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Neurochemical Changes in the Rat Occipital Cortex and Hippocampus after Repetitive and Profound Hypoglycemia During the Neonatal Period: An Ex Vivo 1H Magnetic Resonance Spectroscopy Study

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Abstract

The brain of a human neonate is more vulnerable to hypoglycemia than that of pediatric and adult patients. Repetitive and profound hypoglycemia during the neonatal period (RPHN) causes brain damage and leads to severe neurologic sequelae. Ex vivo high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy was carried out in the present study to detect metabolite alterations in newborn and adolescent rats and investigate the effects of RPHN on their occipital cortex and hippocampus. Results showed that RPHN induces significant changes in a number of cerebral metabolites, and such changes are region-specific. Among the 16 metabolites detected by ex vivo 1H NMR, RPHN significantly increased the levels of creatine, glutamate, glutamine, γ-aminobutyric acid, and aspartate, as well as other metabolites, including succine, taurine, and myo-inositol, in the occipital cortex of neonatal rats compared with the control. By contrast, changes in these neurochemicals were not significant in the hippocampus of neonatal rats. When the rats had developed into adolescence, the changes above were maintained and the levels of other metabolites, including lactate, N-acetyl aspartate, alanine, choline, glycine, acetate, and ascorbate, increased in the occipital cortex. By contrast, most of these metabolites were reduced in the hippocampus. These metabolic changes suggest that complementary mechanisms exist between these two brain areas. RPHN appears to affect occipital cortex and hippocampal activities, neurotransmitter transition, energy metabolism, and other metabolic equilibria in newborn rats; these effects are further aggravated when the newborn rats develop into adolescence. Changes in the metabolism of neurotransmitter system may be an adaptive measure of the central nervous system in response to RPHN.

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Abbreviations

RPHN:

Repetitive and profound hypoglycemia of neonatal period

NMR:

Nuclear magnetic resonance

Glu:

Glutamate

GABA:

γ-Aminobutyric acid

Gln:

Glutamine

Ace:

Acetate

Lac:

Lactate

NAA:

N-acetyl aspartate

Ala:

Alanine

Suc:

Succinate

Asp:

Aspartate

Cre:

Creatine

Tau:

Taurine

m-Ins:

Myo-inositol

Cho:

Choline

Gly:

Glycine

Asc:

Ascorbate

PLS-DA:

Projection to latent structure discriminant analysis

PC:

Principal component

References

  1. McGowan JE (1999) Neonatal hypoglycemia. Pediatr Rev 20(7):6–15

    Article  Google Scholar 

  2. Stanley CA, Baker L (1999) The causes of neonatal hypoglycemia. N Engl J Med 340(15):1200–1201

    Article  CAS  PubMed  Google Scholar 

  3. Caraballo RH, Sakr D, Mozzi M, Guerrero A, Adi JN, Cersosimo RO, Fejerman N (2004) Symptomatic occipital lobe epilepsy following neonatal hypoglycemia. Pediatr Neurol 31(1):24–29

    Article  PubMed  Google Scholar 

  4. Tam EW, Widjaja E, Blaser SI, Macgregor DL, Satodia P, Moore AM (2008) Occipital lobe injury and cortical visual outcomes after neonatal hypoglycemia. Pediatrics 122(3):507–512

    Article  PubMed  Google Scholar 

  5. Udani V, Munot P, Ursekar M, Gupta S (2009) Neonatal hypoglycemic brain-injury a common cause of infantile onset remote symptomatic epilepsy. Indian Pediatr 46(2):127–132

    CAS  PubMed  Google Scholar 

  6. Suh SW, Hamby AM, Swanson RA (2007) Hypoglycemia, brain energetics, and hypoglycemic neuronal death. Glia 55(12):1280–1286

