Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial dysfunction in perinatal asphyxia: role in pathogenesis and potential therapeutic interventions

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Perinatal asphyxia (PA)-induced brain injury may present as hypoxic-ischemic encephalopathy in the neonatal period, and long-term sequelae such as spastic motor deficits, intellectual disability, seizure disorders and learning disabilities. The brain injury is secondary to both the hypoxic-ischemic event and oxygenation–reperfusion following resuscitation. Following PA, a time-dependent progression of neuronal insult takes place in terms of transition of cell death from necrosis to apoptosis. This transition is the result of time-dependent progression of pathomechanisms which involve excitotoxicity, oxidative stress, and ultimately mitochondrial dysfunction in developing brain. More precisely mitochondrial respiration is suppressed and calcium signalling is dysregulated. Consequently, Bax-dependent mitochondrial permeabilization occurs leading to release of cytochrome c and activation of caspases leading to transition of cell death in developing brain. The therapeutic window lies within this transition process. At present, therapeutic hypothermia (TH) is the only clinical treatment available for treating moderate as well as severe asphyxia in new-born as it attenuates secondary loss of high-energy phosphates (ATP) (Solevåg et al. in Free Radic Biol Med 142:113–122, 2019; Gunn et al. in Pediatr Res 81:202–209, 2017), improving both short- and long-term outcomes. Mitoprotective therapies can offer a new avenue of intervention alone or in combination with therapeutic hypothermia for babies with birth asphyxia. This review will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after PA, as a means of identifying new avenues of therapeutic intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Solevåg AL, Schmölzer GM, Cheung PY (2019) Novel interventions to reduce oxidative-stress related brain injury in neonatal asphyxia. Free Radic Biol Med 142:113–122. https://doi.org/10.1016/j.freeradbiomed.2019.04.028

    Article  CAS  PubMed  Google Scholar 

  2. Lawn JE, Kerber K, Enweronu-Laryea C, Cousens S (2010) 3.6 Million neonatal deaths—what is progressing and what is not? Semin Perinatol 34:371–386. https://doi.org/10.1053/j.semperi.2010.09.011

    Article  PubMed  Google Scholar 

  3. https://www.indiaspend.com/indias-under-5-mortality-now-matches-global-average-but-bangladesh-nepal-do-better/. Accessed 11 July 2021

  4. Ebenezer ED, Londhe V, Rathore S, Benjamin S, Ross B, Jeyaseelan L, Mathews JE (2019) Peripartum interventions resulting in reduced perinatal mortality rates, and birth asphyxia rates, over 18 years in a tertiary centre in South India: a retrospective study. BJOG 126(Suppl 4):21–26. https://doi.org/10.1111/1471-0528.15848

    Article  PubMed  Google Scholar 

  5. Fattuoni C, Palmas F, Noto A, Fanos V, Barberini L (2015) Perinatal asphyxia: a review from a metabolomics perspective. Molecules (Basel, Switzerland) 20:7000–7016. https://doi.org/10.3390/molecules20047000

    Article  CAS  Google Scholar 

  6. Rainaldi MA, Perlman JM (2016) Pathophysiology of birth asphyxia. Clin Perinatol 43:409–422. https://doi.org/10.1016/j.clp.2016.04.002

    Article  PubMed  Google Scholar 

  7. Baburamani A, Ek CJ, Walker DW, Castillo-Melendez M (2012) Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair? Front Physiol 3:424

    Article  Google Scholar 

  8. Qin X, Cheng J, Zhong Y, Mahgoub OK, Akter F, Fan Y, Aldughaim M, Xie Q, Qin L, Gu L (2019) Mechanism and treatment related to oxidative stress in neonatal hypoxic-ischemic encephalopathy. Front Mol Neurosci 12:88

    Article  CAS  Google Scholar 

  9. Lafemina MJ, Sheldon RA, Ferriero DM (2006) Acute hypoxia-ischemia results in hydrogen peroxide accumulation in neonatal but not adult mouse brain. Pediatr Res 59:680–683. https://doi.org/10.1203/01.pdr.0000214891.35363.6a

    Article  CAS  PubMed  Google Scholar 

  10. Samaiya PK, Narayan G, Kumar A, Krishnamurthy S (2016) Neonatal anoxia leads to time dependent progression of mitochondrial linked apoptosis in rat cortex and associated long term sensorimotor deficits. J Dev Neurosci 52:55–65. https://doi.org/10.1016/j.ijdevneu.2016.05.005

    Article  CAS  Google Scholar 

  11. Lai M-C, Yang S-N (2011) Perinatal hypoxic-ischemic encephalopathy. BioMed Res Int. https://doi.org/10.1155/2011/609813

