Deoxyglucose prevents neurodegeneration in culture by eliminating microglia

Journal of Neuroinflammation

Guy C Brown¹  Anna Vilalta¹ 

[1] Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK

关键词: Glucose;    Microglia;    Glia;    Energetics;    Alzheimer’s disease;    Brain ischemia;    Brain trauma;    Neuroinflammation;    Glycolysis;    Neurodegeneration;   

Others  :  815159
DOI  :  10.1186/1742-2094-11-58

 received in 2013-10-17, accepted in 2014-03-10,  发布年份 2014

【 摘 要 】

Background

2-Deoxy-D-glucose is an inhibitor of glycolysis, which is protective in animal models of brain pathology, but the mechanisms of this protection are unclear. We examined whether, when and how deoxyglucose protects neurons in co-culture with astrocytes and microglia. Microglia are brain macrophages, which can damage neurons in inflammatory conditions.

Methods

Deoxyglucose was added to primary cultures of microglia and astrocytes from rat cortex, or neurons and glia from rat cerebellum, or the BV-2 microglial cell line, and cell death and cell functions were evaluated.

Results

Surprisingly, addition of deoxyglucose induced microglial loss and prevented spontaneous neuronal loss in long-term cultures of neurons and glia, while elimination of microglia by L-leucine-methyl ester prevented the deoxyglucose-induced neuroprotection. Deoxyglucose also prevented neuronal loss induced by addition of amyloid beta or disrupted neurons (culture models of Alzheimer’s disease and brain trauma respectively). However, deoxyglucose greatly increased the neuronal death induced by hypoxia. Addition of deoxyglucose to pure microglia induced necrosis and loss, preceded by rapid ATP depletion and followed by phagocytosis of the microglia. Deoxyglucose did not kill astrocytes or neurons.

Conclusions

We conclude that deoxyglucose causes microglial loss by ATP depletion, and this can protect neurons from neurodegeneration, except in conditions of hypoxia. Deoxyglucose may thus be beneficial in brain pathologies mediated by microglia, including brain trauma, but not where hypoxia is involved.

