Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice

Journal of Neuroinflammation

Wei-Dong Mi²  Yun-Feng Li¹  Li-Ming Zhang¹  Jiang-Bei Cao²  Xiao-Ying Zhang² 

[1] Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China;Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, China

关键词: Apoptosis;    Oxidative stress;    Memory impairment;    Iron;    Neuroinflammation;    Deferoxamine;   

Others  :  1149676
DOI  :  10.1186/s12974-015-0238-3

 received in 2014-10-13, accepted in 2015-01-06,  发布年份 2015

【 摘 要 】

Background

Neuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that the iron chelator deferoxamine (DFO) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of DFO on the cognitive sequelae of neuroinflammation is unknown.

Methods

A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effects of DFO against LPS-induced memory deficits and neuroinflammation. Adult C57BL/6 mice were treated with 0.5 μg of DFO 3 days prior to intracerebroventricular microinjection of 2 μg of LPS. Cognitive function was assessed using a Morris water maze from post-injection days 1 to 3. Animal behavioral tests, as well as pathological and biochemical assays were performed to evaluate the LPS-induced hippocampal damage and the neuroprotective effect of DFO.

Results

Treatment of mice with LPS resulted in deficits in cognitive performance in the Morris water maze without changing locomotor activity, which were ameliorated by pretreatment with DFO. DFO prevented LPS-induced microglial activation and elevations of IL-1β and TNF-α levels in the hippocampus. Moreover, DFO attenuated elevated expression of caspase-3, modulated GSK3β activity, and prevented LPS-induced increases of MDA and SOD levels in the hippocampus. DFO also significantly blocked LPS-induced iron accumulation and altered expression of proteins related to iron metabolism in the hippocampus.

Conclusions

Our results suggest that DFO may possess a neuroprotective effect against LPS-induced neuroinflammation and cognitive deficits via mechanisms involving maintenance of less brain iron, prevention of neuroinflammation, and alleviation of oxidative stress and apoptosis.

