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A novel hippocampus metabolite signature in diabetes mellitus rat model of diabetic encephalopathy

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Abstract

Diabetic encephalopathy (DE) is one of the chronic complications of diabetes. Even then, the molecular mechanism underlying DE remains unexplored. In this study, we have made an attempt to investigate the metabolic changes associated with the streptozocin (STZ)-induced cognitive dysfunction in the hippocampus of the rat model, a classical rodent model for DE, with the help of Gas Chromatography-Mass Spectrometry-based method. The STZ injections led to the rise of mean blood glucose levels in the diabetes mellitus (DM) group of rats as compared to the control (CON) group of rats throughout the experiment. However, we did not find any significant difference between the blood glucose levels of the DM & the CON groups of rats before the STZ injection. The results indicated a behavioral and morphological cognitive dysfunction in the DM groups of rats. The metabolomic investigation of these DE rats demonstrated a lower level of N-acetylaspartate and dihydroxyacetone phosphate accompanied by a higher level of homocysteine and glutamate as against the CON group of rats. The outcome of this study may unravel the underlying pathophysiological mechanism of DE. Also, the metabolomic data from this study may provide a platform for the development of DE biomarkers.

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Abbreviations

STZ:

Streptozocin

GC/MS:

Gas Chromatography-Mass Spectrometry

LC/MS:

Liquid Chromatography-Mass Spectrum

NMR:

Nuclear magnetic resonance

CON:

CON

DM:

Diabetes mellitus

FBG:

Fasting blood glucose

MWM:

Morris water maze

H&E:

Hematoxylin-eosin staining

TEM:

Transmission electron microscopy

PCA:

Principal components analysis

PLS-DA:

Partial least squares discriminant analysis

OPLS-DA:

Pair-wise orthogonal projections to latent structures discriminant

UV:

Unit variance

VIP:

Variable influence on projection

NAA:

N-acetylaspartate

DHAP:

Dihydroxyacetone phosphate

References

  • Alagiakrishnan K, Sankaralingam S, Ghosh M, Mereu L, Senior P (2013) Antidiabetic drugs and their potential role in treating mild cognitive impairment and Alzheimer’s disease. Discov Med 16:277–286

    PubMed  Google Scholar 

  • Alvarez EO, Ruarte MB (2002) Histaminergic neurons of the ventral hippocampus and the baso-lateral amygdala of the rat: functional interaction on memory and learning mechanisms. Behav Brain Res 128:81–90

    Article  Google Scholar 

  • Alzoubi KH, Aleisa AM, Alkadhi KA Impairment of long-term potentiation in the CA1, but not dentate gyrus, of the hippocampus in Obese Zucker rats. J Mol Neurosci 27:337–346

  • Bao Y, Zhao T, Wang X, Qiu Y, Su M, Jia W, Jia W (2009) Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteers. J Proteome Res 8:1623–1630

    Article  CAS  Google Scholar 

  • Becker A, Smulders YM, van Guldener C, Stehouwer CD (2003) Epidemiology of homocysteine as a risk factor in diabetes. Metab Syndr Relat Disord 1:105–120

    Article  CAS  Google Scholar 

  • Bentley-Lewis R, Huynh J, Xiong G, Lee H, Wenger J, Clish C, Nathan D, Thadhani R, Gerszten R (2015) Metabolomic profiling in the prediction of gestational diabetes mellitus. Diabetologia. 58:1329–1332

    Article  CAS  Google Scholar 

  • Carbone L (2012) Pain management standards in the eighth edition of the guide for the care and use of laboratory animals. Journal of the American Association for Laboratory Animal Science : JAALAS 51:322–328

    CAS  PubMed  Google Scholar 

  • Cetin I, de Santis MS, Taricco E, Radaelli T, Teng C, Ronzoni S, Spada E, Milani S, Pardi G (2005) Maternal and fetal amino acid concentrations in normal pregnancies and in pregnancies with gestational diabetes mellitus. Am J Obstet Gynecol 192:610–617

    Article  CAS  Google Scholar 

  • Cuadros-Inostroza A (2016) GC–MS metabolic profiling of Cabernet Sauvignon and Merlot cultivars during grapevine berry development and network analysis reveals a stage- and cultivar-dependent connectivity of primary metabolites. Metabolomics 12:39

