Skip to main content
SpringerLink
Log in

Time dependent impact of perinatal hypoxia on growth hormone, insulin-like growth factor 1 and insulin-like growth factor binding protein-3

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Hypoxic-ischemia (HI) is a widely used animal model to mimic the preterm or perinatal sublethal hypoxia, including hypoxic-ischemic encephalopathy. It causes diffuse neurodegeneration in the brain and results in mental retardation, hyperactivity, cerebral palsy, epilepsy and neuroendocrine disturbances. Herein, we examined acute and subacute correlations between neuronal degeneration and serum growth factor changes, including growth hormone (GH), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after hypoxic-ischemia (HI) in neonatal rats. In the acute phase of hypoxia, brain volume was increased significantly as compared with control animals, which was associated with reduced GH and IGF-1 secretions. Reduced neuronal survival and increased DNA fragmentation were also noticed in these animals. However, in the subacute phase of hypoxia, neuronal survival and brain volume were significantly decreased, accompanied by increased apoptotic cell death in the hippocampus and cortex. Serum GH, IGF-1, and IGFBP-3 levels were significantly reduced in the subacute phase of HI. Significant retardation in the brain and body development were noted in the subacute phase of hypoxia. Here, we provide evidence that serum levels of growth-hormone and factors were decreased in the acute and subacute phase of hypoxia, which was associated with increased DNA fragmentation and decreased neuronal survival.

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
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aberg ND, Brywe KG, Isgaard J (2006) Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain. Sci World J 18:53–80

    Article  Google Scholar 

  • Abrams RL, Parker ML, Blanco S, Reichlin S, Daughaday WH (1966) Hypothalamic regulation of growth hormone secretion. Endocrinology 78:605–613

    Article  CAS  PubMed  Google Scholar 

  • Beck KD, Powell-Braxton L, Widmer HR, Valverde J, Hefti F (1995) IGF-I gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 14:717–730

    Article  CAS  PubMed  Google Scholar 

  • Beker MC, Caglayan AB, Kelestemur T, Caglayan B, Yalcin E, Yulug B, Kilic U, Hermann DM, Kilic E (2015) Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation. Oncotarget 6:30604–30614

    PubMed  PubMed Central  Google Scholar 

  • Brywe KG, Leverin AL, Gustavsson M, Mallard C, Granata R, Destefanis S, Volante M, Hagberg H, Ghigo E, Isgaard J (2005) Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3beta phosphorylation. Endocrinology 146:4665–4672

    Article  CAS  PubMed  Google Scholar 

  • Ciccone MM, Scicchitano P, Zito A, Gesualdo M, Sassara M, Calderoni G, Di Mauro F, Ladisa G, Di Mauro A, Laforgia N (2011) Different functional cardiac characteristics observed in term/preterm neonates by echocardiography and tissue doppler imaging. Early Hum Dev 87:555–558

    Article  PubMed  Google Scholar 

  • Cohen P, Rosenfeld RG, Griffin JE, Ojeda SR (2002) Growth regulation. Textbook of endocrine physiology, 4th edn. Oxford University Press, Oxford, pp. 286–302

    Google Scholar 

  • Devesa P, Agasse F, Xapelli S, Almengló C, Devesa J, Malva JO, Arce VM (2014) Growth hormone pathways signaling for cell proliferation and survival in hippocampal neural precursors from postnatal mice. BMC Neurosci 15:100

    Article  PubMed  PubMed Central  Google Scholar 

  • Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397

    Article  CAS  PubMed  Google Scholar 

  • Fatemi A, Wilson MA, Johnston MV (2009) Hypoxic ischemic encephalopathy in the term infant. Clin Perinatol 36:835–858

    Article  PubMed  PubMed Central  Google Scholar 

  • Ghaffaripour HA, Jalali M, Nikravesh MR, Seghatoleslam M, Sanchooli J (2015) Neuronal cell reconstruction with umbilical cord blood cells in the brain hypoxia-ischemia. Iran Biomed J 19:29–34

    PubMed  PubMed Central  Google Scholar 

  • Goldenberg N, Barkan A (2007) Factors regulating growth hormone secretion in humans. Endocrinol Metab Clin N Am 36:37–55

    Article  CAS  Google Scholar 

  • Goodman CS, Tessier-Lavigne M (1997) Molecular mechanisms in axon guidance and targeted recognition. In: Cowan WM, Jessell TM, Zipursky SL (eds) Molecular and cellular approaches to neural development. Oxford University Press, New York, pp. 108–178