【 授权许可】

   
2015 Zhang et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Allison DJ, Ditor DS: The common inflammatory etiology of depression and cognitive impairment: a therapeutic target. J Neuroinflammation 2014, 11:151. BioMed Central Full Text
• [2]Ye SM, Johnson RW: Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 1999, 93:139-48.
• [3]Richwine AF, Godbout JP, Berg BM, Chen J, Escobar J, Millard DK, et al.: Improved psychomotor performance in aged mice fed diet high in antioxidants is associated with reduced ex vivo brain interleukin-6 production. Brain Behav Immun 2005, 19:512-20.
• [4]Hovens IB, Schoemaker RG, van der Zee EA, Absalom AR, Heineman E, van Leeuwen BL: Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning. Brain Behav Immun 2014, 38:202-10.
• [5]DeLegge MH, Smoke A: Neurodegeneration and inflammation. Nutr Clin Pract 2008, 23:35-41.
• [6]Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al.: Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007, 55:453-62.
• [7]Deng XH, Ai WM, Lei DL, Luo XG, Yan XX, Li Z: Lipopolysaccharide induces paired immunoglobulin-like receptor B (PirB) expression, synaptic alteration, and learning-memory deficit in rats. Neuroscience 2012, 209:161-70.
• [8]Rosi S, Vazdarjanova A, Ramirez-Amaya V, Worley PF, Barnes CA, Wenk GL: Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience 2006, 142:1303-15.
• [9]Zhu B, Wang ZG, Ding J, Liu N, Wang DM, Ding LC, et al.: Chronic lipopolysaccharide exposure induces cognitive dysfunction without affecting BDNF expression in the rat hippocampus. Exp Ther Med 2014, 7:750-4.
• [10]Schnydrig S, Korner L, Landweer S, Ernst B, Walker G, Otten U, et al.: Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain. Neurosci Lett 2007, 429:69-73.
• [11]Belarbi K, Jopson T, Tweedie D, Arellano C, Luo W, Greig NH, et al.: TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation 2012, 9:23. BioMed Central Full Text
• [12]Bossu P, Cutuli D, Palladino I, Caporali P, Angelucci F, Laricchiuta D, et al.: A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-α and IL-18. J Neuroinflammation 2012, 9:101. BioMed Central Full Text
• [13]Semmler A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, et al.: Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 2007, 204:733-40.
• [14]Huang HJ, Chen YH, Liang KC, Jheng YS, Jhao JJ, Su MT, et al.: Exendin-4 protected against cognitive dysfunction in hyperglycemic mice receiving an intrahippocampal lipopolysaccharide injection. PLoS One 2012, 7:e39656.
• [15]Liu X, Wu Z, Hayashi Y, Nakanishi H: Age-dependent neuroinflammatory responses and deficits in long-term potentiation in the hippocampus during systemic inflammation. Neuroscience 2012, 216:133-42.
• [16]Thomson LM, Sutherland RJ: Systemic administration of lipopolysaccharide and interleukin-1β have different effects on memory consolidation. Brain Res Bull 2005, 67:24-9.
• [17]Kim JJ, Diamond DM: The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002, 3:453-62.
• [18]Monje ML, Toda H, Palmer TD: Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003, 302:1760-5.
• [19]Hritcu L, Ciobica A, Stefan M, Mihasan M, Palamiuc L, Nabeshima T: Spatial memory deficits and oxidative stress damage following exposure to lipopolysaccharide in a rodent model of Parkinson’s disease. Neurosci Res 2011, 71:35-43.
• [20]Ke Y, Qian ZM: Brain iron metabolism: neurobiology and neurochemistry. Prog Neurobiol 2007, 83:149-73.
• [21]Isaya G: Mitochondrial iron-sulfur cluster dysfunction in neurodegenerative disease. Front Pharmacol 2014, 5:29.
• [22]Perez VP, de Lima MN, da Silva RS, Dornelles AS, Vedana G, Bogo MR, et al.: Iron leads to memory impairment that is associated with a decrease in acetylcholinesterase pathways. Curr Neurovasc Res 2010, 7:15-22.
• [23]Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, et al.: Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease. Proc Natl Acad Sci U S A 2008, 105:18578-83.
• [24]Mastroberardino PG, Hoffman EK, Horowitz MP, Betarbet R, Taylor G, Cheng D, et al.: A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease. Neurobiol Dis 2009, 34:417-31.
• [25]Pierce A, Legrand D, Mazurier J: [Lactoferrin: a multifunctional protein]. Med Sci 2009, 25:361-9.
• [26]Raha AA, Vaishnav RA, Friedland RP, Bomford A, Raha-Chowdhury R: The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease. Acta Neuropathol Commun 2013, 1:55. BioMed Central Full Text
• [27]Kalmovarin N, Friedrichs WE, O’Brien HV, Linehan LA, Bowman BH, Yang F: Extrahepatic expression of plasma protein genes during inflammation. Inflammation 1991, 15:369-79.
• [28]Double KL, Halliday GM: New face of neuromelanin. J Neural Transm Suppl 2006, 70:119-23.
• [29]Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, et al.: The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 2008, 455:992-6.