    Article  Google Scholar 

  12. Wassink G, Gunn ER, Drury PP, Bennet L, Gunn AJ (2014) The mechanisms and treatment of asphyxial encephalopathy. Front Neurosci 8:40. https://doi.org/10.3389/fnins.2014.00040

    Article  PubMed  PubMed Central  Google Scholar 

  13. Oorschot DE, Sizemore RJ, Amer AR (2020) Treatment of neonatal hypoxic-ischemic encephalopathy with erythropoietin alone, and erythropoietin combined with hypothermia: history, current status, and future research. Int J Mol Sci. https://doi.org/10.3390/ijms21041487

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee HC, Wei YH (2012) Mitochondria and aging. Adv Exp Med Biol 942:311–327. https://doi.org/10.1007/978-94-007-2869-1_14

    Article  CAS  PubMed  Google Scholar 

  15. Samaiya PK, Krishnamurthy S (2015) Characterization of mitochondrial bioenergetics in neonatal anoxic model of rats. J Bioenerg Biomembr 47:217–222

    Article  CAS  Google Scholar 

  16. Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407. https://doi.org/10.1146/annurev.genet.39.110304.095751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766

    Article  CAS  Google Scholar 

  18. Pregnolato S, Chakkarapani E, Isles AR, Luyt K (2019) Glutamate transport and preterm brain injury. Front Physiol 10:417. https://doi.org/10.3389/fphys.2019.00417

    Article  PubMed  PubMed Central  Google Scholar 

  19. Johnston MV (2005) Excitotoxicity in perinatal brain injury. Brain Pathol 15:234–240. https://doi.org/10.1111/j.1750-3639.2005.tb00526.x

    Article  CAS  PubMed  Google Scholar 

  20. Samaiya PK, Narayan G, Kumar A, Krishnamurthy S (2017) Tempol (4 hydroxy-tempo) inhibits anoxia-induced progression of mitochondrial dysfunction and associated neurobehavioral impairment in neonatal rats. J Neurolog Sci 375:58–67. https://doi.org/10.1016/j.jns.2017.01.021

    Article  CAS  Google Scholar 

  21. Samaiya PK, Narayan G, Kumar A, Krishnamurthy S (2018) 2,4 Dinitrophenol attenuates mitochondrial dysfunction and improves neurobehavioral outcomes postanoxia in neonatal rats. Neurotox Res. https://doi.org/10.1007/s12640-018-9873-7

    Article  PubMed  Google Scholar 

  22. Adam-Vizi V, Starkov AA (2010) Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis 20(Suppl 2):S413–S426. https://doi.org/10.3233/jad-2010-100465

    Article  PubMed  PubMed Central  Google Scholar 

  23. Borutaite V, Toleikis A, Brown GC (2013) In the eye of the storm: mitochondrial damage during heart and brain ischaemia. FEBS J 280:4999–5014. https://doi.org/10.1111/febs.12353

    Article  CAS  PubMed  Google Scholar 

  24. Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495

    Article  CAS  Google Scholar 

  25. Wong R, Steenbergen C, Murphy E (2012) Mitochondrial permeability transition pore and calcium handling. Methods Mol Biol 810:235–242. https://doi.org/10.1007/978-1-61779-382-0_15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hussain Y, Jain SK, Samaiya PK (2018) Short-term westernized (HFFD) diet fed in adolescent rats: Effect on glucose homeostasis, hippocampal insulin signaling, apoptosis and related cognitive and recognition memory function. Behav Brain Res 361:113–121. https://doi.org/10.1016/j.bbr.2018.12.042

    Article  CAS  PubMed  Google Scholar 

  27. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59

    Article  CAS  Google Scholar 

  28. Dewson G (2015) Investigating bax subcellular localization and membrane integration. Cold Spring Harb Protoc. https://doi.org/10.1101/pdb.prot086447

    Article  PubMed  Google Scholar 

  29. Infante SK, Oberhauser AF, Perez-Polo JR (2013) Bax phosphorylation association with nucleus and oligomerization after neonatal hypoxia-ischemia. J Neurosci Res 91:1152–1164. https://doi.org/10.1002/jnr.23224

    Article  CAS  PubMed  Google Scholar 

  30. Monaco G, Decrock E, Arbel N, van Vliet AR, La Rovere RM, De Smedt H, Parys JB, Agostinis P, Leybaert L, Shoshan-Barmatz V, Bultynck G (2015) The BH4 domain of anti-apoptotic Bcl-XL, but not that of the related Bcl-2, limits the voltage-dependent anion channel 1 (VDAC1)-mediated transfer of pro-apoptotic Ca2+ signals to mitochondria. J Biol Chem 290:9150–9161. https://doi.org/10.1074/jbc.M114.622514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ow Y-LP, Green DR, Hao Z, Mak TW (2008) Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol 9:532–542