    Google Scholar 

  • Grafe MR, Woodworth KN, Noppens K, Perez-Polo JR (2008) Long-term histological outcome after post-hypoxic treatment with 100 % or 40 % oxygen in a model of perinatal hypoxic-ischemic brain injury. Int J Dev Neurosci 26:119–124

    Article  CAS  PubMed  Google Scholar 

  • Graulich J, Hoffmann U, Maier RF, Ruscher K, Pomper JK, Ko HK, Gabriel S, Obladen M, Heinemann U (2002) Acute neuronal injury after hypoxia is influenced by the reoxygenation mode in juvenile hippocampal slice cultures. Brain Res Dev Brain Res 137(1):35–42

    Article  CAS  PubMed  Google Scholar 

  • Higgins RD, Raju T, Edwards AD, Azzopardi DV, Bose CL, Clark RH, Ferriero DM, Guillet R, Gunn AJ, Hagberg H, Hirtz D, Inder TE, Jacobs SE, Jenkins D, Juul S, Laptook AR, Lucey JF, Maze M, Palmer C, Papile L, Pfister RH, Robertson NJ, Rutherford M, Shankaran S, Silverstein FS, Soll RF, Thoresen M, Walsh WF, Eunice Kennedy Shriver National Institute of Child Health and Human Development Hypothermia Workshop Speakers and Moderators (2011) Hypothermia and other treatment options for neonatal encephalopathy: an executive summary of the Eunice Kennedy Shriver NICHD workshop. J Pediatr 159:851–858

    Article  PubMed  PubMed Central  Google Scholar 

  • Hirt H, Kimelman J, Birnbaum MJ, Chen EY, Seeburg PH, Eberhardt NL, Barta A (1987) The human growth hormone gene locus: structure, evolution, and allelic variations. DNA 6:59–70

    Article  CAS  PubMed  Google Scholar 

  • Kilic U, Yilmaz B, Reiter RJ, Yüksel A, Kilic E (2013) Effects of memantine and melatonin on signal transduction pathways vascular leakage and brain injury after focal cerebral ischemia in mice. Neuroscience 237:268–276

    Article  CAS  PubMed  Google Scholar 

  • Kilic E, Reitmeir R, Kilic Ü, Caglayan AB, Beker MC, Kelestemur T, Ethemoglu MS, Ozturk G, Hermann DM (2014) HMG-CoA reductase inhibition promotes neurological recovery, peri-lesional tissue remodeling, and contralesional pyramidal tract plasticity after focal cerebral ischemia. Front Cell Neurosci 8:422

    Article  PubMed  PubMed Central  Google Scholar 

  • Klinger G, Beyene J, Shah P, Perlman M (2005) Do hyperoxemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia. Arch Dis Child Fetal Neonatal Ed 90:49–52

    Article  Google Scholar 

  • Lai MC, Yang SN (2011) Perinatal hypoxic-ischemic encephalopathy. J Biomed Biotechnol 2011:e609813

    Article  Google Scholar 

  • Macglilivray MH, Felig P, Frohman LA (2001) Disorders of growth and development. Endocrinology and Metabolism. 4th ed. pp.1265–1316. MacGrawHill

  • Miller SP, Ferriero DM (2009) From selective vulnerability to connectivity: insights from newborn brain imaging. Trends Neurosci 32:496–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moster D, Lie RT, Irgens LM, Bjerkedal T, Markestad T (2001) The association of apgar score with subsequent death and cerebral palsy, a population-based study in term infants. J Pediatr 138:798–803

    Article  CAS  PubMed  Google Scholar 

  • Nakajima W, Ishida A, Lange MS, Gabrielson KL, Wilson MA, Martin LJ, Blue ME, Johnston MV (2000) Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci 20:7994–8004

    CAS  PubMed  Google Scholar 

  • Northington FJ (2006) Brief update on animal models of hypoxic-ischemic encephalopathy and neonatal stroke. ILAR J 47(1):32–38

    Article  CAS  PubMed  Google Scholar 

  • O’Kusky JR, Ye P, D’Ercole AJ (2000) Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 20:8435–8442

    PubMed  Google Scholar 

  • Rice JE, Vannucci RC, Brierley JB (1981) The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9:131–141

    Article  PubMed  Google Scholar 

  • Roohey T, Raju TN, Moustogiannis AN (1997) Animal models for the study of perinatal hypoxic-ischemic encephalopathy: A critical analysis. Early Hum Dev 47:115–146

