1093/brain/awl277.Thompson DK, Warfield SK, Carlin JB, et al. Perinatal risk factors altering regional brain structure in the preterm infant. Brain. 2007;130(3):667–677. doi: 10.1093/brain/awl277.Ment LR, Vohr BR, Makuch RW, et al. Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J Pediatr. 2004;145(6):832–834. doi: 10.1016/j.jpeds.2004.07.035.Ment LR, Vohr BR, Makuch RW, et al. Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J Pediatr. 2004;145(6):832–834. doi: 10.1016/j.jpeds.2004.07.035.Thomazi AP, Boff B, Pires TD, et al. Profile of glutamate uptake and cellular viability in hippocampal slices exposed to oxygen and glucose deprivation: developmental aspects and protection by guanosine. Brain Res. 2008;1188:233–240. doi: 10.1016/j.brainres.2007.10.037.Thomazi AP, Boff B, Pires TD, et al. Profile of glutamate uptake and cellular viability in hippocampal slices exposed to oxygen and glucose deprivation: developmental aspects and protection by guanosine. Brain Res. 2008;1188:233–240. doi: 10.1016/j.brainres.2007.10.037.Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol. 2005;15(3):234–240. doi: 10.1111/j.1750-3639.2005.tb00526.x.Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol. 2005;15(3):234–240. doi: 10.1111/j.1750-3639.2005.tb00526.x.McDonald JW, Silverstein FS, Johnston MV. Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats. Neurosci Lett. 1990;109(1–2):234–238. doi: 10.1016/0304-3940(90)90569-u.McDonald JW, Silverstein FS, Johnston MV. Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats. Neurosci Lett. 1990;109(1–2):234–238. doi: 10.1016/0304-3940(90)90569-u.McDonald JW, Silverstein FS, Johnston MV. Neuroprotective effects of MK-801, TCP, PCP and CPP against N-methyl-D-aspartate induced neurotoxicity in an in vivo perinatal rat model. Brain Res. 1989;490(1):33–40. doi: 10.1016/0006-8993(89)90427-7.McDonald JW, Silverstein FS, Johnston MV. Neuroprotective effects of MK-801, TCP, PCP and CPP against N-methyl-D-aspartate induced neurotoxicity in an in vivo perinatal rat model. Brain Res. 1989;490(1):33–40. doi: 10.1016/0006-8993(89)90427-7.McDonald JW, Johnston MV. Pharmacology of N-methyl-Daspartate-induced brain injury in an in vivo perinatal rat model. Synapse. 1990;6(2):179–188. doi: 10.1002/syn.890060210.McDonald JW, Johnston MV. Pharmacology of N-methyl-Daspartate-induced brain injury in an in vivo perinatal rat model. Synapse. 1990;6(2):179–188. doi: 10.1002/syn.890060210.McDonald JW, Roeser NF, Silverstein FS, Johnston MV. Quantitative assessment of neuroprotection against NMDA-induced brain injury. Exp Neurol. 1989;106(3):289–296. doi: 10.1016/0014-4886(89)90162-3.McDonald JW, Roeser NF, Silverstein FS, Johnston MV. Quantitative assessment of neuroprotection against NMDA-induced brain injury. Exp Neurol. 1989;106(3):289–296. doi: 10.1016/0014-4886(89)90162-3.Talos DM, Fishman RE, Park H, et al. Developmental regulation of alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. I. Rodent cerebral white matter and cortex. J Comp Neurol. 2006;497(1):42–60. doi: 10.1002/cne.20972.Talos DM, Fishman RE, Park H, et al. Developmental regulation of alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. I. Rodent cerebral white matter and cortex. J Comp Neurol. 2006;497(1):42–60. doi: 10.1002/cne.20972.McCarran WJ, Goldberg MP. White matter axon vulnerability to AMPA/kainate receptor- mediated ischemic injury is developmentally regulated. J Neurosci. 2007;27(15):4220–4229. doi: 10.1523/jneurosci.5542-06.2007.McCarran WJ, Goldberg MP. White matter axon vulnerability to AMPA/kainate receptor- mediated ischemic injury is developmentally regulated. J Neurosci. 2007;27(15):4220–4229. doi: 10.1523/jneurosci.5542-06.2007.Deng W, Rosenberg PA, Volpe JJ, Jensen FE. Calcium-permeable AMPA/kainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors. Proc Natl Acad Sci U S A. 2003;100(11):6801–6806. doi: 10.1073/pnas.1136624100.Deng W, Rosenberg PA, Volpe JJ, Jensen FE. Calcium-permeable AMPA/kainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors. Proc Natl Acad Sci U S A. 2003;100(11):6801–6806. doi: 10.1073/pnas.1136624100.Johnston MV, Ferriero DM, Vannucci SJ, Hagberg H. Models of cerebral palsy: which ones are best? J Child Neurol. 2005;20(12): 984–987. doi: 10.1177/08830738050200121001.Johnston MV, Ferriero DM, Vannucci SJ, Hagberg H. Models of cerebral palsy: which ones are best? J Child Neurol. 2005;20(12): 984–987. doi: 10.1177/08830738050200121001.McDonald JW, Trescher WH, Johnston MV. Susceptibility of brain to AMPA induced excitotoxicity transiently peaks during early postnatal development. Brain Res. 1992;583(1– 2):54–70. doi: 10.1016/s0006-8993(10)80009-5.McDonald JW, Trescher WH, Johnston MV. Susceptibility of brain to AMPA induced excitotoxicity transiently peaks during early postnatal development. Brain Res. 1992;583(1– 2):54–70. doi: 10.1016/s0006-8993(10)80009-5.Dammann O, O’Shea TM. Cytokines and perinatal brain damage. Clin Perinatol. 2008;35(4):643–663. doi: 10.1016/j.clp.2008.07.011.Dammann O, O’Shea TM. Cytokines and perinatal brain damage. Clin Perinatol. 2008;35(4):643–663. doi: 10.1016/j.clp.2008.07.011.Bartha AI, Foster-Barber A, Miller SP, et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res. 2004;56(6):960–966. doi: 10.1203/01.pdr.0000144819.45689.bb.Bartha AI, Foster-Barber A, Miller SP, et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res. 2004;56(6):960–966. doi: 10.1203/01.pdr.0000144819.45689.bb.Bona E, Andersson AL, Blomgren K, et al. Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res. 1999;45(4 Pt 1):500–509. doi: 10.1203/00006450-199904010-00008.Bona E, Andersson AL, Blomgren K, et al. Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res. 1999;45(4 Pt 1):500–509. doi: 10.1203/00006450-199904010-00008.Hedtjarn M, Mallard C, Hagberg H. Inflammatory gene profiling in the developing mouse brain after hypoxia-ischemia. J Cereb Blood Flow Metab. 2004;24(12):1333–1351. doi: 10.1097/01.wcb.0000141559.17620.36.Hedtjarn M, Mallard C, Hagberg H. Inflammatory gene profiling in the developing mouse brain after hypoxia-ischemia. J Cereb Blood Flow Metab. 2004;24(12):1333–1351. doi: 10.1097/01.wcb.0000141559.17620.36.Wang X, Hagberg H, Nie C, et al. Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia-ischemia. J Neuropathol Exp Neurol. 2007;66(6):552–561. doi: 10.1097/01.jnen.0000263870.91811.6f.Wang X, Hagberg H, Nie C, et al. Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia-ischemia. J Neuropathol Exp Neurol. 2007;66(6):552–561. doi: 10.1097/01.jnen.0000263870.91811.6f.Lafemina MJ, Sheldon RA, Ferriero DM. Acute hypoxia-ischemia results in hydrogen peroxide accumulation in neonatal but not adult mouse brain. Pediatr Res. 2006;59(5):680– 683. doi: 10.1203/01.pdr.0000214891.35363.6a.Lafemina MJ, Sheldon RA, Ferriero DM. Acute hypoxia-ischemia results in hydrogen peroxide accumulation in neonatal but not adult mouse brain. Pediatr Res. 2006;59(5):680– 683. doi: 10.1203/01.pdr.0000214891.35363.6a.Hagberg H, Andersson P, Lacarewicz J, et al. Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia. J Neurochem. 1987;49(1):227–231. doi: 10.1111/j.1471-4159.1987.tb03419.x.Hagberg H, Andersson P, Lacarewicz J, et al. Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia. J Neurochem. 1987;49(1):227–231. doi: 10.1111/j.1471-4159.1987.tb03419.x.Guglielmotto M, Aragno M, Autelli R, et al. The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem. 2009;108(4):1045–1056. doi: 10.1111/j.1471-4159.2008.05858.x.Guglielmotto M, Aragno M, Autelli R, et al. The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem. 2009;108(4):1045–1056. doi: 10.1111/j.1471-4159.2008.05858.x.Vinas JL, Sola A, Hotter G. Mitochondrial NOS upregulation during renal I/R causes apoptosis in a peroxynitrite-dependent manner. Kidney Int. 2006;69(8):1403–1409. doi: 10.1038/sj.ki.5000361.Vinas JL, Sola A, Hotter G. Mitochondrial NOS upregulation during renal I/R causes apoptosis in a peroxynitrite-dependent manner. Kidney Int. 2006;69(8):1403–1409. doi: 10.1038/sj.ki.5000361.Ishida A, Ishiwa S, Trescher WH, et al. Delayed increase in neuronal nitric oxide synthase immunoreactivity in thalamus and other brain regions after hypoxic-ischemic injury in neonatal rats. Exp Neurol. 2001;168(2):323–333. doi: 10.1006/exnr.2000.7606.Ishida A, Ishiwa S, Trescher WH, et al. Delayed increase in neuronal nitric oxide synthase immunoreactivity in thalamus and other brain regions after hypoxic-ischemic injury in neonatal rats. Exp Neurol. 2001;168(2):323–333. doi: 10.1006/exnr.2000.7606.Boya P, Gonzalez-Polo RA, Poncet D, et al. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene. 2003;22(25): 3927–3936. doi: 10.1038/sj.onc.1206622.Boya P, Gonzalez-Polo RA, Poncet D, et al. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene. 2003;22(25): 3927–3936. doi: 10.1038/sj.onc.1206622.Ferriero DM, Holtzman DM, Black SM, Sheldon RA. Neonatal mice lacking neuronal nitric oxide synthase are less vulnerable to hypoxic-ischemic injury. Neurobiol Dis. 1996;3(1):64– 71. doi: 10.1006/nbdi.1996.0006.Ferriero DM, Holtzman DM, Black SM, Sheldon RA. Neonatal mice lacking neuronal nitric oxide synthase are less vulnerable to hypoxic-ischemic injury. Neurobiol Dis. 1996;3(1):64– 71. doi: 10.1006/nbdi.1996.0006.Muramatsu K, Sheldon RA, Black SM, et al. Nitric oxide synthase activity and inhibition after neonatal hypoxia ischemia in the mouse brain. Brain Res Dev. 2000;123(2):119–127. doi: 10.1016/s0165-3806(00)00088-2.Muramatsu K, Sheldon RA, Black SM, et al. Nitric oxide synthase activity and inhibition after neonatal hypoxia ischemia in the mouse brain. Brain Res Dev. 2000;123(2):119–127. doi: 10.1016/s0165-3806(00)00088-2.Kaminski A, Kasch C, Zhang L, et al. Endothelial nitric oxide synthase mediates protective effects of hypoxic preconditioning in lungs. Respir Physiol Neurobiol. 2007;155(3):280–285. doi: 10.1016/j.resp.2006.06.005.Kaminski A, Kasch C, Zhang L, et al. Endothelial nitric oxide synthase mediates protective effects of hypoxic preconditioning in lungs. Respir Physiol Neurobiol. 2007;155(3):280–285. doi: 10.1016/j.resp.2006.06.005.Huang Z, Huang PL, Ma J, et al. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro- L-arginine. J Cereb Blood Flow Metab. 1996;16(5):981–987. doi: 10.1097/00004647-199609000-00023.Huang Z, Huang PL, Ma J, et al. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro- L-arginine. J Cereb Blood Flow Metab. 1996;16(5):981–987. doi: 10.1097/00004647-199609000-00023.Van Laerhoven H, de Haan TR, Offringa M, et al. Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics. 2013;131(1):88–98. doi: 10.1542/peds.2012-1297.Van Laerhoven H, de Haan TR, Offringa M, et al. Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics. 2013;131(1):88–98. doi: 10.1542/peds.2012-1297.Lv H, Wang Q, Wu S, et al. Neonatal hypoxic ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid. Clin Chim Acta. 2015;450:282–297. doi: 10.1016/j.cca.2015.08.021.Lv H, Wang Q, Wu S, et al. Neonatal hypoxic ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid. Clin Chim Acta. 2015;450:282–297. doi: 10.1016/j.cca.2015.08.021.clinicaltrials.gov [Internet]. Study Record Detail. Developmental Outcomes [cited 2016 Sep 9]. Available from: https://clinicaltrials. gov/ct2/show/NCT02264808? term=Cord+Blood++HIE&rank=11.clinicaltrials.gov [Internet]. Study Record Detail. Developmental Outcomes [cited 2016 Sep 9]. Available from: https://clinicaltrials. gov/ct2/show/NCT02264808? term=Cord+Blood++HIE&rank=11.Nanavati T, Seemaladinne N, Regier M, et al. Can we predict functional outcome in neonates with hypoxic ischemic ence phalopathy by the combination of neuroimaging and electro ence phalography? Pediatr Neonatol. 2015;56(5):307–316. doi: 10.1016/j.pedneo.2014.12.005.Nanavati T, Seemaladinne N, Regier M, et al. Can we predict functional outcome in neonates with hypoxic ischemic ence phalopathy by the combination of neuroimaging and electro ence phalography? Pediatr Neonatol. 2015;56(5):307–316. doi: 10.1016/j.pedneo.2014.12.005.clinicaltrials.gov [Internet]. Study Record Detail. BiHiVE2 Study. The Investigation and Validation of Predictive Biomarkers in Hypo xicischaemic Encephalopathy. (BiHiVE2) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02019147?term=Cord+Blood++HIE&rank=9.clinicaltrials.gov [Internet]. Study Record Detail. BiHiVE2 Study. The Investigation and Validation of Predictive Biomarkers in Hypo xicischaemic Encephalopathy. (BiHiVE2) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02019147?term=Cord+Blood++HIE&rank=9.Wang B, Armstrong JS, Reyes M, et al. White matter apoptosis is increased by delayed hypothermia and rewarming in a neonatal piglet model of hypoxic ischemic encephalopathy. Neuroscience. 