【 授权许可】

   
2014 Vilalta and Brown; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Pelicano H, Martin DS, Xu RH, Huang P: Glycolysis inhibition for anticancer treatment. Oncogene 2006, 25:4633-4646.
• [2]Maher JC, Krishan A, Lampidis TJ: Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol 2004, 53:116-122.
• [3]Lee J, Bruce-Keller AJ, Kruman Y, Chan SL, Mattson MP: 2-Deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: evidence for the involvement of stress proteins. J Neurosci Res 1999, 57:48-61.
• [4]Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender RM, Morrison JF, Ockuly J, Stafstrom C, Sutula T, Roopra A: 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP–dependent metabolic regulation of chromatin structure. Nat Neurosci 2006, 9:1382-1387.
• [5]Tariq M, Khan HA, al Moutaery K, al Deeb S: Protection by 2-deoxy-D-glucose against β, β′-iminodipropionitrile-induced neurobehavioral toxicity in mice. Exp Neurol 1999, 1:229-233.
• [6]Dwarakanath BS, Singh D, Banerji AK, Sarin R, Venkataramana NK, Jalali R, Vishwanath PN, Mohanti BK, Tripathi RP, Kalia VK, Jain V: Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: present status and future prospects. J Cancer Res Ther 2009, 5(Suppl 1):21-26.
• [7]Duan W, Mattson MP: Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J Neurosci Res 1999, 57:195-206.
• [8]Yao J, Chen S, Mao Z, Cadenas E, Brinton RD: 2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer’s disease. PLoS One 2011, 6:e21788.
• [9]Nasrallah FA, Pagès G, Kuchel PW, Golay X, Chuang KH: Imaging brain deoxyglucose uptake and metabolism by glucoCEST MRI. J Cereb Blood Flow Metab 2013, 33:1270-1278.
• [10]Ockuly JC, Gielissen JM, Levenick CV, Zeal C, Groble K, Munsey K, Sutula TP, Stafstrom CE: Behavioral, cognitive, and safety profile of 2-deoxy-2-glucose (2DG) in adult rats. Epilepsy Res 2012, 101:246-252.
• [11]Ingram DK, Roth GS: Glycolytic inhibition as a strategy for developing calorie restriction mimetics. Exp Gerontol 2011, 46:148-154.
• [12]Kettenmann H, Hanisch U, Noda M, Verkhratsky A: Physiology of microglia. Physiol Rev 2011, 91:461-553.
• [13]Block ML, Zecca L, Hong JS: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007, 8:57-69.
• [14]Brown GC, Neher JJ: Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol 2010, 41:242-247.
• [15]Sierra A, Abiega O, Shahraz A, Neumann H: Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci 2013, 7:6.
• [16]Maezawa I, Zimin PI, Wulff H, Jin LW: Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J Biol Chem 2011, 286:3693-3706.
• [17]Neniskyte U, Neher JJ, Brown GC: Neuronal death induced by nanomolar amyloid β is mediated by primary phagocytosis of neurons by microglia. J Biol Chem 2011, 286:39904-39913.
• [18]Loane DJ, Byrnes KR: Role of microglia in neurotrauma. Neurotherapeutics 2010, 7:366-377.
• [19]Kumar A, Loane DJ: Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun 2012, 26:1191-1201.
• [20]Mioduszewska B, Jaworski J, Szklarczyk AW, Klejman A, Kaczmarek L: Inducible cAMP early repressor (ICER)-evoked delayed neuronal death in the organotypic hippocampal culture. J Neurosci Res 2008, 86:61-70.
• [21]Wang Y, Neumann H: Alleviation of neurotoxicity by microglial human Siglec-11. J Neurosci 2010, 30:3482-3488.
• [22]Kinsner A, Pilotto V, Deininger S, Brown GC, Coecke S, Hartung T, Bal-Price A: Inflammatory neurodegeneration induced by lipoteichoic acid from Staphylococcus aureus is mediated by glia activation, nitrosative and oxidative stress, and caspase activation. J Neurochem 2005, 95:1132-1143.
• [23]Bal-Price A, Brown GC: Inflammatory neurodegeneration mediated by nitric oxide from activated glia, inhibiting neuronal respiration, causing glutamate release and excitoxicity. J Neurosci 2001, 21:6480-6491.
• [24]Hamby ME, Uliasz TF, Hewett SJ, Hewett JA: Characterization of an improved procedure for the removal of microglia from confluent monolayers of primary astrocytes. J Neurosci Methods 2006, 150:128-137.
• [25]Neher JJ, Neniskyte U, Zhao ZW, Bal-Price A, Tolkovsky AM, Brown GC: Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J Immunol 2011, 186:4973-4983.
• [26]Neniskyte U, Brown GC: Lactadherin/MFG-E8 is essential for microglia-mediated neuronal loss and phagoptosis induced by amyloid β. J Neurochem 2013, 126:312-317.
• [27]Kurtoglu M, Gao N, Shang J, Maher JC, Lehrman MA, Wangpaichitr M, Savaraj N, Lane AN, Lampidis TJ: Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation. Mol Cancer Ther 2007, 6:3049-3058.
• [28]Merchan JR, Kovács K, Railsback JW, Kurtoglu M, Jing Y, Piña Y, Gao N, Murray TG, Lehrman MA, Lampidis TJ: Antiangiogenic activity of 2-deoxy-D-glucose. PLoS One 2010, 5:e13699.
• [29]Xi H, Kurtoglu M, Liu H, Wangpaichitr M, You M, Liu X, Savaraj N, Lampidis TJ: 2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemother Pharmacol 2011, 67:899-910.
• [30]Bolaños JP, Almeida A, Moncada S: Glycolysis: a bioenergetic or a survival pathway? Trends Biochem Sci 2010, 35:145-149.
• [31]Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, et al.: Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 2013, 496:238-242.
• [32]Ralser M, Wamelink MM, Struys EA, Joppich C, Krobitsch S, Jakobs C, Lehrach H: A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth. Proc Natl Acad Sci U S A 2008, 105:17807-17811.
• [33]Park J, Choi H, Min JS, Park SJ, Kim JH, Park HJ, Kim B, Chae JI, Yim M, Lee DS: Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells. J Neurochem 2013, 127:221-232.
• [34]Voloboueva LA, Emery JF, Sun X, Giffard RG: Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin. FEBS Lett 2013, 587:756-762.
• [35]Witte AV, Fobker M, Gellner R, Knecht S, Flöel A: Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A 2009, 106:1255-1260.
• [36]Combs DJ, Reuland DS, Martin DB, Zelenock GB, D’Alecy LG: Glycolytic inhibition by 2-deoxyglucose reduces hyperglycemia-associated mortality and morbidity in the ischemic rat. Stroke 1986, 17:989-994.