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Transient neonatal hyperglycemia induces metabolic shifts in the rat hippocampus: a 1H NMR-based metabolomics analysis

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Abstract

Diabetes has been reported to induce brain metabolic disturbance, but the effect of transient neonatal hyperglycemia (TNH) on brain metabolism remains unclear. Herein the rats were treated with a single intraperitoneal injection of 100 µg/g body weight of streptozotocin within 12 h after birth and displayed a typical clinical characteristic of TNH. Then we used NMR-based metabolomics to examine the metabolic changes in the hippocampus between TNH and normal control (Ctrl) rats at postnatal 7 days (P7) and 21 days (P21). The results show that TNH rats had significantly increased levels of N-acetyl aspartate, glutamine, aspartate and choline in the hippocampus relative to Ctrl rats at P7. Moreover, we found that the levels of alanine, myo-inositol and choline were significantly lower in TNH rats, although their blood glucose levels have been recovered to the normal level at P21. Therefore, our results suggest that TNH may have a long-term effect on hippocampal metabolic changes mainly involving neurotransmitter metabolism and choline metabolism.

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All data generated or analyzed during this study are included in this paper. Data will be made available on reasonable request.

References

  • Andersen JV, Nissen JD, Christensen SK, Markussen KH, Waagepetersen HS (2017) Impaired hippocampal glutamate and glutamine metabolism in the db/db mouse model of type 2 diabetes mellitus. Neural Plast 2017:2107084

    Article  PubMed  PubMed Central  Google Scholar 

  • Baslow MH (2003) N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 28:941–953

    Article  CAS  PubMed  Google Scholar 

  • Beardsall K (2021) Hyperglycaemia in the newborn infant. Physiology verses pathology. Front Pediatr 9:641306

    Article  PubMed  PubMed Central  Google Scholar 

  • Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, Ong K et al (2010) Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study. J Pediatr 157:715–719

    Article  PubMed  Google Scholar 

  • Bonfanti R, Iafusco D, Rabbone I, Diedenhofen G, Bizzarri C, Patera PI et al (2021) Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy. Eur J Endocrinol 184(4):575–585

    Article  CAS  PubMed  Google Scholar 

  • D’Aniello S, Somorjai I, Garcia-Fernàndez J, Topo E, D’Aniello A (2011) D‐Aspartic acid is a novel endogenous neurotransmitter. FASEB J 25(3):1014–1027

    Article  PubMed  Google Scholar 

  • Delage C, Taib T, Mamma C, Lerouet D, Besson VC (2021) Traumatic brain injury: an age-dependent view of post-traumatic neuroinflammation and its treatment. Pharmaceutics 13(10):1624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao H, Jiang Q, Ji H, Ning J, Li C, Zheng H (2019) Type 1 diabetes induces cognitive dysfunction in rats associated with alterations of the gut microbiome and metabolomes in serum and hippocampus. BBA-Mol Basis Dis 1865(12):165541

    Article  CAS  Google Scholar 

  • Garofano A, Czernichow P, Breant B (1998) Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat. Diabetologia 41:1114–1120

    Article  CAS  PubMed  Google Scholar 

  • Gilmour G, Dix S, Fellini L, Gastambide F, Plath N, Steckler T et al (2012) NMDA receptors, cognition and schizophrenia–testing the validity of the NMDA receptor hypofunction hypothesis. Neuropharmacology 62(3):1401–1412

    Article  CAS  PubMed  Google Scholar 

  • Herring BE, Silm K, Edwards RH, Nicoll RA (2015) Is aspartate an excitatory neurotransmitter? J Neurosci 35(28):10168–10171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang D, Liu D, Yin J, Qian T, Shrestha S, Ni H (2017) Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment. Eur Radiol 27:2698–2705

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ivanisevic J, Siuzdak G (2015) The role of metabolomics in brain metabolism research. J Neuroimmune Pharmacol 10:391–395

    Article  PubMed  PubMed Central  Google Scholar 

  • Lalande J, Halley H, Balayssac S, Gilard V, Dejean S, Martino R et al (2014) 1H NMR metabolomic signatures in five brain regions of the AβPPswe Tg2576 mouse model of Alzheimer’s disease at four ages. J Alzheimer’s Dis 39(1):121–143

    Article  CAS  Google Scholar 

  • Lenzen S (2008) The mechanisms of alloxan-and streptozotocin-induced diabetes. Diabetologia 51:216–226

    Article  CAS  PubMed  Google Scholar 

  • Michel V, Yuan Z, Ramsubir S, Bakovic M (2006) Choline transport for phospholipid synthesis. Exp Biol Med 231(5):490–504