• [30]Johansson AC, Appelqvist H, Nilsson C, Kagedal K, Roberg K, Ollinger K: Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis 2010, 15:527-40.
• [31]Ke Y, Ming QZ: Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol 2003, 2:246-53.
• [32]Droge W, Schipper HM: Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 2007, 6:361-70.
• [33]Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR: Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 2004, 5:863-73.
• [34]Jomova K, Vondrakova D, Lawson M, Valko M: Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 2010, 345:91-104.
• [35]Ong WY, Farooqui AA: Iron, neuroinflammation, and Alzheimer’s disease. J Alzheimers Dis 2005, 8:183-200. discussion 209–115
• [36]Gonzalez H, Elgueta D, Montoya A, Pacheco R: Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 2014, 274:1-13.
• [37]Cahill CM, Lahiri DK, Huang X, Rogers JT: Amyloid precursor protein and α synuclein translation, implications for iron and inflammation in neurodegenerative diseases. Biochim Biophys Acta 2009, 1790:615-28.
• [38]Myhre O, Utkilen H, Duale N, Brunborg G, Hofer T: Metal dyshomeostasis and inflammation in Alzheimer’s and Parkinson’s diseases: possible impact of environmental exposures. Oxid Med Cell Longev 2013, 2013:726954.
• [39]Lovejoy DB, Guillemin GJ: The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis. Front Aging Neurosci 2014, 6:173.
• [40]Skelly DT, Hennessy E, Dansereau MA, Cunningham C: A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, [corrected] TNF-α and IL-6 challenges in C57BL/6 mice. PLoS One 2013, 8:e69123.
• [41]Hua F, Wang J, Ishrat T, Wei W, Atif F, Sayeed I, et al.: Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone. J Neuroinflammation 2011, 8:42. BioMed Central Full Text
• [42]Niesman IR, Schilling JM, Shapiro LA, Kellerhals SE, Bonds JA, Kleschevnikov AM, et al.: Traumatic brain injury enhances neuroinflammation and lesion volume in caveolin deficient mice. J Neuroinflammation 2014, 11:39. BioMed Central Full Text
• [43]Vorhees CV, Williams MT: Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006, 1:848-58.
• [44]Stokes JA, Cheung J, Eddinger K, Corr M, Yaksh TL: Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice. J Neuroinflammation 2013, 10:148. BioMed Central Full Text
• [45]An LN, Yue Y, Guo WZ, Miao YL, Mi WD, Zhang H, et al.: Surgical trauma induces iron accumulation and oxidative stress in a rodent model of postoperative cognitive dysfunction. Biol Trace Elem Res 2013, 151:277-83.
• [46]Astrand E, Wardak C, Ben HS: Selective visual attention to drive cognitive brain-machine interfaces: from concepts to neurofeedback and rehabilitation applications. Front Syst Neurosci 2014, 8:144.
• [47]Reichlin S: Neuroendocrinology of acute immunity. J Endocrinol Invest 2004, 27(Suppl 6):48-61.
• [48]Park SE, Dantzer R, Kelley KW, McCusker RH: Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice. J Neuroinflammation 2011, 8:12. BioMed Central Full Text
• [49]Zielasek J, Hartung HP: Molecular mechanisms of microglial activation. Adv Neuroimmunol 1996, 6:191-2.
• [50]Raber J, Sorg O, Horn TF, Yu N, Koob GF, Campbell IL, et al.: Inflammatory cytokines: putative regulators of neuronal and neuro-endocrine function. Brain Res Brain Res Rev 1998, 26:320-6.
• [51]McGeer PL, McGeer EG: Inflammation and the degenerative diseases of aging. Ann N Y Acad Sci 2004, 1035:104-16.
• [52]Ren L, Lubrich B, Biber K, Gebicke-Haerter PJ: Differential expression of inflammatory mediators in rat microglia cultured from different brain regions. Brain Res Mol Brain Res 1999, 65:198-205.
• [53]Porter AG, Janicke RU: Emerging roles of caspase-3 in apoptosis. Cell Death Differ 1999, 6:99-104.
• [54]Guo C, Wang P, Zhong ML, Wang T, Huang XS, Li JY, et al.: Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int 2013, 62:165-72.
• [55]Kim YM, Song I, Seo YH, Yoon G: Glycogen synthase kinase 3 inactivation induces cell senescence through sterol regulatory element binding protein 1-mediated lipogenesis in chang cells. Endocrinol Metab (Seoul) 2013, 28:297-308.
• [56]Koskenkorva-Frank TS, Weiss G, Koppenol WH, Burckhardt S: The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress. Free Radic Biol Med 2013, 65:1174-94.
• [57]Thomas C, Mackey MM, Diaz AA, Cox DP: Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep 2009, 14:102-8.
• [58]Simonnet Garcia MH: [Contributions of medical hypnosis to DFO treatment]. Orthod Fr 2014, 85:287-97.
• [59]Guo C, Wang T, Zheng W, Shan ZY, Teng WP, Wang ZY: Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging 2013, 34:562-75.
• [60]Fine JM, Forsberg AC, Renner DB, Faltesek KA, Mohan KG, Wong JC, et al.: Intranasally-administered deferoxamine mitigates toxicity of 6-OHDA in a rat model of Parkinsons disease. Brain Res 2014, 1574:96-104.