    Article  CAS  Google Scholar 

  32. Degli Esposti M, Ferry G, Masdehors P, Boutin JA, Hickman JA, Dive C (2003) Post-translational modification of Bid has differential effects on its susceptibility to cleavage by caspase 8 or caspase 3. J Biol Chem 278:15749–15757. https://doi.org/10.1074/jbc.M209208200

    Article  CAS  PubMed  Google Scholar 

  33. Roucou X, Antonsson B, Martinou JC (2001) Involvement of mitochondria in apoptosis. Cardiol Clin 19:45–55. https://doi.org/10.1016/s0733-8651(05)70194-6

    Article  CAS  PubMed  Google Scholar 

  34. Antonsson B (2001) Bax and other pro-apoptotic Bcl-2 family “killer-proteins” and their victim the mitochondrion. Cell Tissue Res 306:347–361. https://doi.org/10.1007/s00441-001-0472-0

    Article  CAS  PubMed  Google Scholar 

  35. Iriyama T, Kamei Y, Kozuma S, Taketani Y (2009) Bax-inhibiting peptide protects glutamate-induced cerebellar granule cell death by blocking Bax translocation. Neurosci Lett 451:11–15. https://doi.org/10.1016/j.neulet.2008.12.021

    Article  CAS  PubMed  Google Scholar 

  36. Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18:157–164. https://doi.org/10.1016/j.tcb.2008.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tait SWG, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632

    Article  CAS  Google Scholar 

  38. Wang X, Carlsson Y, Basso E, Zhu C, Rousset CI, Rasola A, Johansson BR, Blomgren K, Mallard C, Bernardi P, Forte MA, Hagberg H (2009) Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury. J Neurosci 29:2588–2596. https://doi.org/10.1523/jneurosci.5832-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang X, Han W, Du X, Zhu C, Carlsson Y, Mallard C, Jacotot E, Hagberg H (2010) Neuroprotective effect of Bax-inhibiting peptide on neonatal brain injury. Stroke 41:2050–2055. https://doi.org/10.1161/strokeaha.110.589051

    Article  CAS  PubMed  Google Scholar 

  40. Northington FJ, Ferriero DM, Flock DL, Martin LJ (2001) Delayed neurodegeneration in neonatal rat thalamus after hypoxia-ischemia is apoptosis. J Neurosci 21:1931–1938. https://doi.org/10.1523/jneurosci.21-06-01931.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhu C, Wang X, Xu F, Bahr BA, Shibata M, Uchiyama Y, Hagberg H, Blomgren K (2005) The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia. Cell Death Differ 12:162–176. https://doi.org/10.1038/sj.cdd.4401545

    Article  CAS  PubMed  Google Scholar 

  42. Chowdhury I, Tharakan B, Bhat GK (2008) Caspases—an update. Compar Biochem Physiol B Biochem Mol Biol 151:10–27. https://doi.org/10.1016/j.cbpb.2008.05.010

    Article  CAS  Google Scholar 

  43. Kuranaga E, Miura M (2007) Nonapoptotic functions of caspases: caspases as regulatory molecules for immunity and cell-fate determination. Trends Cell Biol 17:135–144. https://doi.org/10.1016/j.tcb.2007.01.001

    Article  CAS  PubMed  Google Scholar 

  44. Szydlowska K, Tymianski M (2010) Calcium, ischemia and excitotoxicity. Cell Calcium 47:122–129. https://doi.org/10.1016/j.ceca.2010.01.003

    Article  CAS  PubMed  Google Scholar 

  45. Edwards AD, Yue X, Cox P, Hope PL, Azzopardi DV, Squier MV, Mehmet H (1997) Apoptosis in the brains of infants suffering intrauterine cerebral injury. Pediatr Res 42:684–689. https://doi.org/10.1203/00006450-199711000-00022

    Article  CAS  PubMed  Google Scholar 

  46. Fleiss B, Gressens P (2012) Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy? Lancet Neurol 11:556–566. https://doi.org/10.1016/s1474-4422(12)70058-3

    Article  Google Scholar 

  47. Park E, Velumian AA, Fehlings MG (2004) The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 21:754–774. https://doi.org/10.1089/0897715041269641

    Article  PubMed  Google Scholar 

  48. Dell’Anna E, Chen Y, Engidawork E, Andersson K, Lubec G, Luthman J, Herrera-Marschitz M (1997) Delayed neuronal death following perinatal asphyxia in rat. Exp Brain Res 115:105–115

    Article  Google Scholar 

  49. Mehmet H, Yue X, Squier MV, Lorek A, Cady E, Penrice J, Sarraf C, Wylezinska M, Kirkbride V, Cooper C et al (1994) Increased apoptosis in the cingulate sulcus of newborn piglets following transient hypoxia-ischaemia is related to the degree of high energy phosphate depletion during the insult. Neurosci Lett 181:121–125. https://doi.org/10.1016/0304-3940(94)90574-6