2016;316:296–310. doi: 10.1016/j.neuroscience.2015.12.046.Wang B, Armstrong JS, Reyes M, et al. White matter apoptosis is increased by delayed hypothermia and rewarming in a neonatal piglet model of hypoxic ischemic encephalopathy. Neuroscience. 2016;316:296–310. doi: 10.1016/j.neuroscience.2015.12.046.Wassink G, Gunn ER, Drury PP, et al. The mechanisms and treatment of asphyxial encephalopathy. Front Neurosci. 2014;8:40. doi: 10.3389/fnins.2014.00040.Wassink G, Gunn ER, Drury PP, et al. The mechanisms and treatment of asphyxial encephalopathy. Front Neurosci. 2014;8:40. doi: 10.3389/fnins.2014.00040.Kimura A, Sakurada S, Ohkuni H, et al. Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells. Crit Care Med. 2002;30(7):1499–1502. doi: 10.1097/00003246-200207000-00017.Kimura A, Sakurada S, Ohkuni H, et al. Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells. Crit Care Med. 2002;30(7):1499–1502. doi: 10.1097/00003246-200207000-00017.Rossouw G, Irlam J, Horn AR. Therapeutic hypothermia for hypoxic ischaemic encephalopathy using low-technology methods: a systematic review and meta-analysis. Acta Paediatr. 2015; 104(12):1217–1228. doi: 10.1111/apa.1283.Rossouw G, Irlam J, Horn AR. Therapeutic hypothermia for hypoxic ischaemic encephalopathy using low-technology methods: a systematic review and meta-analysis. Acta Paediatr. 2015; 104(12):1217–1228. doi: 10.1111/apa.1283.Shah PS. Hypothermia: a systematic review and meta-analysis of clinical trials. Semin Fetal Neonatal Med. 2010;15(5):238–246. doi: 10.1016/j.siny.2010.02.003.Shah PS. Hypothermia: a systematic review and meta-analysis of clinical trials. Semin Fetal Neonatal Med. 2010;15(5):238–246. doi: 10.1016/j.siny.2010.02.003.Azzopardi D, Strohm B, Edwards AD, et al. Steering Group and TOBY Cooling Register participants. Treatment of asphyxiated newborns with moderate hypothermia in routine clinical practice: how cooling is managed in the UK outside a clinical trial. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):F260–264. doi: 10.1136/adc.2008.146977.Azzopardi D, Strohm B, Edwards AD, et al. Steering Group and TOBY Cooling Register participants. Treatment of asphyxiated newborns with moderate hypothermia in routine clinical practice: how cooling is managed in the UK outside a clinical trial. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):F260–264. doi: 10.1136/adc.2008.146977.Azzopardi D, Strohm B, Linsell L, et al. Implementation and conduct of therapeutic hypothermia for perinatal asphyxial encephalopathy in the UK-analysis of national data. PLoS One. 2012; 7(6):e38504. doi: 10.1371/journal.pone.0038504.Azzopardi D, Strohm B, Linsell L, et al. Implementation and conduct of therapeutic hypothermia for perinatal asphyxial encephalopathy in the UK-analysis of national data. PLoS One. 2012; 7(6):e38504. doi: 10.1371/journal.pone.0038504.Osredkar D, Thoresen M, Maes E, et al. Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation. 2014;85(4):567– 572. doi: 10.1016/j.resuscitation.2013.12.006.Osredkar D, Thoresen M, Maes E, et al. Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury. Resuscitation. 2014;85(4):567– 572. doi: 10.1016/j.resuscitation.2013.12.006.Villa P, Bigini P, Mennini T, et al. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med. 2003;198(6):971–975. doi: 10.1084/jem.20021067.Villa P, Bigini P, Mennini T, et al. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med. 2003;198(6):971–975. doi: 10.1084/jem.20021067.Wang L, Zhang Z, Wang Y, et al. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and impro ves neurological function in rats. Stroke. 2004;35(7):1732–1737. doi: 10.1161/01.str.0000132196.49028.a4.Wang L, Zhang Z, Wang Y, et al. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and impro ves neurological function in rats. Stroke. 2004;35(7):1732–1737. doi: 10.1161/01.str.0000132196.49028.a4.Juul SE. Hypothermia plus erythropoietin for neonatal neuro protection? Pediatr Res. 2013;73(1):10–11. doi: 10.1038/pr.2012.148.Juul SE. Hypothermia plus erythropoietin for neonatal neuro protection? Pediatr Res. 2013;73(1):10–11. doi: 10.1038/pr.2012.148.Juul SE, Yachnis AT, Rojiani AM, Christensen RD. Immu nohisto chemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol. 1999;2(2):148–158. doi: 10.1007/s100249900103.Juul SE, Yachnis AT, Rojiani AM, Christensen RD. Immu nohisto chemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol. 1999;2(2):148–158. doi: 10.1007/s100249900103.Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuro protection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012;130(4):683–691. doi: 10.1542/peds.2012-0498.Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuro protection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012;130(4):683–691. doi: 10.1542/peds.2012-0498.Kumral A, Uysal N, Tugyan K, et al. Erythropoietin improves longterm spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats. Behav Brain Res. 2004;153(1):77–86. doi: 10.1016/j.bbr.2003.11.002.Kumral A, Uysal N, Tugyan K, et al. Erythropoietin improves longterm spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats. Behav Brain Res. 2004;153(1):77–86. doi: 10.1016/j.bbr.2003.11.002.Gonzalez FF, Abel R, Almli CR, et al. Erythropoietin sustains cognitive function and brain volume after neonatal stroke. Dev Neurosci. 2009;31(5):403–411. doi: 10.1159/000232558.Gonzalez FF, Abel R, Almli CR, et al. Erythropoietin sustains cognitive function and brain volume after neonatal stroke. Dev Neurosci. 2009;31(5):403–411. doi: 10.1159/000232558.Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009;124(2):e218–226. doi: 10.1542/peds.2008-3553.Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009;124(2):e218–226. doi: 10.1542/peds.2008-3553.Rogers EE, Bonifacio SL, Glass HC, et al. Erythropoietin and hypothermia for hypoxic- ischemic encephalopathy. Pediatr Neurol. 2014;51(5):657–662. doi: 10.1016/j.pediatrneurol.2014.08.010.Rogers EE, Bonifacio SL, Glass HC, et al. Erythropoietin and hypothermia for hypoxic- ischemic encephalopathy. Pediatr Neurol. 2014;51(5):657–662. doi: 10.1016/j.pediatrneurol.2014.08.010.Elmahdy H, El-Mashad AR, El-Bahrawy H, et al. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics. 2010;125(5):e1135–1142. doi: 10.1542/peds.2009-2268.Elmahdy H, El-Mashad AR, El-Bahrawy H, et al. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics. 2010;125(5):e1135–1142. doi: 10.1542/peds.2009-2268.clinicaltrials.gov [Internet]. Study Record Detail. Neonatal Erythropoietin And Therapeutic Hypothermia Outcomes in Newborn Brain Injury (NEATO) (NEATO) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT01913340.clinicaltrials.gov [Internet]. Study Record Detail. Neonatal Erythropoietin And Therapeutic Hypothermia Outcomes in Newborn Brain Injury (NEATO) (NEATO) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT01913340.clinicaltrials.gov [Internet]. Study Record Detail. Efficacy of Erythropoietin to Improve Survival and Neurological Outcome in Hypoxic Ischemic Encephalopathy (Neurepo) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT01732146.clinicaltrials.gov [Internet]. Study Record Detail. Efficacy of Erythropoietin to Improve Survival and Neurological Outcome in Hypoxic Ischemic Encephalopathy (Neurepo) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT01732146.Leuchter RH, Gui L, Poncet A, et al. Association between early administration of high- dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age. JAMA. 2014;312(8): 817–824. doi: 10.1001/jama.2014.9645.Leuchter RH, Gui L, Poncet A, et al. Association between early administration of high- dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age. JAMA. 2014;312(8): 817–824. doi: 10.1001/jama.2014.9645.Ohls RK, Kamath-Rayne BD, Christensen RD, et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics. 2014;133(6):1023–1030. doi: 10.1542/peds.2013-4307.Ohls RK, Kamath-Rayne BD, Christensen RD, et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics. 2014;133(6):1023–1030. doi: 10.1542/peds.2013-4307.Dworschak M. Pharmacologic neuroprotection-is xenon the light at the end of the tunnel? Crit Care Med. 2008;36(8):2477–2479. doi: 10.1097/ccm.0b013e31818113d2.Dworschak M. Pharmacologic neuroprotection-is xenon the light at the end of the tunnel? Crit Care Med. 2008;36(8):2477–2479. doi: 10.1097/ccm.0b013e31818113d2.Istaphanous GK, Loepke AW. General anesthetics and the developing brain. Curr Opin Anaesthesiol. 2009;22(3):368–373. doi: 10.1097/aco.0b013e3283294c9e.Istaphanous GK, Loepke AW. General anesthetics and the developing brain. Curr Opin Anaesthesiol. 2009;22(3):368–373. doi: 10.1097/aco.0b013e3283294c9e.David HN, Haelewyn B, Rouillon C, et al. Neuroprotective effects of xenon: a therapeutic window of opportunity in rats subjected to transient cerebral ischemia. FASEB J. 2008;22(4):1275–1286. doi: 10.1096/fj.07-9420com.David HN, Haelewyn B, Rouillon C, et al. Neuroprotective effects of xenon: a therapeutic window of opportunity in rats subjected to transient cerebral ischemia. FASEB J. 2008;22(4):1275–1286. doi: 10.1096/fj.07-9420com.Ma D, Hossain M, Chow A, et al. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol. 2005;58(2):182–193. doi: 10.1002/ana.20547.Ma D, Hossain M, Chow A, et al. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol. 2005;58(2):182–193. doi: 10.1002/ana.20547.Thoresen M, Hobbs CE, Wood T, et al. Cooling combined with immediate or delayed xenon inhalation provides equivalent longterm neuroprotection after neonatal hypoxia- ischemia. Cereb Blood Flow Metab. 2009;29(4):707–714. doi: 10.1038/jcbfm.2008.163.Thoresen M, Hobbs CE, Wood T, et al. Cooling combined with immediate or delayed xenon inhalation provides equivalent longterm neuroprotection after neonatal hypoxia- ischemia. Cereb Blood Flow Metab. 2009;29(4):707–714. doi: 10.1038/jcbfm.2008.163.Dingley J, Tooley J, Liu X, et al. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics. 2014;133(5):809–818. doi: 10.1542/peds.2013-0787.Dingley J, Tooley J, Liu X, et al. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics. 2014;133(5):809–818. doi: 10.1542/peds.2013-0787.Azzopardi D, Robertson NJ, Bainbridge A, et al. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY- Xe): a proof-ofconcept, open-label, randomised controlled trial. Lancet Neurol. 2016;(15)2:145–153. doi: 10.1016/s1474-4422(15)00347-6.Azzopardi D, Robertson NJ, Bainbridge A, et al. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY- Xe): a proof-ofconcept, open-label, randomised controlled trial. Lancet Neurol. 2016;(15)2:145–153. doi: 10.1016/s1474-4422(15)00347-6.Alonso-Alconada D, Alvarez A, Arteaga O, et al. Neuroprotective effect of melatonin: a novel therapy against perinatal hypoxiaischemia. Int J Mol Sci. 2013;14(5):9379–9395. doi: 10.3390/ijms14059379.Alonso-Alconada D, Alvarez A, Arteaga O, et al. Neuroprotective effect of melatonin: a novel therapy against perinatal hypoxiaischemia. Int J Mol Sci. 2013;14(5):9379–9395. doi: 10.3390/ijms14059379.Carloni S, Perrone S, Buonocore G, et al. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res. 2008;44(2):157–164. doi: 10.1111/j.1600-079x.2007.00503.x.Carloni S, Perrone S, Buonocore G, et al. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res. 2008;44(2):157–164. doi: 10.1111/j.1600-079x.2007.00503.x.Robertson NJ, Faulkner S, Fleiss B, et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain. 2013;136(1):90–105. doi: 10.1093/brain/aws285.Robertson NJ, Faulkner S, Fleiss B, et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain. 2013;136(1):90–105. doi: 10.1093/brain/aws285.Aly H, Elmahdy H, El-Dib M, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol. 2015;35(3):186–191. doi: 10.1038/jp.2014.186.Aly H, Elmahdy H, El-Dib M, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol. 2015;35(3):186–191. doi: 10.1038/jp.2014.186.Merchant NM, Azzopardi DV, Hawwa AF, McElnay JC, Middleton B, et al. Pharmacokinetics of melatonin in preterm infants. Br J Clin Pharmacol. 2013;76(5):725–33.Merchant NM, Azzopardi DV, Hawwa AF, McElnay JC, Middleton B, et al. Pharmacokinetics of melatonin in preterm infants. Br J Clin Pharmacol. 2013;76(5):725–33.Zalewska T, Jaworska J, Ziemka-Nalecz M. Current and experimental pharmacological approaches in neonatal hypoxic- ischemic encephalopathy. Curr Pharm Des. 2015;21(11):1433–1439. doi: 10.2174/1381612820999141029162457.Zalewska T, Jaworska J, Ziemka-Nalecz M. Current and experimental pharmacological approaches in neonatal hypoxic- ischemic encephalopathy. Curr Pharm Des. 2015;21(11):1433–1439. doi: 10.2174/1381612820999141029162457.Shea KL, Palanisamy A. What can you do to protect the newborn brain? Curr Opin Anaesthesiol. 2015;28(3):261–266. doi: 10.1097/aco.0000000000000184.Shea KL, Palanisamy A. What can you do to protect the newborn brain? Curr Opin Anaesthesiol. 