• [61]Weinreb O, Mandel S, Youdim MB, Amit T: Targeting dysregulation of brain iron homeostasis in Parkinson’s disease by iron chelators. Free Radic Biol Med 2013, 62:52-64.
• [62]Zhang WJ, Wei H, Frei B: The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice. Exp Biol Med (Maywood) 2010, 235:633-41.
• [63]da Pinheiro Silva F, Machado MC, Velasco IT: Neuropeptides in sepsis: from brain pathology to systemic inflammation. Peptides 2013, 44:135-8.
• [64]Hernandes MS, D’Avila JC, Trevelin SC, Reis PA, Kinjo ER, Lopes LR, et al.: The role of Nox2-derived ROS in the development of cognitive impairment after sepsis. J Neuroinflammation 2014, 11:36. BioMed Central Full Text
• [65]D’Hooge R, De Deyn PP: Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 2001, 36:60-90.
• [66]Dong Z, Bai Y, Wu X, Li H, Gong B, Howland JG, et al.: Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze. Neuropharmacology 2013, 64:65-73.
• [67]Brandeis R, Brandys Y, Yehuda S: The use of the Morris Water Maze in the study of memory and learning. Int J Neurosci 1989, 48:29-69.
• [68]Huang Y, Henry CJ, Dantzer R, Johnson RW, Godbout JP: Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol Aging 2008, 29:1744-53.
• [69]Fu X, Zunich SM, O’Connor JC, Kavelaars A, Dantzer R, Kelley KW: Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures. J Neuroinflammation 2010, 7:43. BioMed Central Full Text
• [70]Lawson MA, McCusker RH, Kelley KW: Interleukin-1β converting enzyme is necessary for development of depression-like behavior following intracerebroventricular administration of lipopolysaccharide to mice. J Neuroinflammation 2013, 10:54. BioMed Central Full Text
• [71]Zhang Z, Zhang K, Du X, Li Y: Neuroprotection of desferrioxamine in lipopolysaccharide-induced nigrostriatal dopamine neuron degeneration. Mol Med Rep 2012, 5:562-6.
• [72]Hoffbrand AV, Wonke B: Iron chelation therapy. J Intern Med Suppl 1997, 740:37-41.
• [73]Cabantchik ZI, Munnich A, Youdim MB, Devos D: Regional siderosis: a new challenge for iron chelation therapy. Front Pharmacol 2013, 4:167.
• [74]Kakhlon O, Manning H, Breuer W, Melamed-Book N, Lu C, Cortopassi G, et al.: Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation. Blood 2008, 112:5219-27.
• [75]Zhang R, Huang Q, Zou L, Cao X, Huang H, Chu X: Beneficial effects of deferoxamine against astrocyte death induced by modified oxygen glucose deprivation. Brain Res 2014, 1583:23-33.
• [76]Ownby RL: Neuroinflammation and cognitive aging. Curr Psychiatry Rep 2010, 12:39-45.
• [77]Saijo K, Glass CK: Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 2011, 11:775-87.
• [78]Mairuae N, Connor JR, Cheepsunthorn P: Increased cellular iron levels affect matrix metalloproteinase expression and phagocytosis in activated microglia. Neurosci Lett 2011, 500:36-40.
• [79]Wang G, Wang W, Zhao J, Ni Y, Zhou X, Zhang W: Ghrelin prevents neuronal apoptosis and cognitive impairments in sepsis-associated encephalopathy. Neuroreport 2011, 22:959-64.
• [80]Zhou TF, Yu JG: Recombinant human erythropoietin attenuates neuronal apoptosis and cognitive defects via JAK2/STAT3 signaling in experimental endotoxemia. J Surg Res 2013, 183:304-12.
• [81]He Y, Zhou A, Jiang W: Toll-like receptor 4-mediated signaling participates in apoptosis of hippocampal neurons. Neural Regen Res 2013, 8:2744-53.
• [82]Abdi A, Sadraie H, Dargahi L, Khalaj L, Ahmadiani A: Apoptosis inhibition can be threatening in Aβ-induced neuroinflammation, through promoting cell proliferation. Neurochem Res 2011, 36:39-48.
• [83]Martin M, Rehani K, Jope RS, Michalek SM: Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 2005, 6:777-84.
• [84]Jope RS, Yuskaitis CJ, Beurel E: Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res 2007, 32:577-95.
• [85]Llorens-Martin M, Fuster-Matanzo A, Teixeira CM, Jurado-Arjona J, Ulloa F, Defelipe J, et al.: GSK-3β overexpression causes reversible alterations on postsynaptic densities and dendritic morphology of hippocampal granule neurons in vivo. Mol Psychiatry 2013, 18:451-60.
• [86]Uranga RM, Giusto NM, Salvador GA: Iron-induced oxidative injury differentially regulates PI3K/Akt/GSK3β pathway in synaptic endings from adult and aged rats. Toxicol Sci 2009, 111:331-44.
• [87]Qian ZM, He X, Liang T, Wu KC, Yan YC, Lu LN, et al.: Lipopolysaccharides upregulate hepcidin in neuron via microglia and the IL-6/STAT3 signaling pathway. Mol Neurobiol 2014, 50:811-20.
• [88]Urrutia P, Aguirre P, Esparza A, Tapia V, Mena NP, Arredondo M, et al.: Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells. J Neurochem 2013, 126:541-9.
• [89]Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X, et al.: Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 2010, 59:290-4.
• [90]de Silva DM, Aust SD: Ferritin and ceruloplasmin in oxidative damage: review and recent findings. Can J Physiol Pharmacol 1993, 71:715-20.