Neonatal hypoxic-ischemic encephalopathy (HIE) is a disease caused by insufficient blood supply in the brain in newborns during the perinatal period. Severe HIE leads to patient death, and patients with mild HIE are at increased risk of cognitive deficits and behavioral abnormalities. The NMDA receptor is an important excitatory receptor in the central nervous system, and in adult hypoxic-ischemic injury both subtypes of the NMDA receptor play important but distinct roles. The GluN2A-containing NMDA receptor (GluN2A-NMDAR) could activate neuronal protective signaling pathway, while the GluN2B-NMDAR subtype is coupled to the apoptosis-inducing signaling pathway and leads to neuronal death. However, the expression level of GluN2B is higher in newborns than in adults, while the expression of GluN2A is lower. Therefore, it is not clear whether the roles of different NMDA receptor subtypes in HIE are consistent with those in adults. We investigated this issue in this study and found that in HIE, GluN2B plays a protective role by mediating the protective pathway through binding with PSD95, which is quite different to that in adults. The results of this study provided new theoretical support for the clinical treatment of neonatal hypoxic ischemia.

Department of Physiology School of Basic Medicine Kunming Medical University Kunming Yunnan Province China

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Arteaga O, Revuelta M, Urigüen L, Álvarez A, Montalvo H, Hilario E. Pretreatment with resveratrol prevents neuronal injury and cognitive deficits induced by perinatal hypoxia-ischemia in rats. PLoS One. 2015;10:e0142424. doi: 10.1371/journal.pone.0142424. PubMed DOI PMC

Millar LJ, Shi L, Hoerder-Suabedissen A, Molnár Z. Neonatal hypoxia ischaemia: Mechanisms, models, and therapeutic challenges. Front Cell Neurosci. 2017;11:78. doi: 10.3389/fncel.2017.00078. PubMed DOI PMC

Perlman JM. Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy. Pediatrics. 2006;117:S28–S33. doi: 10.1542/peds.2005-0620E. PubMed DOI

Riljak V, Lastuvka Z, Myslivecek J, Borbelyova V, Otahal J. Early Postnatal hypoxia induces behavioral deficits but not morphological damage in the hippocampus in adolescent rat. Physiol Res. 2020;69:165–179. doi: 10.33549/physiolres.934234. PubMed DOI PMC

Piesova M, Mach M. Impact of Perinatal Hypoxia on the Developing Brain. Physiol Res. 2020;69:199–213. doi: 10.33549/physiolres.934198. PubMed DOI PMC

Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14:383–400. doi: 10.1038/nrn3504. PubMed DOI

Forrest D, Yuzaki M, Soares HD, Ng L, Luk DC, Sheng M, Stewart CL, et al. Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron. 1994;13:325–338. doi: 10.1016/0896-6273(94)90350-6. PubMed DOI

Chesnoy-Marchais D, Barthe JY. Voltage-dependent block of NMDA responses by 5-HT agonists in ventral spinal cord neurons. Br J Pharmacol. 1996;117:133–141. doi: 10.1111/j.1476-5381.1996.tb15165.x. PubMed DOI PMC

Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurons. Nature. 1984;307:462–465. doi: 10.1038/307462a0. PubMed DOI

Wu QJ, Tymianski M. Targeting nmda receptors in stroke: New hope in neuroprotection. Mol Brain. 2018;11:15. doi: 10.1186/s13041-018-0357-8. PubMed DOI PMC

Wu Y, Chen C, Yang Q, Jiao M, Qiu S. Endocytosis of GluN2B-containing NMDA receptor mediates NMDA-induced excitotoxicity. Mol Pain. 2017;13:1744806917701921. doi: 10.1177/1744806917701921. PubMed DOI PMC

Wroge CM, Hogins J, Eisenman L, Mennerick S. Synaptic NMDA receptors mediate hypoxic excitotoxic death. J Neurosci. 2012;32:6732–6742. doi: 10.1523/JNEUROSCI.6371-11.2012. PubMed DOI PMC

Knox R, Zhao C, Miguel-Perez D, Wang S, Yuan J, Ferriero D, Jiang X. Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia-ischemia in mice with neuronal Fyn overexpression. Neurobiol Dis. 2013;51:113–119. doi: 10.1016/j.nbd.2012.10.024. PubMed DOI PMC

Hardingham GE. Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem Soc Trans. 2009;37:1147–1160. doi: 10.1042/BST0371147. PubMed DOI PMC

Hetman M, Kharebava G. Survival signaling pathways activated by NMDA receptors. Curr Top Med Chem. 2006;6:787–799. doi: 10.2174/156802606777057553. PubMed DOI