    Article  PubMed  Google Scholar 

  7. Yager JY (2002) Hypoglycemic injury to the immature brain. Clin Perinatol 29(4):651–674

    Article  PubMed  Google Scholar 

  8. Agardh CD, Folbergrova J, Siesjo BK (1978) Cerebral metabolic changes in profound, insulin-induced hypoglycemia, and in the recovery period following glucose administration. J Neurochem 31(5):1135–1142

    Article  CAS  PubMed  Google Scholar 

  9. Agardh CD, Kalimo H, Olsson Y, Siesjo BK (1980) Hypoglycemic brain injury. I. Metabolic and light microscopic findings in rat cerebral cortex during profound insulin-induced hypoglycemia and in the recovery period following glucose administration. Acta Neuropathol 50(1):31–41

    Article  CAS  PubMed  Google Scholar 

  10. Butterworth RF, Merkel AD, Landreville F (1982) Regional amino acid distribution in relation to function in insulin hypoglycaemia. J Neurochem 38(5):1483–1489

    Article  CAS  PubMed  Google Scholar 

  11. Sandberg M, Butcher SP, Hagberg H (1986) Extracellular overflow of neuroactive amino acids during severe insulin-induced hypoglycemia: in vivo dialysis of the rat hippocampus. J Neurochem 47(1):178–184

    Article  CAS  PubMed  Google Scholar 

  12. Butcher SP, Sandberg M, Hagberg H, Hamberger A (1987) Cellular origins of endogenous amino acids released into the extracellular fluid of the rat striatum during severe insulin-induced hypoglycemia. J Neurochem 48(3):722–778

    Article  CAS  PubMed  Google Scholar 

  13. Hagberg H, Ichord R, Palmer C, Yager JY, Vannucci SJ (2002) Animal models of developmental brain injury: relevance to human disease. A summary of the panel discussion from the Third Hershey Conference on Developmental Cerebral Blood Flow and Metabolism. Dev Neurosci 24(5):364–366

    Article  CAS  PubMed  Google Scholar 

  14. Ennis K, Tran PV, Seaquist ER, Rao R (2008) Postnatal age influences hypoglycemia-induced neuronal injury in the rat brain. Brain Res 1224:119–126

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Rao R, Ennis K, Long JD, Ugurbil K, Gruetter R, Tkac I (2010) Neurochemical changes in the developing rat hippocampus during prolonged hypoglycemia. J Neurochem 114(3):728–738

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Zhou D, Qian J, Liu CX, Chang H, Sun RP (2008) Repetitive and profound insulin-induced hypoglycemia results in brain damage in newborn rats: an approach to establish an animal model of brain injury induced by neonatal hypoglycemia. Eur J Pediatr 167(10):1169–1174

    Article  CAS  PubMed  Google Scholar 

  17. Beckonert O, Keun HC, Ebbels TM, Bundy J, Holmes E, Lindon JC, Nicholson JK (2007) Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat Protoc 2(11):2692–2703

    Article  CAS  PubMed  Google Scholar 

  18. Gao H, Dong B, Liu X, Xuan H, Huang Y, Lin D (2008) Metabonomic profiling of renal cell carcinoma: high-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis. Anal Chim Acta 624(2):269–277

    Article  CAS  PubMed  Google Scholar 

  19. Gao H, Xiang Y, Sun N, Zhu H, Wang Y, Liu M, Ma Y, Lei H (2007) Metabolic changes in rat prefrontal cortex and hippocampus induced by chronic morphine treatment studied ex vivo by high resolution 1H NMR spectroscopy. Neurochem Int 50(2):386–394

    Article  CAS  PubMed  Google Scholar 

  20. Govindaraju V, Young K, Maudsley AA (2000) Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 13(3):129–153

    Article  CAS  PubMed  Google Scholar 

  21. Auer RN (2004) Hypoglycemic brain damage. Metab Brain Dis 19(3–4):169–175

    Article  PubMed  Google Scholar 

  22. Saransaari P, Oja SS (1997) Enhanced GABA release in cell-damaging conditions in the adult and developing mouse hippocampus. Int J Dev Neurosci 15(2):163–174

