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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1G93A mice model of ALS

Authors: Inna Rabinovich-Nikitin, Assaf Ezra, Beka Barbiro, Polina Rabinovich-Toidman, Beka Solomon

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease, involving both upper and lower motor neurons. The disease is induced by multifactorial pathologies, and as such, it requires a multifaceted therapeutic approach. CXCR4, a chemokine receptor widely expressed in neurons and glial cells and its ligand, CXCL12, also known as stromal-cell-derived factor (SDF1), modulate both neuronal function and apoptosis by glutamate release signaling as well as hematopoietic stem and progenitor cells (HSPCs) migration into the blood and their homing towards injured sites. Inhibition approaches towards the CXCR4/CXCL12 signaling may result in preventing neuronal apoptosis and alter the HSPCs migration and homing. Such inhibition can be achieved by means of treatment with AMD3100, an antagonist of the chemokine receptor CXCR4.

Methods

We chronically treated male and female transgenic mice model of ALS, SOD1G93A mice, with AMD3100. Mice body weight and motor function, evaluated by Rotarod test, were recorded once a week. The most effective treatment regimen was repeated for biochemical and histological analyses in female mice.

Results

We found that chronic administration of AMD3100 to SOD1G93A mice led to significant extension in mice lifespan and improved motor function and weight loss. In addition, the treatment significantly improved microglial pathology and decreased proinflammatory cytokines in spinal cords of treated female mice. Furthermore, AMD3100 treatment decreased blood-spinal cord barrier (BSCB) permeability by increasing tight junction proteins levels and increased the motor neurons count in the lamina X area of the spinal cord, where adult stem cells are formed.