    Article  CAS  PubMed  Google Scholar 

  50. Northington FJ, Chavez-Valdez R, Martin LJ (2011) Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol 69:743–758. https://doi.org/10.1002/ana.22419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Horng LY, Hsu PL, Chen LW, Tseng WZ, Hsu KT, Wu CL, Wu RT (2015) Activating mitochondrial function and haemoglobin expression with EH-201, an inducer of erythropoietin in neuronal cells, reverses memory impairment. Br J Pharmacol 172:4741–4756. https://doi.org/10.1111/bph.13248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Aridas JDS, Yawno T, Sutherland AE, Nitsos I, Ditchfield M, Wong FY, Hunt RW, Fahey MC, Malhotra A, Wallace EM, Jenkin G, Miller SL (2018) Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs. J Pineal Res 64:e12479–e12479. https://doi.org/10.1111/jpi.12479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Colella M, Biran V, Baud O (2016) Melatonin and the newborn brain. Early Hum Dev 102:1–3. https://doi.org/10.1016/j.earlhumdev.2016.09.001

    Article  CAS  PubMed  Google Scholar 

  54. García S, Martín Giménez VM, Mocayar Marón FJ, Reiter RJ, Manucha W (2020) Melatonin and cannabinoids: mitochondrial-targeted molecules that may reduce inflammaging in neurodegenerative diseases. Histol Histopathol. https://doi.org/10.14670/hh-18-212

    Article  PubMed  Google Scholar 

  55. Wongprayoon P, Govitrapong P (2017) Melatonin as a mitochondrial protector in neurodegenerative diseases. Cell Mol Life Sci 74:3999–4014. https://doi.org/10.1007/s00018-017-2614-x

    Article  CAS  PubMed  Google Scholar 

  56. Malhotra A, Castillo-Melendez M, Allison BJ, Sutherland AE, Nitsos I, Pham Y, McDonald CA, Fahey MC, Polglase GR, Jenkin G, Miller SL (2020) Neurovascular effects of umbilical cord blood-derived stem cells in growth-restricted newborn lambs: UCBCs for perinatal brain injury. Stem Cell Res Ther 11:17. https://doi.org/10.1186/s13287-019-1526-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hsu Y-C, Wu Y-T, Yu T-H, Wei Y-H (2016) Mitochondria in mesenchymal stem cell biology and cell therapy: from cellular differentiation to mitochondrial transfer. Elsevier, Berlin, pp 119–131

    Google Scholar 

  58. Min K, Song J, Kang JY, Ko J, Ryu JS, Kang MS, Jang SJ, Kim SH, Oh D, Kim MK (2013) Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial. Stem Cell 31:581–591

    Article  CAS  Google Scholar 

  59. Lowe DW, Fraser JL, Rollins LG, Bentzley J, Nie X, Martin R, Singh I, Jenkins D (2017) Vitamin D improves functional outcomes in neonatal hypoxic ischemic male rats treated with N-acetylcysteine and hypothermia. Neuropharmacology 123:186–200. https://doi.org/10.1016/j.neuropharm.2017.06.004

    Article  CAS  PubMed  Google Scholar 

  60. Nie X, Lowe DW, Rollins LG, Bentzley J, Fraser JL, Martin R, Singh I, Jenkins D (2016) Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia. Neurosci Res 108:24–33. https://doi.org/10.1016/j.neures.2016.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Adams LE, Moss HG, Lowe DW, Brown T, Wiest DB, Hollis BW, Singh I, Jenkins DD (2021) NAC and vitamin D restore CNS glutathione in endotoxin-sensitized neonatal hypoxic-ischemic rats. Antioxidant (Basel). https://doi.org/10.3390/antiox10030489

    Article  Google Scholar 

  62. Bhat MA, Charoo BA, Bhat JI, Ahmad SM, Ali SW, Mufti MU (2009) Magnesium sulfate in severe perinatal asphyxia: a randomized, placebo-controlled trial. Pediatr 123:e764–e769. https://doi.org/10.1542/peds.2007-3642

    Article  Google Scholar 

  63. Jameson RA, Bernstein HB (2019) Magnesium sulfate and novel therapies to promote neuroprotection. Clin Perinatol 46:187–201. https://doi.org/10.1016/j.clp.2019.02.008

    Article  PubMed  Google Scholar 

  64. Kaptanoglu E, Beskonakli E, Okutan O, Surucu HS, Taskin Y (2003) Effect of magnesium sulphate in experimental spinal cord injury: evaluation with ultrastructural findings and early clinical results. J Clin Neurosci 10:329–334