    Article  Google Scholar 

  • de Luis DA, Fernandez N, Arranz M, Aller R, Izaola O (2002) Total homocysteine and cognitive deterioration in people with type 2 diabetes. Diabetes Res Clin Pract 55:185–190

    Article  Google Scholar 

  • Feng L, Isaac V, Sim S, Ng TP, Krishnan KR, Chee MW (2013) Associations between elevated homocysteine, cognitive impairment, and reduced white matter volume in healthy old adults. The American Journal of Geriatric Psychiatry : Official Journal of the American Association for Geriatric Psychiatry 21:164–172

    Article  Google Scholar 

  • Grillo CA, Piroli GG, Wood GE, Reznikov LR, Mcewen BS, Reagan LP, Grillo CA, Piroli GG, Wood GE, Reznikov LR, BS ME, Reagan LP (2005) Immunocytochemical analysis of synaptic proteins provides new insights into diabetes-mediated plasticity in the rat hippocampus. Neuroscience 136:477–486

    Article  CAS  Google Scholar 

  • Hascup ER, Broderick SO, Russell MK, Fang Y, Bartke A, Boger HA et al (2019) Diet-induced insulin resistance elevates hippocampal glutamate as well as VGLUT1 and GFAP expression in AbetaPP/PS1 mice. 148:219–237

  • Hatano T, Saiki S, Okuzumi A, Mohney RP, Hattori N (n.d.) Identification of novel biomarkers for Parkinson\"s disease by metabolomic technologies. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2014-309676

  • Heijer TD, Vermeer SE, Dijk EJ, Prins ND, Koudstaal PJ, Hofman A et al Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46:1604–1610

  • Hušek P, Švagera Z, Hanzlíková D, Řimnáčová L, Zahradníčková H, Opekarová I et al Profiling of urinary amino-carboxylic metabolites by in-situ heptafluorobutyl chloroformate mediated sample preparation and gas chromatography–mass spectrometry. J Chromatogr A 1443:211–232

  • Ibrahim FA, Wahba ME (2014) Orthogonal projection to latent structures combined with artificial neural networks in non-destructive analysis of ebastine powder. Acta Chim Slov 61:11–18

    CAS  PubMed  Google Scholar 

  • Jahagirdar V, Ramcharitar J, Cotero VE, McNay EC (2012) Moderate recurrent hypoglycemia markedly impairs set-shifting ability in a rodent model: cognitive and neurochemical effects. The Open Diabetes Journal 5:1–7

    Article  Google Scholar 

  • Johnson CH, Ivanisevic J, Siuzdak G Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol

  • Korf ESC, White LR, Scheltens P, Launer LJ Brain aging in very old men with type 2 diabetes: the Honolulu-Asia aging study. Diabetes Care 29:2268–2274

  • Kyriakides M, Rama N, Sidhu J, Gabra H, El-Bahrawy M (2016) Metabonomic analysis of ovarian tumour cyst fluid by proton nuclear magnetic resonance spectroscopy. Oncotarget 7:7216–7226

    Article  Google Scholar 

  • Launer LJ Diabetes and brain aging: Epidemiologic evidence. 5:59–63

  • Li J, Wang P, Zhu Y, Chen Z, Shi T, Lei W et al (2015) Curcumin inhibits neuronal loss in the retina and elevates Ca(2)(+)/calmodulin-dependent protein kinase II activity in diabetic rats. Journal of Ocular Pharmacology and Therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 31:555–562

    Article  CAS  Google Scholar 

  • Luedemann A, Strassburg K, Erban A, Kopka J (2008) TagFinder for the quantitative analysis of gas chromatography--mass spectrometry (GC-MS)-based metabolite profiling experiments. Bioinformatics (Oxford, England) 24:732–737

    Article  CAS  Google Scholar 

  • Magarinos AM, McEwen BS Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress. Proc Natl Acad Sci 97:11056–11061

  • Mangia S, Kumar AF, Moheet AA, Roberts RJ, Eberly LE, Seaquist ER et al (2013) Neurochemical profile of patients with type 1 diabetes measured by (1)H-MRS at 4 T. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 33:754–759

    Article  CAS  Google Scholar 

  • McEntee WJ, Crook TH (1993) Glutamate: its role in learning, memory, and the aging brain. Psychopharmacology. 111:391–401

    Article  CAS  Google Scholar 

  • Mcfarland MS, Cripps R (2010) Diabetes mellitus and increased risk of cancer: focus on metformin and the insulin analogs. Pharmacotherapy the Journal of Human Pharmacology & Drug Therapy 30:1159–1178