Conclusions

These data, relevant to the corresponding disease mechanism in human ALS, suggest that blocking CXCR4 by the small molecule, AMD3100, may provide a novel candidate for ALS therapy with an increased safety.
Appendix
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Literature
1.
2.
3.
4.
Sargsyan SA, Monk PN, Shaw PJ. Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis. Glia. 2005;51:241–53.CrossRefPubMed
5.
West M, Mhatre M, Ceballos A, Floyd RA, Grammas P, Gabbita SP, Hamdheydari L, Mai T, Mou S, Pye QN, Stewart C, West S, Williamson KS, Zemlan F, Hensley K. The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice. J Neurochem. 2004;91:133–43.CrossRefPubMed
6.
Tikka TM, Vartiainen NE, Goldsteins G, Oja SS, Andersen PM, Marklund SL, Koistinaho J. Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brain. 2002;125(Pt 4):722–31.CrossRefPubMed
7.
Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Suzumura A. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology. 2004;46:404–11.CrossRefPubMed
8.
Nikodemova M, Small AL, Smith SMC, Mitchell GS, Watters JJ. Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats. Neurobiol Dis. 2014;69:43–53.CrossRefPubMedPubMedCentral
9.
Roberts K, Zeineddine R, Corcoran L, Li W, Campbell IL, Yerbury JJ. Extracellular aggregated Cu/Zn superoxide dismutase activates microglia to give a cytotoxic phenotype. Glia. 2013;61:409–19.CrossRefPubMed
10.
Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006;312:1389–92.CrossRefPubMed
11.
Kim Y-J, Park H-J, Lee G, Bang OY, Ahn YH, Joe E, Kim HO, Lee PH. Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia. 2009;57:13–23.CrossRefPubMed
12.
Ohtaki H, Ylostalo JH, Foraker JE, Robinson AP, Reger RL, Shioda S, Prockop DJ. Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses. Proc Natl Acad Sci U S A. 2008;105:14638–43.CrossRefPubMedPubMedCentral
13.
Sheikh AM, Nagai A, Wakabayashi K, Narantuya D, Kobayashi S, Yamaguchi S, Kim SU. Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia: contribution of fractalkine and IL-5. Neurobiol Dis. 2011;41:717–24.CrossRefPubMed
14.
Ripoll CB, Flaat M, Klopf-Eiermann J, Fisher-Perkins JM, Trygg CB, Scruggs BA, McCants ML, Leonard HP, Lin AF, Zhang S, Eagle ME, Alvarez X, Li YT, Li SC, Gimble JM, Bunnell BA. Mesenchymal lineage stem cells have pronounced anti-inflammatory effects in the twitcher mouse model of Krabbe’s disease. Stem Cells. 2011;29:67–77.CrossRefPubMedPubMedCentral
15.
Vercelli A, Mereuta OM, Garbossa D, Muraca G, Mareschi K, Rustichelli D, Ferrero I, Mazzini L, Madon E, Fagioli F. Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2008;31:395–405.CrossRefPubMed
16.
Shin J-W, Lee JK, Lee JE, Min W-K, Schuchman EH, Jin HK, Bae J-S. Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1α in an Alzheimer’s disease mouse model. Stem Cells. 2011;29:1075–89.CrossRefPubMed
17.
Tran PB, Miller RJ. Chemokine receptors: signposts to brain development and disease. Nat Rev Neurosci. 2003;4:444–55.CrossRefPubMed
18.
Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci. 2001;4:702–10.CrossRefPubMed
19.
De Clercq E. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil). Biochem Pharmacol. 2009;77:1655–64.CrossRefPubMed
20.
Arimitsu N, Shimizu J, Fujiwara N, Takai K, Takada E, Kono T, Ueda Y, Suzuki T, Suzuki N. Role of SDF1/CXCR4 interaction in experimental hemiplegic models with neural cell transplantation. Int J Mol Sci. 2012;13:2636–49.CrossRefPubMedPubMedCentral
21.
Huang J, Li Y, Tang Y, Tang G, Yang G-Y, Wang Y. CXCR4 antagonist AMD3100 protects blood-brain barrier integrity and reduces inflammatory response after focal ischemia in mice. Stroke. 2013;44:190–7.CrossRefPubMed
22.
Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, Wang Y, Zhong Z, Sullivan JS, Griffin JH, Cleveland DW, Zlokovic BV. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A. 2014;111:E1035–42.CrossRefPubMedPubMedCentral
23.
Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O’Banion MK, Stojanovic K, Sagare A, Boillee S, Cleveland DW, Zlokovic BV. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci. 2008;11:420–2.CrossRefPubMedPubMedCentral
24.
Engelhardt JI, Appel SH. IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch Neurol. 1990;47:1210–6.CrossRefPubMed
25.
Garbuzova-Davis S, Saporta S, Haller E, Kolomey I, Bennett SP, Potter H, Sanberg PR. Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS One. 2007;2:e1205.CrossRefPubMedPubMedCentral
26.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–5.CrossRefPubMed