    Article  CAS  Google Scholar 

  65. Romero J, Muñiz J, Logica Tornatore T, Holubiec M, González J, Barreto GE, Guelman L, Lillig CH, Blanco E, Capani F (2014) Dual role of astrocytes in perinatal asphyxia injury and neuroprotection. Neurosci lett 565:42–46. https://doi.org/10.1016/j.neulet.2013.10.046

    Article  CAS  PubMed  Google Scholar 

  66. Bye N, Habgood MD, Callaway JK, Malakooti N, Potter A, Kossmann T, Morganti-Kossmann MC (2007) Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol 204:220–233. https://doi.org/10.1016/j.expneurol.2006.10.013

    Article  CAS  PubMed  Google Scholar 

  67. Bylicky MA, Mueller GP, Day RM (2018) Mechanisms of endogenous neuroprotective effects of astrocytes in brain injury. Oxid Med Cell long 2018:6501031–6501031. https://doi.org/10.1155/2018/6501031

    Article  CAS  Google Scholar 

  68. Dai C, Ciccotosto GD, Cappai R, Wang Y, Tang S, Xiao X, Velkov T (2017) Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress. J Antimicrob Chemother 72:1635–1645. https://doi.org/10.1093/jac/dkx037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bellos I, Pandita A, Yachha M (2019) Effectiveness of theophylline administration in neonates with perinatal asphyxia: a meta-analysis. J Matern Fetal Neonatal Med. https://doi.org/10.1080/14767058.2019.1673722

    Article  PubMed  Google Scholar 

  70. Raina A, Pandita A, Harish R, Yachha M, Jamwal A (2016) Treating perinatal asphyxia with theophylline at birth helps to reduce the severity of renal dysfunction in term neonates. Acta Paediatr (Oslo) 105:e448–e451. https://doi.org/10.1111/apa.13469

    Article  CAS  Google Scholar 

  71. Hüttemann M, Nantwi KD, Lee I, Liu J, Mohiuddin S, Petrov T (2010) Theophylline treatment improves mitochondrial function after upper cervical spinal cord hemisection. Exp Neurol 223:523–528. https://doi.org/10.1016/j.expneurol.2010.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Singh LP, Devi TS, Nantwi KD (2012) Theophylline regulates inflammatory and neurotrophic factor signals in functional recovery after C2-hemisection in adult rats. Exp Neurol 238:79–88. https://doi.org/10.1016/j.expneurol.2012.08.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Annink KV, Franz AR, Derks JB, Rudiger M, Fv B, Benders MJNL (2017) Allopurinol: old drug, new indication in neonates? Curr Pharm Des 23:5935–5942. https://doi.org/10.2174/1381612823666170918123307

    Article  CAS  PubMed  Google Scholar 

  74. Maiwald CA, Annink KV, Rüdiger M, Benders MJNL, van Bel F, Allegaert K, Naulaers G, Bassler D, Klebermaß-Schrehof K, Vento M, Guimarães H, Stiris T, Cattarossi L, Metsäranta M, Vanhatalo S, Mazela J, Metsvaht T, Jacobs Y, Franz AR (2019) Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III). BMC Pediatr 19:210–210. https://doi.org/10.1186/s12887-019-1566-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Van Velthoven CT, Kavelaars A, Van Bel F, Heijnen CJ (2010) Repeated mesenchymal stem cell treatment after neonatal hypoxia–ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function. J Neurosci 30:9603–9611

    Article  Google Scholar 

  76. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ (2010) Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun 24:387–393

    Article  Google Scholar 

  77. Donega V, Nijboer CH, Braccioli L, Slaper-Cortenbach I, Kavelaars A, Van Bel F, Heijnen CJ (2014) Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions. PLoS ONE 9:e112339

    Article  Google Scholar 

  78. Tapia-Bustos A, Lespay-Rebolledo C, Vío V, Pérez-Lobos R, Casanova-Ortiz E, Ezquer F, Herrera-Marschitz M, Morales P (2021) Neonatal mesenchymal stem cell treatment improves myelination impaired by global perinatal asphyxia in rats. Int J Mol Sci. https://doi.org/10.3390/ijms22063275

    Article  PubMed  PubMed Central  Google Scholar 

  79. Qin X, Cheng J, Zhong Y, Mahgoub OK, Akter F, Fan Y, Aldughaim M, Xie Q, Qin L, Gu L, Jian Z, Xiong X, Liu R (2019) Mechanism and treatment related to oxidative stress in neonatal hypoxic-ischemic encephalopathy. Front Mol Neurosci 12:88. https://doi.org/10.3389/fnmol.2019.00088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Farfán N, Carril J, Redel M, Zamorano M, Araya M, Monzón E, Alvarado R, Contreras N, Tapia-Bustos A, Quintanilla ME, Ezquer F, Valdés JL, Israel Y, Herrera-Marschitz M, Morales P (2020) Intranasal administration of mesenchymal stem cell secretome reduces hippocampal oxidative stress, neuroinflammation and cell death, improving the behavioral outcome following perinatal asphyxia. Int J Mol Sci. https://doi.org/10.3390/ijms21207800