    Article  CAS  Google Scholar 

  • Mitanchez-Mokhtari D, Lahlou N, Kieffer F, Magny JF, Roger M, Voyer M (2004) Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants. Pediatrics 113:537–541

    Article  PubMed  Google Scholar 

  • Palazzo E, Luongo L, Guida F, Marabese I, Romano R, Iannotta M et al (2016) D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice. Amino Acids 48:1553–1567

    Article  CAS  PubMed  Google Scholar 

  • Paulsen ME, Rao RB (2022) Cerebral effects of neonatal dysglycemia. Clin Perinatol 49(2):405–426

    Article  PubMed  PubMed Central  Google Scholar 

  • Rao R, Nashawaty M, Fatima S, Ennis K, Tkac I (2018) Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus. NMR Biomed 31(5):e3910

    Article  PubMed  PubMed Central  Google Scholar 

  • Romijn HJ, Hofman MA, Gramsbergen A (1991) At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? Early Hum Dev 26(1):61–67

    Article  CAS  PubMed  Google Scholar 

  • Rosa AP, Mescka CP, Catarino FM, de Castro AL, Teixeira RB, Campos C et al (2018) Neonatal hyperglycemia induces cell death in the rat brain. Metab Brain Dis 33:333–342

    Article  CAS  PubMed  Google Scholar 

  • Satrom KM, Ennis K, Sweis BM, Matveeva TM, Chen J, Hanson L et al (2018) Neonatal hyperglycemia induces CXCL10/CXCR3 signaling and microglial activation and impairs long-term synaptogenesis in the hippocampus and alters behavior in rats. J Neuroinflam 15:1–11

    Article  Google Scholar 

  • Schuff N, Meyerhoff DJ, Mueller S, Chao L, Sacrey DT, Laxer K, Weiner MW (2006) N-acetylaspartate as a marker of neuronal injury in neurodegenerative disease. Adv Exp Med Biol 576:241–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Selvarajah D, Wilkinson ID, Emery CJ, Shaw PJ, Griffiths PD, Gandhi R, Tesfaye S (2008) Thalamic neuronal dysfunction and chronic sensorimotor distal symmetrical polyneuropathy in patients with type 1 diabetes mellitus. Diabetologia 51:2088–2092

    Article  CAS  PubMed  Google Scholar 

  • Sickmann HM, Waagepetersen HS, Schousboe A, Benie AJ, Bouman SD (2012) Brain glycogen and its role in supporting glutamate and GABA homeostasis in a type 2 diabetes rat model. Neurochem Int 60(3):267–275

    Article  CAS  PubMed  Google Scholar 

  • Sonnewald U, Schousboe A (2016) Introduction to the glutamate-glutamine cycle. Adv Neurobiol 13:1–7

  • Tabassum S, Haider S, Ahmad S, Madiha S, Parveen T (2017) Chronic choline supplementation improves cognitive and motor performance via modulating oxidative and neurochemical status in rats. Pharmacol Biochem Behav 159:90–99

    Article  CAS  PubMed  Google Scholar 

  • Tayebati SK, Tomassoni D, Di Stefano A, Sozio P, Cerasa LS, Amenta F (2011) Effect of choline-containing phospholipids on brain cholinergic transporters in the rat. J Neurol Sci 302(1–2):49–57

    Article  CAS  PubMed  Google Scholar 

  • Tayman C, Yis U, Hirfanoglu I, Oztekin O, Göktaş G, Bilgin BC (2014) Effects of hyperglycemia on the developing brain in newborns. Pediatr Neurol 51:239–245

    Article  PubMed  Google Scholar 

  • Tiedje KE, Stevens K, Barnes S, Weaver DF (2010) β-Alanine as a small molecule neurotransmitter. Neurochem Int 57(3):177–188

    Article  CAS  PubMed  Google Scholar 

  • Vasilopoulou CG, Margarity M, Klapa MI (2016) Metabolomic analysis in brain research: opportunities and challenges. Front Physiol 7:183

    Article  PubMed  PubMed Central  Google Scholar 

  • Virel A, Dudka I, Laterveer R, af Bjerkén S (2019) 1H NMR profiling of the 6-OHDA parkinsonian rat brain reveals metabolic alterations and signs of recovery after N-acetylcysteine treatment. Mol Cell Neurosci 98:131–139