27.
Ezra A, Rabinovich-Nikitin I, Rabinovich-Toidman P, Solomon B. Multifunctional effect of human serum albumin reduces Alzheimer’s disease related pathologies in the 3xTg mouse model. J Alzheimers Dis. 2015;50:175–88.CrossRefPubMed
28.
Ślusarczyk J, Trojan E, Głombik K, Budziszewska B, Kubera M, Lasoń W, Popiołek-Barczyk K, Mika J, Wędzony K, Basta-Kaim A. Prenatal stress is a vulnerability factor for altered morphology and biological activity of microglia cells. Front Cell Neurosci. 2015;9:82.PubMedPubMedCentral
29.
Fornai F, Ferrucci M, Lenzi P, Falleni A, Biagioni F, Flaibani M, Siciliano G, Giannessi F, Paparelli A. Plastic changes in the spinal cord in motor neuron disease. Biomed Res Int. 2014;2014:670756.CrossRefPubMedPubMedCentral
30.
Oliván S, Calvo AC, Rando A, Muñoz MJ, Zaragoza P, Osta R. Comparative study of behavioural tests in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Exp Anim. 2015;64:147–53.CrossRefPubMedPubMedCentral
31.
32.
Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11:155–61.CrossRefPubMedPubMedCentral
33.
34.
Alexianu ME, Kozovska M, Appel SH. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology. 2001;57:1282–9.CrossRefPubMed
35.
36.
Stamatovic SM, Keep RF, Kunkel SL, Andjelkovic AV. Potential role of MCP-1 in endothelial cell tight junction “opening”: signaling via Rho and Rho kinase. J Cell Sci. 2003;116(Pt 22):4615–28.CrossRefPubMed
37.
Sabelström H, Stenudd M, Frisén J. Neural stem cells in the adult spinal cord. Exp Neurol. 2014;260:44–9.CrossRefPubMed
38.
Hensley K, Fedynyshyn J, Ferrell S, Floyd RA, Gordon B, Grammas P, Hamdheydari L, Mhatre M, Mou S, Pye QN, Stewart C, West M, West S, Williamson KS. Message and protein-level elevation of tumor necrosis factor alpha (TNF alpha) and TNF alpha-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis. Neurobiol Dis. 2003;14:74–80.CrossRefPubMed
39.
Poloni M, Facchetti D, Mai R, Micheli A, Agnoletti L, Francolini G, Mora G, Camana C, Mazzini L, Bachetti T. Circulating levels of tumour necrosis factor-alpha and its soluble receptors are increased in the blood of patients with amyotrophic lateral sclerosis. Neurosci Lett. 2000;287:211–4.CrossRefPubMed
40.
Rossi D, Brambilla L, Valori CF, Crugnola A, Giaccone G, Capobianco R, Mangieri M, Kingston AE, Bloc A, Bezzi P, Volterra A. Defective tumor necrosis factor-alpha-dependent control of astrocyte glutamate release in a transgenic mouse model of Alzheimer disease. J Biol Chem. 2005;280:42088–96.CrossRefPubMed
41.
Moreau C, Devos D, Brunaud-Danel V, Defebvre L, Perez T, Destée A, Tonnel AB, Lassalle P, Just N. Elevated IL-6 and TNF-alpha levels in patients with ALS: inflammation or hypoxia? Neurology. 2005;65:1958–60.CrossRefPubMed
42.
Ono S, Hu J, Shimizu N, Imai T, Nakagawa H. Increased interleukin-6 of skin and serum in amyotrophic lateral sclerosis. J Neurol Sci. 2001;187:27–34.CrossRefPubMed
43.
Tang C-H, Chuang J-Y, Fong Y-C, Maa M-C, Way T-D, Hung C-H. Bone-derived SDF-1 stimulates IL-6 release via CXCR4, ERK and NF-kappaB pathways and promotes osteoclastogenesis in human oral cancer cells. Carcinogenesis. 2008;29:1483–92.CrossRefPubMedPubMedCentral
44.
Walter HL, van der Maten G, Antunes AR, Wieloch T, Ruscher K. Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke. J Neuroinflammation. 2015;12:24.CrossRefPubMedPubMedCentral
45.
Henkel JS, Beers DR, Wen S, Bowser R, Appel SH. Decreased mRNA expression of tight junction proteins in lumbar spinal cords of patients with ALS. Neurology. 2009;72:1614–6.CrossRefPubMed
46.
Garbuzova-Davis S, Hernandez-Ontiveros DG, Rodrigues MCO, Haller E, Frisina-Deyo A, Mirtyl S, Sallot S, Saporta S, Borlongan CV, Sanberg PR. Impaired blood-brain/spinal cord barrier in ALS patients. Brain Res. 2012;1469:114–28.CrossRefPubMed
47.
Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125:111–20.CrossRefPubMedPubMedCentral
48.
Garbuzova-Davis S, Haller E, Saporta S, Kolomey I, Nicosia SV, Sanberg PR. Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res. 2007;1157:126–37.CrossRefPubMed
49.
Johansson BB. Regeneration and plasticity in the brain and spinal cord. J Cereb Blood Flow Metab. 2007;27:1417–30.CrossRefPubMed
Metadata
Title
Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1G93A mice model of ALS
Authors
Inna Rabinovich-Nikitin
Assaf Ezra
Beka Barbiro
Polina Rabinovich-Toidman
Beka Solomon
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0587-6

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