    Article  CAS  PubMed  Google Scholar 

  • Rousset CI, Leiper FC, Kichev A, Gressens P, Carling D, Hagberg H, Thornton C (2015) A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic-ischaemic brain injury in mice. J Neurochem 133:242–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheepens A, Sirimanne E, Beilharz E, Breier BH, Waters MJ, et al. (1999) Alterations in the neural growth hormone axis following hypoxic-ischemic braininjury. Brain Res Mol Brain Res 68:88–100

    Article  CAS  PubMed  Google Scholar 

  • Scheepens A, Williams CE, Breier BH, Guan J, Gluckman PD (2000) A role for the somatotropic axis in neural development, injury and disease. J Ped Endoc Metabol 13:1483–1491

    Google Scholar 

  • Schwartz PH, Massarweh WF, Vinters HV, Wasterlain CG (1992) A rat model of severe neonatal hypoxic-ischemic brain injury. Stroke 23:539–546

    Article  CAS  PubMed  Google Scholar 

  • Sheldon RA, Chuai J, Ferriero DM (1996) A rat model for hypoxicischemic brain damage in very premature infants. Biol Neonate 69:327–341

    Article  CAS  PubMed  Google Scholar 

  • Traub ML, De Butte-Smith M, Zukin RS, Etgen AM (2009) Oestradiol and insulin-like growth factor-1 reduce cell loss after global ischaemia in middle-aged female rats. J Neuroendocrinol 21:1038–1044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vannucci SJ, Hagberg H (2004) Hypoxia–ischemia in the immature brain. J Exp Biol 207:3149–3154

    Article  CAS  PubMed  Google Scholar 

  • Vannucci RC, Perlman JM (1997) Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 100:1004–1014

    Article  CAS  PubMed  Google Scholar 

  • Varvarigou A, Vagenakis AG, Makri M, Frimas C, Beratis NG (1996) Prolactin and growth hormone in perinatal asphyxia. Biol Neonate 69:76–83

    Article  CAS  PubMed  Google Scholar 

  • Volpe JJ (2001) Perinatal brain injury from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 7:56–64

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Wang W, Li D, Li M, Wang P, Wen J, Liang M, Su B, Yin Y (2014) IGF-1 alleviates NMDA-induced excitotoxicity in cultured hippocampal neurons against autophagy via the NR2B/PI3K-AKT-mTOR pathway. J Cell Physiol 229:1618–1629

    Article  CAS  PubMed  Google Scholar 

  • Wilson JD, Foster DW, Kronenberg HM (1998) Williams textbook of endocrinology. 9th ed. pp. 249–326. W.B. Saunders Company

  • Zhang GY, Lu XM, Sun RP, Wang SZ (2006) Serum growth hormone and prolactin levels in neonates with hypoxic-ischemic encephalopathy. Chin J Contemp Pediatr 8:450–452

    CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by EMBO (European Molecular Biology Organization) installation Grant and The Turkish Academy of Sciences (TUBA).

Author information

Authors and Affiliations

  1. Department of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler cad. 19, TR-34810, Istanbul, Turkey

    Ömer Kartal, Ayşe Tuğba Kartal, Taha Kelestemur, Ahmet Burak Caglayan, Mustafa Caglar Beker, Burak Yulug & Ertugrul Kilic

  2. Department of Pediatrics, Gulhane Military Medical Academy, Haydarpasa Teaching Hospital, Istanbul, Turkey

    Ömer Kartal, Seçil Aydınöz, Ferhan Karademir, Selami Süleymanoğlu & Mustafa Kul

  3. Department of Pediatrics, Marmaris State Hospital, Mugla, Turkey

    Ayşe Tuğba Kartal

Authors
  1. Ömer Kartal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seçil Aydınöz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ayşe Tuğba Kartal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Taha Kelestemur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmet Burak Caglayan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mustafa Caglar Beker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ferhan Karademir
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Selami Süleymanoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mustafa Kul
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Burak Yulug
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ertugrul Kilic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ertugrul Kilic.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kartal, Ö., Aydınöz, S., Kartal, A.T. et al. Time dependent impact of perinatal hypoxia on growth hormone, insulin-like growth factor 1 and insulin-like growth factor binding protein-3. Metab Brain Dis 31, 827–835 (2016). https://doi.org/10.1007/s11011-016-9816-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-016-9816-z

Keywords

Search

Navigation