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European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 6/2016

01-06-2016 | Original Article

In vivo imaging of system xc- as a novel approach to monitor multiple sclerosis

Authors: Abraham Martín, Nuria Vázquez-Villoldo, Vanessa Gómez-Vallejo, Daniel Padro, Federico N. Soria, Boguslaw Szczupak, Sandra Plaza-García, Ander Arrieta, Torsten Reese, Jordi Llop, Maria Domercq, Carlos Matute

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 6/2016

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Abstract

Purpose

Glutamate excitotoxicity contributes to oligodendroglial and axonal damage in multiple sclerosis pathology. Extracellular glutamate concentration in the brain is controlled by cystine/glutamate antiporter (system xc-), a membrane antiporter that imports cystine and releases glutamate. Despite this, the system xc− activity and its connection to the inflammatory reaction in multiple sclerosis (MS) is largely unknown.

Methods

Longitudinal in vivo magnetic resonance (MRI) and positron emission tomography (PET) imaging studies with 2-[18F]Fluoro-2-deoxy-D-glucose ([18F]FDG), [11C]-(R)-(1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarboxamide ([11C]PK11195) and (4S)-4-(3-18F-fluoropropyl)-L-glutamate ([18F]FSPG) were carried out during the course of experimental autoimmune encephalomyelitis (EAE) induction in rats.

Results

[18F]FSPG showed a significant increase of system xc− function in the lumbar section of the spinal cord at 14 days post immunization (dpi) that stands in agreement with the neurological symptoms and ventricle edema formation at this time point. Likewise, [18F]FDG did not show significant changes in glucose metabolism throughout central nervous system and [11C]PK11195 evidenced a significant increase of microglial/macrophage activation in spinal cord and cerebellum 2 weeks after EAE induction. Therefore, [18F]FSPG showed a major capacity to discriminate regions of the central nervous system affected by the MS in comparison to [18F]FDG and [11C]PK11195. Additionally, clodronate-treated rats showed a depletion in microglial population and [18F]FSPG PET signal in spinal cord confirming a link between neuroinflammatory reaction and cystine/glutamate antiporter activity in EAE rats.