    Article  CAS  PubMed  Google Scholar 

  23. Li S, Huang M, Wang X, Chen F, Lei H, Jiang F (2011) Retinal metabolic changes in an experimental model of optic nerve transection by ex vivo 1H magnetic resonance spectroscopy. Neurochem Res 36(12):2427–2433

    Article  CAS  PubMed  Google Scholar 

  24. Iltis I, Koski DM, Eberly LE, Nelson CD, Deelchand DK, Valette J, Ugurbil K, Lim KO, Henry PG (2009) Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized 1H MRS study. NMR Biomed 22(7):737–744

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Globus MY, Busto R, Dietrich WD, Martinez E, Valdes I, Ginsberg MD (1988) Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 51(5):1455–1464

    Article  CAS  PubMed  Google Scholar 

  26. Gao HC, Zhu H, Song CY, Lin L, Xiang Y, Yan ZH, Bai GH, Ye FQ, Li XK (2013) Metabolic changes detected by ex vivo high resolution (1)H NMR spectroscopy in the striatum of 6-OHDA-induced Parkinson's rat. Mol Neurobiol 47(1):123–130

    Article  CAS  PubMed  Google Scholar 

  27. Miller BL (1991) A review of chemical issues in 1H NMR spectroscopy: N-acetyl-l-aspartate, creatine and choline. NMR Biomed 4(2):47–52

    Article  CAS  PubMed  Google Scholar 

  28. Xiang Y, Gao H, Zhu H, Sun N, Ma Y, Lei H (2006) Neurochemical changes in brain induced by chronic morphine treatment: NMR studies in thalamus and somatosensory cortex of rats. Neurochem Res 31(10):1255–1261

    Article  CAS  PubMed  Google Scholar 

  29. Isaacks RE, Bender AS, Kim CY, Prieto NM, Norenberg MD (1994) Osmotic regulation of myo-inositol uptake in primary astrocyte cultures. Neurochem Res 19(3):331–338

    Article  CAS  PubMed  Google Scholar 

  30. Hardy DL, Norwood TJ (1998) Spectral editing technique for the in vitro and in vivo detection of taurine. J Magn Reson 133(1):70–78

    Article  CAS  PubMed  Google Scholar 

  31. Cecil KM, Jones BV (2001) Magnetic resonance spectroscopy of the pediatric brain. Top Magn Reson Imaging 12(6):435–452

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the grants from National Natural Science Foundation of China (Nos. 81171306 and 21175099), and Wenzhou Science and Technology Bureau (No. Y20100176).

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Authors and Affiliations

  1. Radiology Department of the Second Affiliated Hospital, Wenzhou Medical College, Wenzhou, 325035, People’s Republic of China

    Kun Liu, Xin-Jian Ye, Gui-Yan Zhang, Guang-Hui Bai, Jia-Wei He & Zhi-Han Yan

  2. School of Pharmacy, Wenzhou Medical College, Wenzhou, 325035, People’s Republic of China

    Wen-Yi Hu, Liang-Cai Zhao, Huan Zhu & Hong-Chang Gao

  3. Wuhan Medical and Health Center for Women and Children, Huazhong University of Science and Technology, Wuhan, 430015, People’s Republic of China

    Jian-Bo Shao

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  1. Kun Liu
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Correspondence to Zhi-Han Yan or Hong-Chang Gao.

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Kun Liu, Xin-Jian Ye, and Wen-Yi Hu contributed equally to this work.

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Liu, K., Ye, XJ., Hu, WY. et al. Neurochemical Changes in the Rat Occipital Cortex and Hippocampus after Repetitive and Profound Hypoglycemia During the Neonatal Period: An Ex Vivo 1H Magnetic Resonance Spectroscopy Study. Mol Neurobiol 48, 729–736 (2013). https://doi.org/10.1007/s12035-013-8446-2

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  • DOI: https://doi.org/10.1007/s12035-013-8446-2

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