    Article  CAS  Google Scholar 

  • Miao Y, He T (2015) Activation of hippocampal CREB by Rolipram partially recovers balance between TNF-α and IL-10 levels and improves cognitive deficits in diabetic rats. Cell Mol Neurobiol 35:1157–1164

  • Ndrepepa G, Kastrati A, Braun S, Koch W, Kolling K, Mehilli J et al (2008) Circulating homocysteine levels in patients with type 2 diabetes mellitus. Nutrition, Metabolism, and Cardiovascular Diseases : NMCD 18:66–73

    Article  CAS  Google Scholar 

  • Nunes AR, Alves MG, Tomas GD, Conde VR, Cristovao AC, Moreira PI et al (2015) Daily consumption of white tea (Camellia sinensis (L.)) improves the cerebral cortex metabolic and oxidative profile in prediabetic Wistar rats. Br J Nutr 113:832–842

    Article  CAS  Google Scholar 

  • Okubo Y, Sekiya H, Namiki S, Sakamoto H, Iinuma S, Yamasaki M, Watanabe M, Hirose K, Iino M (2010) Imaging extrasynaptic glutamate dynamics in the brain. Proc Natl Acad Sci U S A 107:6526–6531

    Article  CAS  Google Scholar 

  • Reisi P, Alaei H, Babri S, Sharifi MR, Mohaddes G, Soleimannejad E (2009) Determination of the extracellular basal levels of glutamate and GABA at dentate gyrus of streptozotocin-induced diabetic rats. Pathophysiology : the Official Journal of the International Society for Pathophysiology 16:63–66

    Article  CAS  Google Scholar 

  • Reisi P, Alaei H, Babri S, Sharifi MR, Mohaddes G, Soleimannejad E, Rashidi B (2010) Effects of treadmill running on extracellular basal levels of glutamate and GABA at dentate gyrus of streptozotocin-induced diabetic rats. Journal of Research in Medical Sciences : the Official Journal of Isfahan University of Medical Sciences 15:172–174

    Google Scholar 

  • Reynolds LM, Reynolds GP (2011) Differential regional N-acetylaspartate deficits in postmortem brain in schizophrenia, bipolar disorder and major depressive disorder. J Psychiatr Res 45:54–59

    Article  Google Scholar 

  • Robbins MA, Elias MF, Budge MM, Brennan SL, Elias PK (2005) Homocysteine, type 2 diabetes mellitus, and cognitive performance: the Maine-Syracuse study. Clin Chem Lab Med 43:1101–1106

    Article  CAS  Google Scholar 

  • Sasaki-Hamada S, Tamaki K, Otsuka H, Ueno T, Sacai H, Niu Y, Matsumoto K, Oka J (2014) Chotosan, a Kampo formula, ameliorates hippocampal LTD and cognitive deficits in juvenile-onset diabetes rats. J Pharmacol Sci 124:192–200

    Article  CAS  Google Scholar 

  • Shi X, Zhang Y, Niu H, Wang R, Shen J, Zhou S et al (2016) Correlation between cognitive impairment and diabetic nephropathy in patients with Type 2 diabetes mellitus. Zhong nan da xue xue bao Yi xue ban = Journal of Central South University Medical sciences 41:143–150

    CAS  PubMed  Google Scholar 

  • Shimomura T, Anan F, Masaki T, Umeno Y, Eshima N, Saikawa T, Yoshimatsu H, Fujiki M, Kobayashi H (2011) Homocysteine levels are associated with hippocampus volume in type 2 diabetic patients. Eur J Clin Investig 41:751–758

    Article  CAS  Google Scholar 

  • Sima AA (2010) Encephalopathies: the emerging diabetic complications. Acta Diabetol 47:279–293

    Article  CAS  Google Scholar 

  • Sinha S, Ekka M, Sharma U, Raghunandan P, Pandey RM, Jagannathan NR (2014) Assessment of changes in brain metabolites in Indian patients with type-2 diabetes mellitus using proton magnetic resonance spectroscopy. BMC Res Notes 7:41

    Article  Google Scholar 

  • Slawek J, Roszmann A, Robowski P, Dubaniewicz M, Sitek EJ, Honczarenko K et al (2013) The impact of MRI white matter hyperintensities on dementia in Parkinson's disease in relation to the homocysteine level and other vascular risk factors. Neurodegener Dis 12:1–12