2015;28(3):261–266. doi: 10.1097/aco.0000000000000184.Liao Y, Cotten M, Tan S, et al. Rescuing the neonatal brain from hypoxic injury with autologous cord blood. Bone Marrow Transplant. 2013;48(7):890–900. doi: 10.1038/bmt.2012.169.Liao Y, Cotten M, Tan S, et al. Rescuing the neonatal brain from hypoxic injury with autologous cord blood. Bone Marrow Transplant. 2013;48(7):890–900. doi: 10.1038/bmt.2012.169.Sun J, Allison J, McLaughlin C, et al. Differences in quali ty between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion. 2010;50(9):1980–1987. doi: 10.1111/j.1537-2995.2010.02720.x.Sun J, Allison J, McLaughlin C, et al. Differences in quali ty between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion. 2010;50(9):1980–1987. doi: 10.1111/j.1537-2995.2010.02720.x.Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Engl J Med. 2005;352(20):2069–2081. doi: 10.1056/nejmoa042604.Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Engl J Med. 2005;352(20):2069–2081. doi: 10.1056/nejmoa042604.Cotten CM, Murtha AP, Goldberg RN, et al. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr. 2014;164(5):973–979.e1. doi: 10.1016/j.jpeds.2013.11.036.Cotten CM, Murtha AP, Goldberg RN, et al. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr. 2014;164(5):973–979.e1. doi: 10.1016/j.jpeds.2013.11.036.clinicaltrials.gov [Internet]. Study Record Detail. Cord Blood for Neonatal Hypoxic- ischemic Encephalopathy [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT00593242?term=NCT00593242&rank=1.clinicaltrials.gov [Internet]. Study Record Detail. Cord Blood for Neonatal Hypoxic- ischemic Encephalopathy [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT00593242?term=NCT00593242&rank=1.clinicaltrials.gov [Internet]. Study Record Detail. Autologous Cord Blood Cell Therapy for Neonatal Encephalopathy [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02256618?term=Cord+Blood++HIE&rank=7.clinicaltrials.gov [Internet]. Study Record Detail. Autologous Cord Blood Cell Therapy for Neonatal Encephalopathy [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02256618?term=Cord+Blood++HIE&rank=7.clinicaltrials.gov [Internet]. Study Record Detail. Autologous Cord Blood and Human Placental Derived Stem Cells in Neonates With Severe Hypoxic-Ischemic Encephalopathy (HPDSC+HIE) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02434965?term=Cord+Blood++HIE&rank=2.clinicaltrials.gov [Internet]. Study Record Detail. Autologous Cord Blood and Human Placental Derived Stem Cells in Neonates With Severe Hypoxic-Ischemic Encephalopathy (HPDSC+HIE) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02434965?term=Cord+Blood++HIE&rank=2.clinicaltrials.gov [Internet]. Study Record Detail. Cytokines Associated With Cord Blood Cell Therapy for Neonatal Encephalopathy [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02455830?term=Cord+Blood++HIE&rank=8.clinicaltrials.gov [Internet]. Study Record Detail. Cytokines Associated With Cord Blood Cell Therapy for Neonatal Encephalopathy [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02455830?term=Cord+Blood++HIE&rank=8.Doycheva D, Shih G, Chen H, et al. Granulocyte-colony stimulating factor in combination with stem cell factor confers greater neuroprotection after hypoxic-ischemic brain damage in the neonatal rats than a solitary treatment. Transl Stroke Res. 2013; 4(2):171–178. doi: 10.1007/s12975-012-0225-2.Doycheva D, Shih G, Chen H, et al. Granulocyte-colony stimulating factor in combination with stem cell factor confers greater neuroprotection after hypoxic-ischemic brain damage in the neonatal rats than a solitary treatment. Transl Stroke Res. 2013; 4(2):171–178. doi: 10.1007/s12975-012-0225-2.Katsuragi S, Ikeda T, Date I, et al. Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats. Am J Obstet Gynecol. 2005;192(4):1028– 1037. doi: 10.1016/j.ajog.2004.09.099.Katsuragi S, Ikeda T, Date I, et al. Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats. Am J Obstet Gynecol. 2005;192(4):1028– 1037. doi: 10.1016/j.ajog.2004.09.099.Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;41 Suppl 1:S3–9. doi: 10.1111/j.1528-1157.2000.tb02163.x.Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;41 Suppl 1:S3–9. doi: 10.1111/j.1528-1157.2000.tb02163.x.Ozyener F, Cetinkaya M, Alkan T, et al. Neuroprotective effects of melatonin administered alone or in combination with topiramate in neonatal hypoxic-ischemic rat model. Restor Neurol Neurosci. 2012;30(5):435–444.Ozyener F, Cetinkaya M, Alkan T, et al. Neuroprotective effects of melatonin administered alone or in combination with topiramate in neonatal hypoxic-ischemic rat model. Restor Neurol Neurosci. 2012;30(5):435–444.Noh MR, Kim SK, Sun W, et al. Neuroprotective effect of topiramate on hypoxic ischemic brain injury in neonatal rats. Exp Neurol. 2006;201(2):470–478. doi: 10.1016/j.expneurol.2006.04.038.Noh MR, Kim SK, Sun W, et al. Neuroprotective effect of topiramate on hypoxic ischemic brain injury in neonatal rats. Exp Neurol. 2006;201(2):470–478. doi: 10.1016/j.expneurol.2006.04.038.Sfaello I, Baud O, Arzimanoglou A, Gressens P. Topiramate prevents excitotoxic damage in the newborn rodent brain. Neurobiol Dis. 2005;20(3):837–848. doi: 10.1016/j.nbd.2005.05.019.Sfaello I, Baud O, Arzimanoglou A, Gressens P. Topiramate prevents excitotoxic damage in the newborn rodent brain. Neurobiol Dis. 2005;20(3):837–848. doi: 10.1016/j.nbd.2005.05.019.Filippi L, Fiorini P, Daniotti M, et al. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI). BMC Pediatr. 2012;12:144. doi: 10.1186/1471-2431-12-144.Filippi L, Fiorini P, Daniotti M, et al. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI). BMC Pediatr. 2012;12:144. doi: 10.1186/1471-2431-12-144.clinicaltrials.gov [Internet]. Study Record Detail. Topiramate in Neonates Receiving Whole Body Cooling for Hypoxic Ischemic Encephalopathy [cited 2016 Sep 9]. Available from: https://clinicaltrials. gov/ct2/show/NCT01765218?term=NCT01765218&rank=1.clinicaltrials.gov [Internet]. Study Record Detail. Topiramate in Neonates Receiving Whole Body Cooling for Hypoxic Ischemic Encephalopathy [cited 2016 Sep 9]. Available from: https://clinicaltrials. gov/ct2/show/NCT01765218?term=NCT01765218&rank=1.Zeevalk GD, Nicklas WJ. Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-D-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J Neurochem. 1992;59(4):1211–1220. doi: 10.1111/j.1471- 4159.1992.tb08430.x.Zeevalk GD, Nicklas WJ. Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-D-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J Neurochem. 1992;59(4):1211–1220. doi: 10.1111/j.1471- 4159.1992.tb08430.x.Sugimoto J, Romani AM, Valentin-Torres AM, et al. Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol. 2012;188(12):6338–6346. doi: 10.4049/jimmunol.1101765.Sugimoto J, Romani AM, Valentin-Torres AM, et al. Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol. 2012;188(12):6338–6346. doi: 10.4049/jimmunol.1101765.Hoffman DJ, Marro PJ, McGowan JE, et al. Protective effect of MgSO4 infusion on nmda receptor binding characteristics during cerebral cortical hypoxia in the newborn piglet. Brain Res. 1994;644(1):144–149. doi: 10.1016/0006-8993(94)90357-3.Hoffman DJ, Marro PJ, McGowan JE, et al. Protective effect of MgSO4 infusion on nmda receptor binding characteristics during cerebral cortical hypoxia in the newborn piglet. Brain Res. 1994;644(1):144–149. doi: 10.1016/0006-8993(94)90357-3.Shokry M, Elsedfy GO, Bassiouny MM, et al. Effects of antenatal magnesium sulfate therapy on cerebral and systemic hemodynamics in preterm newborns. Acta Obstet Gynecol Scand. 2010;89(6):801–806. doi: 10.3109/00016341003739542.Shokry M, Elsedfy GO, Bassiouny MM, et al. Effects of antenatal magnesium sulfate therapy on cerebral and systemic hemodynamics in preterm newborns. Acta Obstet Gynecol Scand. 2010;89(6):801–806. doi: 10.3109/00016341003739542.Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and metaanalysis. Am J Obstet Gynecol. 2009;200(6):595–609. doi: 10.1016/j.ajog.2009.04.005.Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and metaanalysis. Am J Obstet Gynecol. 2009;200(6):595–609. doi: 10.1016/j.ajog.2009.04.005.Zhu H, Meloni BP, Bojarski C, et al. 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(2):361–368. doi: 10.1016/j.expneurol.2005.01.022.Zhu H, Meloni BP, Bojarski C, et al. 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(2):361–368. doi: 10.1016/j.expneurol.2005.01.022.Tataranno ML, Perrone S, Longini M, Buonocore G. New antioxidant drugs for neonatal brain injury. Oxid Med Cell Longev. 2015;2015:108251. doi: 10.1155/2015/108251.Tataranno ML, Perrone S, Longini M, Buonocore G. New antioxidant drugs for neonatal brain injury. Oxid Med Cell Longev. 2015;2015:108251. doi: 10.1155/2015/108251.Ovbiagele B, Kidwell CS, Starkman S, Saver JL. Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke. Curr Treat Options Neurol. 2003;5(5):367–375. doi: 10.1007/s11940-003-0027-7.Ovbiagele B, Kidwell CS, Starkman S, Saver JL. Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke. Curr Treat Options Neurol. 2003;5(5):367–375. doi: 10.1007/s11940-003-0027-7.Costantine MM, Weiner SJ. Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis. Obstet Gynecol. 2009;114(2 Pt 1): 354–364. doi: 10.1097/aog.0b013e3181ae98c2.Costantine MM, Weiner SJ. Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis. Obstet Gynecol. 2009;114(2 Pt 1): 354–364. doi: 10.1097/aog.0b013e3181ae98c2.Magee L, Sawchuck D, Synnes A, et al. Magnesium sulphate for fetal neuroprotection. J Obstet Gynaecol Can. 2011;33(5): 516–529. doi: 10.1016/S1701-2163(16)34886-1.Magee L, Sawchuck D, Synnes A, et al. Magnesium sulphate for fetal neuroprotection. J Obstet Gynaecol Can. 2011;33(5): 516–529. doi: 10.1016/S1701-2163(16)34886-1.Ramsey PS, Rouse DJ. Magnesium sulfate as a tocolytic agent. Semin Perinatol. 2001;25(4):236–247. doi: 10.1053/sper. 2001.27546.Ramsey PS, Rouse DJ. Magnesium sulfate as a tocolytic agent. Semin Perinatol. 2001;25(4):236–247. doi: 10.1053/sper. 2001.27546.Galinsky R, Bennet L, Groenendaal F, et al. Magnesium is not consistently neuroprotective for perinatal hypoxia-ischemia in terme quivalent models in preclinical studies: a systematic review. Dev Neurosci. 2014;36(2):73–82. doi: 10.1159/000362206.Galinsky R, Bennet L, Groenendaal F, et al. Magnesium is not consistently neuroprotective for perinatal hypoxia-ischemia in terme quivalent models in preclinical studies: a systematic review. Dev Neurosci. 2014;36(2):73–82. doi: 10.1159/000362206.clinicaltrials.gov [Internet]. Study Record Detail. Efficacy Study of Hypothermia Plus Magnesium Sulphate(MgSO4) in the Management of Term and Near Term Babies With Hypoxic Ischemic Encephalopathy (MagCool) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT01646619?term=NCT01646619&rank=1.clinicaltrials.gov [Internet]. Study Record Detail. Efficacy Study of Hypothermia Plus Magnesium Sulphate(MgSO4) in the Management of Term and Near Term Babies With Hypoxic Ischemic Encephalopathy (MagCool) [cited 2016 Sep 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT01646619?term=NCT01646619&rank=1.Levene M, Blennow M, Whitelaw A, et al. Acute effects of two different doses of magnesium sulphate in infants with birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 1995;73(3):F174–177. doi: 10.1136/fn.73.3.f174.Levene M, Blennow M, Whitelaw A, et al. Acute effects of two different doses of magnesium sulphate in infants with birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 1995;73(3):F174–177. doi: 10.1136/fn.73.3.f174.Robertson NJ, Tan S, Groenendaal F, et al. Which neuroprotective agents are ready for bench to bedside translation in the newborn infant? J Pediatr. 2012;160(4):544–552.e4. doi: 10.1016/j.jpeds.2011.12.052.Robertson NJ, Tan S, Groenendaal F, et al. Which neuroprotective agents are ready for bench to bedside translation in the newborn infant? J Pediatr. 2012;160(4):544–552.e4. doi: 10.1016/j.jpeds.2011.12.052.Peeters-Scholte C, Braun K, Koster J, et al. Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia. Pediatr Res. 2003;54(4):516–522. doi: 10.1203/01.pdr.0000081297.53793.c6.Peeters-Scholte C, Braun K, Koster J, et al. Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia. Pediatr Res. 2003;54(4):516–522. doi: 10.1203/01.pdr.0000081297.53793.c6.Marro PJ, Mishra OP, 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.Marro PJ, Mishra OP, 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.Palmer C, Towfighi J, Roberts RL, Heitjan DF. Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats. Pediatr Res. 1993;33(4):405–411. doi: 10.1203/00006450-199333040-00018.Palmer C, Towfighi J, Roberts RL, Heitjan DF. Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats. Pediatr Res. 1993;33(4):405–411. doi: 10.1203/00006450-199333040-00018.Peeters C, Hoelen D, Groenendaal F, et al. Deferoxamine, allopurinol and oxypurinol are not neuroprotective after oxygen/ glucose deprivation in an organotypic hippocampal model, lacking functional endothelial cells. Brain Res. 2003;963(1–2):72–80. doi: 10.1016/s0006-8993(02)03843-x.Peeters C, Hoelen D, Groenendaal F, et al. Deferoxamine, allopurinol and oxypurinol are not neuroprotective after oxygen/ glucose deprivation in an organotypic hippocampal model, lacking functional endothelial cells. Brain Res. 2003;963(1–2):72–80. doi: 10.1016/s0006-8993(02)03843-x.Benders MJ, Bos AF, Rademaker CM, et al. Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 2006;91(3):F163–165. doi: 10.1136/adc.2005.086652.Benders MJ, Bos AF, Rademaker CM, et al. Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed. 2006;91(3):F163–165. doi: 10.1136/adc.2005.086652.Kaandorp JJ, van Bel F, Veen S, et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed. 2012;97(3):F162–166. doi: 10.1136/archdischild-2011-300356.Kaandorp JJ, van Bel F, Veen S, et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed. 2012;97(3):F162–166. doi: 10.1136/archdischild-2011-300356.Juul SE, Ferriero DM. Pharmacologic neuroprotective strategies in neonatal brain injury. Clin Perinatol. 2014 Mar;41(1):119–131. doi: 10.1016/j.clp.2013.09.004.Juul SE, Ferriero DM. Pharmacologic neuroprotective strategies in neonatal brain injury. Clin Perinatol. 2014 Mar;41(1):119–131. doi: 10.1016/j.clp.2013.09.004.Kaandorp JJ, Benders MJ, Schuit E, et al. Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed. 2015;100(3): F216–223. doi: 10.1136/archdischild-2014-306769.Kaandorp JJ, Benders MJ, Schuit E, et al. Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed. 2015;100(3): F216–223. doi: 10.1136/archdischild-2014-306769.Torrance HL, Benders MJ, Derks JB, et al. Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S100B. Pediatrics. 2009;124(1):350–357. doi: 10.1542/peds.2008-2228.Torrance HL, Benders MJ, Derks JB, et al. Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S100B. Pediatrics. 2009;124(1):350–357. doi: 10.1542/peds.2008-2228.Gunes T, Ozturk MA, Koklu E, et al. Effect of allopurinol sup plementation on nitric oxide levels in asphyxiated new borns. Pediatr Neurol. 2007;36(1):17–24. doi: 10.1016/j.pediatrneurol.2006.08.005.Gunes T, Ozturk MA, Koklu E, et al. Effect of allopurinol sup plementation on nitric oxide levels in asphyxiated new borns. Pediatr Neurol. 2007;36(1):17–24. doi: 10.1016/j.pediatrneurol.2006.08.005.Lee TF, Tymafichuk CN, Bigam DL, Cheung PY. Effects of postresuscitation N- acetylcysteine on cerebral free radical production and perfusion during reoxygenation of hypoxic newborn piglets. Pediatr Res. 2008;64(3):256–261. doi: 10.1203/pdr.0b013e31817cfcc0.Lee TF, Tymafichuk CN, Bigam DL, Cheung PY. Effects of postresuscitation N- acetylcysteine on cerebral free radical production and perfusion during reoxygenation of hypoxic newborn piglets. Pediatr Res. 2008;64(3):256–261. doi: 10.1203/pdr.0b013e31817cfcc0.Aremu DA, Madejczyk MS, Ballatori N. N-acetylcysteine as a potential antidote and biomonitoring agent of methylmercury exposure. Environ Health Perspect. 2008;116(1):26– 31. doi: 10.1289/ehp.10383.Aremu DA, Madejczyk MS, Ballatori N. N-acetylcysteine as a potential antidote and biomonitoring agent of methylmercury exposure. Environ Health Perspect. 2008;116(1):26– 31. doi: 10.1289/ehp.10383.Wang X, Svedin P, Nie C, et al. N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury. Ann Neurol. 2007;61(3):263–271. doi: 10.1002/ana.21066.Wang X, Svedin P, Nie C, et al. N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury. Ann Neurol. 2007;61(3):263–271. doi: 10.1002/ana.21066.Jenkins DD, Wiest DB, Mulvihill DM, et al. Fetal and neonatal effects of n- acetylcysteine when used for neuroprotection in maternal chorioamnionitis. J Pediatr. 2016;168:67–76.e6. doi: 10.1016/j.jpeds.2015.09.076.Jenkins DD, Wiest DB, Mulvihill DM, et al. Fetal and neonatal effects of n- acetylcysteine when used for neuroprotection in maternal chorioamnionitis. J Pediatr. 2016;168:67–76.e6. doi: 10.1016/j.jpeds.2015.09.076.Marzocchi B, Perrone S, Paffetti P, et al. Nonprotein-bound iron and plasma protein oxidative stress at birth. Pediatr Res. 2005;58(6):1295–1299. doi: 10.1203/01.pdr.0000183658.17854.28.Marzocchi B, Perrone S, Paffetti P, et al. Nonprotein-bound iron and plasma protein oxidative stress at birth. Pediatr Res. 2005;58(6):1295–1299. doi: 10.1203/01.pdr.0000183658.17854.28.Wayenberg JL, Ransy V, Vermeylen D, et al. Nitrated plasma albumin as a marker of nitrative stress and neonatal encephalopathy in perinatal asphyxia. Free Radic Biol Med. 2009;47(7): 975–982. doi: 10.1016/j.freeradbiomed.2009.07.003.Wayenberg JL, Ransy V, Vermeylen D, et al. Nitrated plasma albumin as a marker of nitrative stress and neonatal encephalopathy in perinatal asphyxia. Free Radic Biol Med. 2009;47(7): 975–982. doi: 10.1016/j.freeradbiomed.2009.07.003.Liu Y, Belayev L, Zhao W, et al. Neuroprotective effect of treatment with human albumin in permanent focal cerebral ischemia: histopathology and cortical perfusion studies. Eur J Pharmacol. 2001;428(2):193–201. doi: 10.1016/s0014-2999(01)01255-9.Liu Y, Belayev L, Zhao W, et al. Neuroprotective effect of treatment with human albumin in permanent focal cerebral ischemia: histopathology and cortical perfusion studies. Eur J Pharmacol. 2001;428(2):193–201. doi: 10.1016/s0014-2999(01)01255-9.Ginsberg MD, Hill MD, Palesch YY, et al. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke I: Physiological responses and safety results. Stroke. 2006;37(8):2100–2106. doi: 10.1161/01.str.0000231388.72646.05.Ginsberg MD, Hill MD, Palesch YY, et al. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke I: Physiological responses and safety results. Stroke. 2006;37(8):2100–2106. doi: 10.1161/01.str.0000231388.72646.05.van Velthoven CT, Heijnen CJ, van Bel F, Kavelaars А. Osteopontin enhances endogenous repair after neonatal hypoxicischemic brain injury. Stroke. 2011;42(8):2294– 2301. doi: 10.1161/strokeaha.110.608315.van Velthoven CT, Heijnen CJ, van Bel F, Kavelaars А. Osteopontin enhances endogenous repair after neonatal hypoxicischemic brain injury. Stroke. 2011;42(8):2294– 2301. doi: 10.1161/strokeaha.110.608315.Chen W, Ma Q, Suzuki H, et al. Osteopontin reduced hypoxiaischemia neonatal brain injury by suppression of apoptosis in a rat pup model. Stroke. 