Conclusions

Altogether, these results suggest that in vivo PET imaging of system xc− could become a valuable tool for the diagnosis and treatment evaluation of MS.
Literature
1.
Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8:647–56.CrossRefPubMed
2.
Zamvil SS, Steinman L. Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron. 2003;38:685–8.CrossRefPubMed
3.
Bitsch A, Kuhlmann T, Da Costa C, Bunkowski S, Polak T, Bruck W. Tumour necrosis factor alpha mRNA expression in early multiple sclerosis lesions: correlation with demyelinating activity and oligodendrocyte pathology. Glia. 2000;2:366–75.CrossRef
4.
Rasmussen S, Wang Y, Kivisakk P, Bronson RT, Meyer M, Imitola J, et al. Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing--remitting experimental autoimmune encephalomyelitis. Brain. 2007;130:2816–29.CrossRefPubMed
5.
Domercq M, Sanchez-Gomez MV, Sherwin C, Etxebarria E, Fern R, Matute C. System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes. J Immunol. 2007;178:6549–56.CrossRefPubMed
6.
Pampliega O, Domercq M, Soria FN, Villoslada P, Rodriguez-Antiguedad A, et al. Increased expression of cystine/glutamate antiporter in multiple sclerosis. J Neuroinflammation. 2011;8:1742–2094.CrossRef
7.
Matute C, Sanchez-Gomez MV, Martinez-Millan L, Miledi R. Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci U S A. 1997;94:8830–5.CrossRefPubMedPubMedCentral
8.
Domercq M, Etxebarria E, Perez-Samartin A, Matute C. Excitotoxic oligodendrocyte death and axonal damage induced by glutamate transporter inhibition. Glia. 2005;52:36–46.CrossRefPubMed
9.
Schiepers C, Van Hecke P, Vandenberghe R, Van Oostende S, Dupont P, Demaerel P, et al. Positron emission tomography, magnetic resonance imaging and proton NMR spectroscopy of white matter in multiple sclerosis. Mult Scler. 1997;3:8–17.CrossRefPubMed
10.
Debruyne JC, Versijpt J, Van Laere KJ, De Vos F, Keppens J, Strijckmans K, et al. PET visualization of microglia in multiple sclerosis patients using [11C]PK11195. Eur J Neurol. 2003;10:257–64.CrossRefPubMed
11.
Radu CG, Shu CJ, Shelly SM, Phelps ME, Witte ON. Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2007;104:1937–42.CrossRefPubMedPubMedCentral
12.
Buck D, Forschler A, Lapa C, Schuster T, Vollmar P, Korn T, et al. 18F-FDG PET detects inflammatory infiltrates in spinal cord experimental autoimmune encephalomyelitis lesions. J Nucl Med. 2012;53:1269–76.CrossRefPubMed
13.
Takano A, Piehl F, Hillert J, Varrone A, Nag S, Gulyas B, et al. In vivo TSPO imaging in patients with multiple sclerosis: a brain PET study with [18F]FEDAA1106. EJNMMI Res. 2013;3:3–30.CrossRef
14.
Airas L, Dickens AM, Elo P, Marjamaki P, Johansson J, Eskola O, et al. In vivo PET imaging demonstrates diminished microglial activation after fingolimod treatment in an animal model of multiple sclerosis. J Nucl Med. 2015;56:305–10.CrossRefPubMed
15.
Mattner F, Staykova M, Berghofer P, Wong HJ, Fordham S, Callaghan P, et al. Central nervous system expression and PET imaging of the translocator protein in relapsing-remitting experimental autoimmune encephalomyelitis. J Nucl Med. 2013;54:291–8.CrossRefPubMed
16.
Xie L, Yamasaki T, Ichimaru N, Yui J, Kawamura K, Kumata K, et al. [(11)C]DAC-PET for noninvasively monitoring neuroinflammation and immunosuppressive therapy efficacy in rat experimental autoimmune encephalomyelitis model. J Neuroimmune Pharmacol. 2012;7:231–42.CrossRefPubMed
17.
Abourbeh G, Theze B, Maroy R, Dubois A, Brulon V, Fontyn Y, et al. Imaging microglial/macrophage activation in spinal cords of experimental autoimmune encephalomyelitis rats by positron emission tomography using the mitochondrial 18 kDa translocator protein radioligand [(1)(8)F]DPA-714. J Neurosci. 2012;32:5728–36.CrossRefPubMed
18.
Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owenset T, et al. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci Res. 1997;50:345–53.CrossRefPubMed
19.
Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain. 2000;123:2321–37.CrossRefPubMed
20.
Baek S, Choi CM, Ahn SH, Lee JW, Gong G, Ryu JS, et al. Exploratory clinical trial of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate for imaging xc- transporter using positron emission tomography in patients with non-small cell lung or breast cancer. Clin Cancer Res. 2012;18:5427–37.CrossRefPubMed
21.
Baek S, Mueller A, Lim YS, Lee HC, Lee YJ, Gong G, et al. (4S)-4-(3-18F-fluoropropyl)-L-glutamate for imaging of xC transporter activity in hepatocellular carcinoma using PET: preclinical and exploratory clinical studies. J Nucl Med. 2013;54:117–23.CrossRefPubMed