    Article  CAS  Google Scholar 

  • Soininen H, Puranen M, Helkala E-L, Laakso M, Riekkinen PJ Diabetes mellitus and brain atrophy: a computed tomography study in an elderly population. Neurobiol Aging 13:717–721

  • Squire LR (1992) Memory and the Hippocampus : finding with rats, monkeys, and humans. Psychol Rev 99

  • Tian Y, Nie X, Xu S, Li Y, Huang T, Tang H et al Integrative metabonomics as potential method for diagnosis of thyroid malignancy. Sci Rep 5:14869

  • Tong J, Geng H, Zhang Z, Zhu X, Meng Q, Sun X et al (2014) Brain metabolite alterations demonstrated by proton magnetic resonance spectroscopy in diabetic patients with retinopathy. Magn Reson Imaging 32:1037–1042

    Article  CAS  Google Scholar 

  • Tuzcu M, Baydas G Effect of melatonin and vitamin E on diabetes-induced learning and memory impairment in rats. 537:106–110

  • Valastro B, Cossette J, Lavoie N, Gagnon S, Trudeau F, Massicotte G (2002) Up-regulation of glutamate receptors is associated with LTP defects in the early stages of diabetes mellitus. Diabetologia. 45:642–650

    Article  CAS  Google Scholar 

  • Veyrat-Durebex C, Corcia P, Piver E, Devos D, Dangoumau A, Gouel F et al Disruption of TCA cycle and glutamate metabolism identified by metabolomics in an in vitro model of amyotrophic lateral sclerosis

  • Wang X, Zhao L Calycosin ameliorates diabetes-induced cognitive impairments in rats by reducing oxidative stress via the PI3K/Akt/GSK-3β signaling pathway. Biochem Biophys Res Commun S0006291X16303370

  • Yang R, Chen RP, Chen H, Zhang H, Cai DH (2014) Folic acid attenuates cognitive dysfunction in streptozotocin-induced diabetic rats. Int J Clin Exp Med 7:4214–4219

    PubMed  PubMed Central  Google Scholar 

  • Zhang H, Huang M, Gao L, Lei H (2015) Region-specific cerebral metabolic alterations in streptozotocin-induced type 1 diabetic rats: an in vivo proton magnetic resonance spectroscopy study. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 35:1738–1745

    Article  CAS  Google Scholar 

  • Zheng H, Zhao L, Xia H, Xu C, Wang D, Liu K et al (2015) NMR-based metabolomics reveal a recovery from metabolic changes in the striatum of 6-OHDA-induced rats treated with basic fibroblast growth factor. 53:1–8

  • Zhou X, Zhu Q, Han X, Chen R, Liu Y, Fan H, Yin X (2015) Quantitative-profiling of neurotransmitter abnormalities in the disease progression of experimental diabetic encephalopathy rat. Can J Physiol Pharmacol 93:1007–1013

    Article  CAS  Google Scholar 

  • Zhu B, Jiang RY, Yang C, Liu N (2015) Adenosine monophosphate-activated protein kinase activation mediates the leptin-induced attenuation of cognitive impairment in a streptozotocin-induced rat model. Exp Ther Med 9:1998–2002

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 812310026).

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Author notes

  1. Guanghui Chen and Yizhong Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430071, China

    Guanghui Chen

  2. Xiangyang No.1 People’ Hospital, Hubei University of Medicine, Xiangyang, 441000, China

    Yizhong Wang

  3. Department of Pharmacy, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430071, China

    Yang Li

  4. Department of Neurology, Renmin Hospital of Wuhan University, 430071, No.99, Zhang zhi dong Road, Wuchang District, Wuhan, Hubei Province, China

    Lujun Zhang & Meixue Dong

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  1. Guanghui Chen
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  4. Lujun Zhang
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Guanghui Chen and Meixue Dong performed the research; Lujun Zhang and Yang Li analysed the data; Guanghui Chen and Yizhong Wang wrote and revised the paper; all authors approved the final manuscript.

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Correspondence to Meixue Dong.

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Chen, G., Wang, Y., Li, Y. et al. A novel hippocampus metabolite signature in diabetes mellitus rat model of diabetic encephalopathy. Metab Brain Dis 35, 895–904 (2020). https://doi.org/10.1007/s11011-020-00541-2

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