2011;42(3):764–769. doi: 10.1161/strokeaha.110.599118.Chen W, Ma Q, Suzuki H, et al. Osteopontin reduced hypoxiaischemia neonatal brain injury by suppression of apoptosis in a rat pup model. Stroke. 2011;42(3):764–769. doi: 10.1161/strokeaha.110.599118.Albertsson AM, Zhang X, Leavenworth J, et al. The effect of osteopontin and osteopontin-derived peptides on preterm brain injury. J Neuroinflammation. 2014;11:197. doi: 10.1186/s12974-014-0197-0.Albertsson AM, Zhang X, Leavenworth J, et al. The effect of osteopontin and osteopontin-derived peptides on preterm brain injury. J Neuroinflammation. 2014;11:197. doi: 10.1186/s12974-014-0197-0.Bonestroo HJ, Nijboer CH, van Velthoven CT, et al. The neonatal brain is not protected by osteopontin peptide treatment after hypoxia-ischemia. Dev Neurosci. 2015;37(2):142– 152. doi: 10.1159/000369093.Bonestroo HJ, Nijboer CH, van Velthoven CT, et al. The neonatal brain is not protected by osteopontin peptide treatment after hypoxia-ischemia. Dev Neurosci. 2015;37(2):142– 152. doi: 10.1159/000369093.Fathali N, Khatibi NH, Ostrowski RP, Zhang JH. The evolving landscape of neuroinflammation after neonatal hypoxia-ischemia. In: Zhang J, Colohan A, editors. Intracerebral hemorrhage research. Acta Neurochirurgica Supplementum. V. 111. Vienna: Springer Vienna; 2011. p. 93–100. doi: 10.1007/978-3-7091-0693-8_15.Fathali N, Khatibi NH, Ostrowski RP, Zhang JH. The evolving landscape of neuroinflammation after neonatal hypoxia-ischemia. In: Zhang J, Colohan A, editors. Intracerebral hemorrhage research. Acta Neurochirurgica Supplementum. V. 111. Vienna: Springer Vienna; 2011. p. 93–100. doi: 10.1007/978-3-7091-0693-8_15.Veldhuis WB, Floris S, van der Meide PH, et al. Interferonbeta prevents cytokine- induced neutrophil infiltration and attenuates blood-brain barrier disruption. J Cereb Blood Flow Metab. 2003;23(9): 1060–1069. doi: 10.1097/01.wcb.0000080701.47016.24.Veldhuis WB, Floris S, van der Meide PH, et al. Interferonbeta prevents cytokine- induced neutrophil infiltration and attenuates blood-brain barrier disruption. J Cereb Blood Flow Metab. 2003;23(9): 1060–1069. doi: 10.1097/01.wcb.0000080701.47016.24.Inacio AR, Liu Y, Clausen BH, et al. Endogenous IFN- signaling exerts anti-inflammatory actions in experimentally induced focal cerebral ischemia. J Neuroinflammation. 2015;12:211. doi: 10.1186/s12974-015-0427-0.Inacio AR, Liu Y, Clausen BH, et al. Endogenous IFN- signaling exerts anti-inflammatory actions in experimentally induced focal cerebral ischemia. J Neuroinflammation. 2015;12:211. doi: 10.1186/s12974-015-0427-0.Maier CM, Yu F, Nishi T, et al. Interferon-beta fails to protect in a model of transient focal stroke. Stroke. 2006;37(4):1116–1119. doi: 10.1161/01.str.0000208214.46093.d5.Maier CM, Yu F, Nishi T, et al. Interferon-beta fails to protect in a model of transient focal stroke. Stroke. 2006;37(4):1116–1119. doi: 10.1161/01.str.0000208214.46093.d5.Bogoyevitch MA, Boehm I, Oakley A, et al. Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. Biochim Biophys Acta. 2004;1697(1– 2):89–101. doi: 10.1016/j.bbapap.2003.11.016.Bogoyevitch MA, Boehm I, Oakley A, et al. Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. Biochim Biophys Acta. 2004;1697(1– 2):89–101. doi: 10.1016/j.bbapap.2003.11.016.Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene. 2008;27(48):6245–6251. doi: 10.1038/onc.2008.301.Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene. 2008;27(48):6245–6251. doi: 10.1038/onc.2008.301.Nijboer CH, Heijnen CJ, Groenendaal F, et al. Alternate pathways preserve tumor necrosis factor-alpha production after nuclear factor-kappa B inhibition in neonatal cerebral hypoxiaischemia. Stroke. 2009;40(10):3362–3368. doi: 10.1161/strokeaha.109.560250.Nijboer CH, Heijnen CJ, Groenendaal F, et al. Alternate pathways preserve tumor necrosis factor-alpha production after nuclear factor-kappa B inhibition in neonatal cerebral hypoxiaischemia. Stroke. 2009;40(10):3362–3368. doi: 10.1161/strokeaha.109.560250.Nijboer CH, Bonestroo HJ, Zijlstra J, et al. Mitochondrial JNK phosphorylation as a novel therapeutic target to inhibit neuroinflammation and apoptosis after neonatal ischemic brain damage. Neurobiol Dis. 2013;54:432–444. doi: 10.1016/j.nbd.2013.01.017.Nijboer CH, Bonestroo HJ, Zijlstra J, et al. Mitochondrial JNK phosphorylation as a novel therapeutic target to inhibit neuroinflammation and apoptosis after neonatal ischemic brain damage. Neurobiol Dis. 2013;54:432–444. doi: 10.1016/j.nbd.2013.01.017.Noor JI, Ikeda T, Mishima K, et al. Short-term administration of a new free radical scavenger, Edaravone, is more effective than its long-term administration for the treatment of neonatal hypoxicischemic encephalopathy. Stroke. 2005;36(11):2468–2474. doi: 10.1161/01.str.0000185653.49740.c6.Noor JI, Ikeda T, Mishima K, et al. Short-term administration of a new free radical scavenger, Edaravone, is more effective than its long-term administration for the treatment of neonatal hypoxicischemic encephalopathy. Stroke. 2005;36(11):2468–2474. doi: 10.1161/01.str.0000185653.49740.c6.Takizawa Y, Miyazawa T, Nonoyama S, et al. Edaravone inhibits DNA peroxidation and neuronal cell death in neonatal hypoxicischemic encephalopathy model rat. Pediatr Res. 2009;65(6): 636–641. doi: 10.1203/pdr.0b013e3181a16a9f.Takizawa Y, Miyazawa T, Nonoyama S, et al. Edaravone inhibits DNA peroxidation and neuronal cell death in neonatal hypoxicischemic encephalopathy model rat. Pediatr Res. 2009;65(6): 636–641. doi: 10.1203/pdr.0b013e3181a16a9f.Noor JI, Ueda Y, Ikeda T, Ikenoue T. Edaravone inhibits lipid peroxidation in neonatal hypoxic-ischemic rats: an in vivo microdialysis study. Neurosci Lett. 2007;414(1):5–9. doi: 10.1016/j.neulet.2006.10.024.Noor JI, Ueda Y, Ikeda T, Ikenoue T. Edaravone inhibits lipid peroxidation in neonatal hypoxic-ischemic rats: an in vivo microdialysis study. Neurosci Lett. 2007;414(1):5–9. doi: 10.1016/j.neulet.2006.10.024.Ni X, Yang ZJ, Carter EL, et al. Striatal neuroprotection from neonatal hypoxia-ischemia in piglets by antioxidant treatment with EUK-134 or Edaravone. Dev Neurosci. 2011;33(3– 4):299–311. doi: 10.1159/000327243.Ni X, Yang ZJ, Carter EL, et al. Striatal neuroprotection from neonatal hypoxia-ischemia in piglets by antioxidant treatment with EUK-134 or Edaravone. Dev Neurosci. 2011;33(3– 4):299–311. doi: 10.1159/000327243.

The authors declare that there are no conflicts of interest present.