    Article  PubMed  PubMed Central  Google Scholar 

  81. Korde AS, Pettigrew LC, Craddock SD, Maragos WF (2005) The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia. J Neurochem 94:1676–1684. https://doi.org/10.1111/j.1471-4159.2005.03328.x

    Article  CAS  PubMed  Google Scholar 

  82. Freitas-Correa L, Lourenco MV, Acquarone M, da Costa RFM, Galina A, Rehen SK, Ferreira ST (2013) 2,4-dinitrophenol induces neural differentiation of murine embryonic stem cells. Stem Cell Res 11:1407–1416. https://doi.org/10.1016/j.scr.2013.09.016

    Article  CAS  PubMed  Google Scholar 

  83. Hubbard WB, Harwood CL, Geisler JG, Vekaria HJ, Sullivan PG (2018) Mitochondrial uncoupling prodrug improves tissue sparing, cognitive outcome, and mitochondrial bioenergetics after traumatic brain injury in male mice. J Neurosci Res 96:1677–1688. https://doi.org/10.1002/jnr.24271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Miller DM, Singh IN, Wang JA, Hall ED (2015) Nrf2–ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumatic brain injury in mice. Exp Neurol 264:103–110. https://doi.org/10.1016/j.expneurol.2014.11.008

    Article  CAS  PubMed  Google Scholar 

  85. de Oliveira MR, Peres A, Ferreira GC, Schuck PF, Gama CS, Bosco SMD (2017) Carnosic acid protects mitochondria of human neuroblastoma SH-SY5Y cells exposed to paraquat through activation of the Nrf2/HO-1Axis. Mol Neurobiol 54:5961–5972. https://doi.org/10.1007/s12035-016-0100-3

    Article  CAS  PubMed  Google Scholar 

  86. Liu P, Dong J (2017) Protective effects of carnosic acid against mitochondria-mediated injury in H9c2 cardiomyocytes induced by hypoxia/reoxygenation. Exp Ther Med 14:5629–5634. https://doi.org/10.3892/etm.2017.5243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Xiong Y, Singh IN, Hall ED (2009) Tempol protection of spinal cord mitochondria from peroxynitrite-induced oxidative damage. Free Radic Res 43:604–612. https://doi.org/10.1080/10715760902977432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Maiese K, Chong ZZ (2003) Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain. Trends Pharmacol Sci 24:228–232. https://doi.org/10.1016/s0165-6147(03)00078-6

    Article  CAS  PubMed  Google Scholar 

  89. Chong ZZ, Lin SH, Maiese K (2004) The NAD+ precursor nicotinamide governs neuronal survival during oxidative stress through protein kinase B coupled to FOXO3a and mitochondrial membrane potential. J Cereb Blood Flow Metab 24:728–743. https://doi.org/10.1097/01.wcb.0000122746.72175.0e

    Article  CAS  PubMed  Google Scholar 

  90. Feng Y, Paul IA, LeBlanc MH (2006) Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat. Brain Res Bull 69:117–122. https://doi.org/10.1016/j.brainresbull.2005.11.011

    Article  CAS  PubMed  Google Scholar 

  91. Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson MP (2009) Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. Neuromol Med 11:28–42. https://doi.org/10.1007/s12017-009-8058-1

    Article  CAS  Google Scholar 

  92. Herrera-Marschitz M, Neira-Pena T, Rojas-Mancilla E, Espina-Marchant P, Esmar D, Perez R, Muñoz V, Gutierrez-Hernandez M, Rivera B, Simola N, Bustamante D, Morales P, Gebicke-Haerter PJ (2014) Perinatal asphyxia: CNS development and deficits with delayed onset. Front Neurosci 8:47. https://doi.org/10.3389/fnins.2014.00047

    Article  PubMed  PubMed Central  Google Scholar 

  93. Leaw B, Nair S, Lim R, Thornton C, Mallard C, Hagberg H (2017) Mitochondria, bioenergetics and excitotoxicity: new therapeutic targets in perinatal brain injury. Front Cell Neurosci 11:199–199. https://doi.org/10.3389/fncel.2017.00199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Soane L, Kahraman S, Kristian T, Fiskum G (2007) Mechanisms of impaired mitochondrial energy metabolism in acute and chronic neurodegenerative disorders. J Neurosci Res 85:3407–3415. https://doi.org/10.1002/jnr.21498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Seppet E, Gruno M, Peetsalu A, Gizatullina Z, Nguyen HP, Vielhaber S, Wussling MH, Trumbeckaite S, Arandarcikaite O, Jerzembeck D, Sonnabend M, Jegorov K, Zierz S, Striggow F, Gellerich FN (2009) Mitochondria and energetic depression in cell pathophysiology. Int J Mol Sci 10:2252–2303. https://doi.org/10.3390/ijms10052252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Newnam KM, DeLoach DL (2011) Neonatal hypothermia: a method to provide neuroprotection after hypoxic ischemic encephalopathy. Newborn Infant Nurs Rev 11:113–124. https://doi.org/10.1053/j.nainr.2011.07.003