    Article  CAS  PubMed  Google Scholar 

  • Wang WT, Lee P, Yeh HW, Smirnova IV, Choi IY (2012) Effects of acute and chronic hyperglycemia on the neurochemical profiles in the rat brain with streptozotocin-induced diabetes detected using in vivo 1H MR spectroscopy at 9.4 T. J Neurochem 121(3):407–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wishart DS, Guo A, Oler E, Wang F, Anjum A, Peters H et al (2022) HMDB 5.0: the human metabolome database for 2022. Nucleic Acids Res 50(D1):622–631

    Article  Google Scholar 

  • Wu GY, Zhang Q, Wu JL, Jing L, Tan Y, Qiu TC, Zhao J (2017) Changes in cerebral metabolites in type 2 diabetes mellitus: a meta-analysis of proton magnetic resonance spectroscopy. J Clin Neurosci 45:9–13

    Article  CAS  PubMed  Google Scholar 

  • Xiong F, Gong K, Xu H, Tu Y, Lu J, Zhou Y et al (2023) Optimized integration of metabolomics and lipidomics reveals brain region-specific changes of oxidative stress and neuroinflammation in type 1 diabetic mice with cognitive decline. J Adv Res 43:233–245

    Article  CAS  PubMed  Google Scholar 

  • Zamir I, Sjöström ES, Ahlsson F, Hansen-Pupp I, Serenius F, Domellöf M (2021) Neonatal hyperglycaemia is associated with worse neurodevelopmental outcomes in extremely preterm infants. Arch Dis Child Fetal Neonatal Ed 106(5):460–466

    Article  PubMed  Google Scholar 

  • Zhang T, Zheng H, Fan K, Xia N, Li J, Yang C et al (2020) NMR-based metabolomics characterizes metabolic changes in different brain regions of streptozotocin-induced diabetic mice with cognitive decline. Metab Brain Dis 35:1165–1173

    Article  CAS  PubMed  Google Scholar 

  • Zheng H, Zheng Y, Zhao L, Chen M, Bai G, Hu Y et al (2017a) Cognitive decline in type 2 diabetic db/db mice may be associated with brain region-specific metabolic disorders. BBA-Mol Basis Dis 1863(1):266–273

    Article  CAS  Google Scholar 

  • Zheng H, Lin Q, Wang D, Xu P, Zhao L, Hu W et al (2017b) NMR-based metabolomics reveals brain region-specific metabolic alterations in streptozotocin-induced diabetic rats with cognitive dysfunction. Metab Brain Dis 32:585–593

    Article  CAS  PubMed  Google Scholar 

  • Zheng Y, Yang Y, Dong B, Zheng H, Lin X, Du Y et al (2016) Metabonomic profiles delineate potential role of glutamate-glutamine cycle in db/db mice with diabetes-associated cognitive decline. Mol Brain 9(1):1–9

    Article  CAS  Google Scholar 

  • Zheng H, Zhou Q, Du Y, Li C, Xu P, Lin L et al (2018) The hypothalamus as the primary brain region of metabolic abnormalities in APP/PS1 transgenic mouse model of Alzheimer’s disease. BBA-Mol Basis Dis 1864(1):263–273

    Article  CAS  Google Scholar 

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Funding

This work was supported by the Medical and Health Science and Technology Project of Zhejiang Province (No.: 2022KY1215).

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Author notes

  1. Yinli Huang, Junli Chen and Jiahui Lu contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, Pingyang Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325400, China

    Yinli Huang, Wei Dong, Minjie Lin & Hong Zheng

  2. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Junli Chen, Jiahui Lu, Hanqi Luo, Na Ying & Hong Zheng

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  1. Yinli Huang
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  2. Junli Chen
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  3. Jiahui Lu
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  6. Wei Dong
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  7. Minjie Lin
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  8. Hong Zheng
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Contributions

HZ contributed to the experimental design. JHL, JLC and HQL contributed to animal experiments. JHL, JLC, YLH, NY, WD and MJL contributed to the sample collection and NMR metabolomic analysis. HZ and YLH contributed to the data analysis, result interpretation and writing. All authors have read, revised and approved the final manuscript.

Corresponding author

Correspondence to Hong Zheng.

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This study was approved by the Institutional Animal Care and Use Committee of Wenzhou Medical University (Approval No.: xmsq-2022-0372).

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Huang, Y., Chen, J., Lu, J. et al. Transient neonatal hyperglycemia induces metabolic shifts in the rat hippocampus: a 1H NMR-based metabolomics analysis. Metab Brain Dis 38, 2281–2288 (2023). https://doi.org/10.1007/s11011-023-01255-x

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