Zhou X, Ding Q, Chen Z, Yun H, Wang H. Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic N-methyl-D-aspartate receptor function and neuronal excitotoxicity. J Biol Chem. 2013;288:24151–24159. doi: 10.1074/jbc.M113.482000. PubMed DOI PMC

Chen M, Lu TJ, Chen XJ, Zhou Y, Chen Q, Feng XY, Xu L, Duan WH, Xiong ZQ. Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke. 2008;39:3042–3048. doi: 10.1161/STROKEAHA.108.521898. PubMed DOI

Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci. 2007;27:2846–2857. doi: 10.1523/JNEUROSCI.0116-07.2007. PubMed DOI PMC

Martel MA, Wyllie DJA, Hardingham GE. In developing hippocampal neurons, NR2B-containing N-methyl-d-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death. Neuroscience. 2009;158:334–343. doi: 10.1016/j.neuroscience.2008.01.080. PubMed DOI PMC

Rice JE, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol. 1981;9:131–141. doi: 10.1002/ana.410090206. PubMed DOI

Yuan Y, Zha H, Rangarajan P, Ling EA, Wu C. Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia. BMC Neurosci. 2014;15:125. doi: 10.1186/s12868-014-0125-3. PubMed DOI PMC

Chen M, Hou Y, Lin D. Polydatin protects bone marrow stem cells against oxidative injury: Involvement of Nrf 2/ARE pathways. Stem Cells Int. 2016;2016:9394150. doi: 10.1155/2016/9394150. PubMed DOI PMC

Samakova A, Gazova A, Sabova N, Valaskova S, Jurikova M, Kyselovic J. The PI3k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia. Physiol Res. 2019;68(Suppl 2):S131–S138. doi: 10.33549/physiolres.934345. PubMed DOI

Gascón S, Sobrado M, Roda JM, Rodríguez-Pe~a A, Díaz-Guerra M. Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95. Mol Psychiatry. 2008;13:99–114. doi: 10.1038/sj.mp.4002017. PubMed DOI

Takagi N, Logan R, Teves L, Wallace MC, Gurd JW. Altered interaction between PSD-95 and the NMDA receptor following transient global ischemia. J Neurochem. 2000;74:169–178. doi: 10.1046/j.1471-4159.2000.0740169.x. PubMed DOI

Teves LM, Cui H, Tymianski M. Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species. J Cereb Blood Flow Metab. 2016;36:555–561. doi: 10.1177/0271678X15612099. PubMed DOI PMC

Edman S, McKay S, MacDonald LJ, Samadi M, Liversey MR, Hardingham GE, Wyllie DJA. TCN 201 selectively blocks GluN2A-containing NMDARs in a GluN1 co-agonist dependent but non-competitive manner. Neuropharmacology. 2012;63:441–449. doi: 10.1016/j.neuropharm.2012.04.027. PubMed DOI PMC

Hildebrand ME, Pitcher GM, Harding EK, Li H, Beggs S, Salter MW. GluN2B and GluN2D NMDARs dominate synaptic responses in the adult spinal cord. Sci Rep. 2014;4:4094. doi: 10.1038/srep04094. PubMed DOI PMC

Doğan A, Rao AM, Baskaya MK, Rao VL, Rastl J, Donaldson D, Dempsey RJ. Effects of ifenprodil, a polyamine site NMDA receptor antagonist, on reperfusion injury after transient focal cerebral ischemia. J Neurosurg. 1997;87:921–926. doi: 10.3171/jns.1997.87.6.0921. PubMed DOI

Mishra V, Verma R, Singh N, Raghubir R. The neuroprotective effects of NMDAR antagonist, ifenprodil and ASIC1a inhibitor, flurbiprofen on post-ischemic cerebral injury. Brain Res. 2011;1389:152–160. doi: 10.1016/j.brainres.2011.03.011. PubMed DOI

Landucci E, Filippi L, Gerace E, Catarzi S, Guerrini R, Pellegrini-Giampietro DE. Neuroprotective effects of topiramate and memantine in combination with hypothermia in hypoxic-ischemic brain injury in vitro and in vivo. Neurosci Lett. 2018;668:103–107. doi: 10.1016/j.neulet.2018.01.023. PubMed DOI

Amico-Ruvio SA, Paganelli MA, Myers JM, Popescu GK. Ifenprodil effects on GluN2B-containing glutamate receptors. Mol Pharmacol. 2012;82:1074–1081. doi: 10.1124/mol.112.078998. PubMed DOI PMC

Cui H, Hayashi A, Sun HS, Belmares MP, Cobey C, Phan T, Schweizer J, et al. PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J Neurosci. 2007;27:9901–9915. doi: 10.1523/JNEUROSCI.1464-07.2007. PubMed DOI PMC