22.
Soria FN, Perez-Samartin A, Martin A, Gona KB, Llop J, Szczupak B. Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage. J Clin Invest. 2014;124:3645–55.CrossRefPubMedPubMedCentral
23.
Wilson AA, Garcia A, Jin L, Houle S. Radiotracer synthesis from [(11)C]-iodomethane: a remarkably simple captive solvent method. Nucl Med Biol. 2000;l 27:529–32.CrossRef
24.
Koglin N, Mueller A, Berndt M, Schmitt-Willich H, Toschi L, Stephens AW, et al. Specific PET imaging of xC- transporter activity using a (1)(8)F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism. Clin Cancer Res. 2011;17:6000–11.CrossRefPubMed
25.
Bakshi R, Miletich RS, Kinkel PR, Emmet ML, Kinkel WR. High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J Neuroimaging. 1998;8:228–34.CrossRefPubMed
26.
Blinkenberg M, Jensen CV, Holm S, Paulson OB, Sorensen PS. A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS. Neurology. 1999;53:149–53.CrossRefPubMed
27.
28.
Faustino JV, Wang X, Johnson CE, Klibanov A, Derugin N, Wendland MF, et al. Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J Neurosci. 2011;31:12992–3001.CrossRefPubMedPubMedCentral
29.
McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121–7.CrossRefPubMed
30.
Filippi M, Rocca MA, De Stefano N, Enzinger C, Fisher E, Horsfield MA, et al. Magnetic resonance techniques in multiple sclerosis: the present and the future. Arch Neurol. 2011;68:1514–20.CrossRefPubMed
31.
de Paula Faria D, de Vries EF, Sijbesma JW, Buchpiguel CA, Dierckx RA, Copray SC. PET imaging of glucose metabolism, neuroinflammation and demyelination in the lysolecithin rat model for multiple sclerosis. Mult Scler. 2014;20:1443–52.CrossRefPubMed
32.
Stankoff B, Wang Y, Bottlaender M, Aigrot MS, Dolle F, Wu C, et al. Imaging of CNS myelin by positron-emission tomography. Proc Natl Acad Sci U S A. 2006;103:9304–9.CrossRefPubMedPubMedCentral
33.
de Paula Faria D, de Vries EF, Sijbesma JW, Dierckx RA, Buchpiguel CA, Copray S. PET imaging of demyelination and remyelination in the cuprizone mouse model for multiple sclerosis: a comparison between [11C]CIC and [11C]MeDAS. Neuroimage. 2014;87:395–402.CrossRefPubMed
34.
de Paula Faria D, Vlaming ML, Copray SC, Tielen F, Anthonijsz HJ, Sijbesma JW, et al. PET imaging of disease progression and treatment effects in the experimental autoimmune encephalomyelitis rat model. J Nucl Med. 2014;55:1330–5.CrossRefPubMed
35.
Aharoni R, Sasson E, Blumenfeld-Katzir T, Eilam R, Sela M, Assaf Y, et al. Magnetic resonance imaging characterization of different experimental autoimmune encephalomyelitis models and the therapeutic effect of glatiramer acetate. Exp Neurol. 2013;240:130–44.CrossRefPubMed
36.
Blinkenberg M, Rune K, Jensen CV, Ravnborg M, Kyllingsbaek S, Holm S, et al. Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS. Neurology. 2000;54:558–64.CrossRefPubMed
37.
Winkeler A, Boisgard R, Martin A, Tavitian B. Radioisotopic imaging of neuroinflammation. J Nucl Med. 2010;51:1–4.CrossRefPubMed
38.
Banati RB, Middleton RJ, Chan R, Hatty CR, Kam WW, Quin C, et al. Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat Commun. 2014;5:5452.CrossRefPubMedPubMedCentral
39.
Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain. 2005;128:1016–25.CrossRefPubMed
40.
Buckingham SC, Campbell SL, Haas BR, Montana V, Robel S, Ogunrinu T, et al. Glutamate release by primary brain tumors induces epileptic activity. Nat Med. 2001;17:1269–74.CrossRef
41.
Patel SA, Warren BA, Rhoderick JF, Bridges RJ. Differentiation of substrate and non-substrate inhibitors of transport system xc(−): an obligate exchanger of L-glutamate and L-cystine. Neuropharmacology. 2004;46:273–84.CrossRefPubMed
42.
Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes BT. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol. 1999;158:351–65.CrossRefPubMed
43.
Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. 2011;14:1142–9.CrossRefPubMed
Metadata
Title
In vivo imaging of system xc- as a novel approach to monitor multiple sclerosis
Authors
Abraham Martín
Nuria Vázquez-Villoldo
Vanessa Gómez-Vallejo
Daniel Padro
Federico N. Soria
Boguslaw Szczupak
Sandra Plaza-García
Ander Arrieta
Torsten Reese
Jordi Llop
Maria Domercq
Carlos Matute
Publication date
01-06-2016
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 6/2016
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-015-3275-3

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