    Article  Google Scholar 

  97. Roka A, Azzopardi D (2010) Therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy. Early Hum Dev 86:361–367. https://doi.org/10.1016/j.earlhumdev.2010.05.013

    Article  PubMed  Google Scholar 

  98. Gunn AJ, Laptook AR, Robertson NJ, Barks JD, Thoresen M, Wassink G, Bennet L (2017) Therapeutic hypothermia translates from ancient history in to practice. Pediatr Res 81:202–209. https://doi.org/10.1038/pr.2016.198

    Article  PubMed  Google Scholar 

  99. Silveira RC, Procianoy RS (2015) Hypothermia therapy for newborns with hypoxic ischemic encephalopathy. J Pediatr (Rio J) 91:S78–S83. https://doi.org/10.1016/j.jped.2015.07.004

    Article  Google Scholar 

  100. Subirós N, Del Barco DG, Coro-Antich RM (2012) Erythropoietin: still on the neuroprotection road. Ther Adv Neurol Disord 5:161–173

    Article  Google Scholar 

  101. Genc S, Koroglu TF, Genc K (2004) Erythropoietin as a novel neuroprotectant. Restor Neurol Neurosci 22:105–119

    CAS  PubMed  Google Scholar 

  102. Spandou E, Papadopoulou Z, Soubasi V, Karkavelas G, Simeonidou C, Pazaiti A, Guiba-Tziampiri O (2005) Erythropoietin prevents long-term sensorimotor deficits and brain injury following neonatal hypoxia–ischemia in rats. Brain Res 1045:22–30. https://doi.org/10.1016/j.brainres.2005.03.013

    Article  CAS  PubMed  Google Scholar 

  103. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35:1732–1737

    Article  CAS  Google Scholar 

  104. Malla RR, Asimi R, Teli MA, Shaheen F, Bhat MA (2017) Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. J Perinatol 37:596–601. https://doi.org/10.1038/jp.2017.17

    Article  CAS  PubMed  Google Scholar 

  105. Avasiloaiei A, Dimitriu C, Moscalu M, Paduraru L, Stamatin M (2013) High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns. Pediatr Int 55:589–593. https://doi.org/10.1111/ped.12121

    Article  CAS  PubMed  Google Scholar 

  106. Nair J, Kumar VHS (2018) Current and emerging therapies in the management of hypoxic ischemic encephalopathy in neonates. Children (Basel, Switzerland) 5:99. https://doi.org/10.3390/children5070099

    Article  Google Scholar 

  107. Aly H, Elmahdy H, El-Dib M, Rowisha M, Awny M, El-Gohary T, Elbatch M, Hamisa M, El-Mashad AR (2015) Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol 35:186–191. https://doi.org/10.1038/jp.2014.186

    Article  CAS  PubMed  Google Scholar 

  108. Boruczkowski D, Pujal JM, Zdolińska-Malinowska I (2019) Autologous cord blood in children with cerebral palsy: a review. Int J Mol Sci. https://doi.org/10.3390/ijms20102433

    Article  PubMed  PubMed Central  Google Scholar 

  109. Serrenho I, Rosado M, Dinis A et al (2021) Stem cell therapy for neonatal hypoxic-ischemic encephalopathy: a systematic review of preclinical studies. Int J Mol Sci. https://doi.org/10.3390/ijms22063142

    Article  PubMed  PubMed Central  Google Scholar 

  110. Cotten CM, Murtha AP, Goldberg RN, Grotegut CA, Smith PB, Goldstein RF, Fisher KA, Gustafson KE, Waters-Pick B, Swamy GK, Rattray B, Tan S, Kurtzberg J (2014) Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr 164:973–979. https://doi.org/10.1016/j.jpeds.2013.11.036

    Article  PubMed  Google Scholar 

  111. Moss HG, Brown TR, Wiest DB, Jenkins DD (2018) N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab 38:950–958. https://doi.org/10.1177/0271678x18765828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kim HS, Suh YH (2009) Minocycline and neurodegenerative diseases. Behav Brain Res 196:168–179. https://doi.org/10.1016/j.bbr.2008.09.040

    Article  CAS  PubMed  Google Scholar 

  113. Chen SD, Yin JH, Hwang CS, Tang CM, Yang DI (2012) Anti-apoptotic and anti-oxidative mechanisms of minocycline against sphingomyelinase/ceramide neurotoxicity: implication in Alzheimer’s disease and cerebral ischemia. Free Radic Res 46:940–950. https://doi.org/10.3109/10715762.2012.674640

    Article  CAS  PubMed  Google Scholar 

  114. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W (2005) Minocycline as a neuroprotective agent. Neuroscientist 11:308–322. https://doi.org/10.1177/1073858405275175

    Article  CAS  PubMed  Google Scholar 

  115. Buller KM, Carty ML, Reinebrant HE, Wixey JA (2009) Minocycline: a neuroprotective agent for hypoxic-ischemic brain injury in the neonate? J Neurosci Res 87:599–608. https://doi.org/10.1002/jnr.21890

    Article  CAS  PubMed  Google Scholar 

  116. Fan LW, Lin S, Pang Y, Rhodes PG, Cai Z (2006) Minocycline attenuates hypoxia-ischemia-induced neurological dysfunction and brain injury in the juvenile rat. Eur J Neurosci 24:341–350. https://doi.org/10.1111/j.1460-9568.2006.04918.x

    Article  PubMed  Google Scholar 

  117. Kabataş S, Civelek E, İnci Ç, Yalçınkaya EY, Günel G, Kır G, Albayrak E, Öztürk E, Adaş G, Karaöz E (2018) Wharton’s jelly-derived mesenchymal stem cell transplantation in a patient with hypoxic-ischemic encephalopathy: a pilot study. Cell Transplant 27:1425–1433. https://doi.org/10.1177/0963689718786692

    Article  PubMed  PubMed Central  Google Scholar 

  118. Gonzales-Portillo GS, Reyes S, Aguirre D, Pabon MM, Borlongan CV (2014) Stem cell therapy for neonatal hypoxic-ischemic encephalopathy. Front Neurol 5:147. https://doi.org/10.3389/fneur.2014.00147

    Article  PubMed  PubMed Central  Google Scholar 

  119. de Oliveira MR (2018) Carnosic acid as a promising agent in protecting mitochondria of brain cells. Mol Neurobiol 55:6687–6699. https://doi.org/10.1007/s12035-017-0842-6

    Article  CAS  PubMed  Google Scholar 

  120. Xiong Y, Rabchevsky AG, Hall ED (2007) Role of peroxynitrite in secondary oxidative damage after spinal cord injury. J Neurochem 100:639–649. https://doi.org/10.1111/j.1471-4159.2006.04312.x

    Article  CAS  PubMed  Google Scholar 

  121. Singh IN, Sullivan PG, Hall ED (2007) Peroxynitrite-mediated oxidative damage to brain mitochondria: protective effects of peroxynitrite scavengers. J Neurosci Res 85:2216–2223. https://doi.org/10.1002/jnr.21360

    Article  CAS  PubMed  Google Scholar 

  122. Chiarotto GB, Drummond L, Cavarretto G, Bombeiro AL, de Oliveira AL (2014) Neuroprotective effect of tempol (4 hydroxy-tempo) on neuronal death induced by sciatic nerve transection in neonatal rats. Brain Res Bull 106:1–8. https://doi.org/10.1016/j.brainresbull.2014.04.010

    Article  CAS  PubMed  Google Scholar 

  123. Lespay-Rebolledo C, Tapia-Bustos A, Bustamante D, Morales P, Herrera-Marschitz M (2019) The long-term impairment in redox homeostasis observed in the hippocampus of rats subjected to global perinatal asphyxia (PA) implies changes in glutathione-dependent antioxidant enzymes and TIGAR-dependent shift towards the pentose phosphate pathways: effect of nicotinamide. Neurotox Res 36:472–490. https://doi.org/10.1007/s12640-019-00064-4

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, Shri G.S. Institute of Technology and Science, Indore, MP, 452003, India

    Puneet K. Samaiya

  2. Neurotherapeutics Lab, Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India

    Sairam Krishnamurthy

  3. Department of Pediatrics, Institute of Medical Sciences, BHU, Varanasi, UP, India

    Ashok Kumar

Authors
  1. Puneet K. Samaiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sairam Krishnamurthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashok Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PKS wrote the manuscript. SK and AK edited the manuscript.

Corresponding author

Correspondence to Puneet K. Samaiya.

Ethics declarations

Conflict of interest

The authors declare no competing interest as well as no financial support.

Ethical approval and consent to participate

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Samaiya, P.K., Krishnamurthy, S. & Kumar, A. Mitochondrial dysfunction in perinatal asphyxia: role in pathogenesis and potential therapeutic interventions. Mol Cell Biochem 476, 4421–4434 (2021). https://doi.org/10.1007/s11010-021-04253-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-021-04253-8

Keywords

Search

Navigation