Skip to main content
Log in

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

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8:647–56.

    Article  CAS  PubMed  Google Scholar 

  2. Zamvil SS, Steinman L. Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron. 2003;38:685–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  27. Chen MK, Guilarte TR. Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Ther. 2008;118:1–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  37. Winkeler A, Boisgard R, Martin A, Tavitian B. Radioisotopic imaging of neuroinflammation. J Nucl Med. 2010;51:1–4.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank M González, A Leukona and M Errasti for technical support in the radiosynthesis, and A Cano and C Muñoz for technical assistance in the PET studies.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Abraham Martín or Carlos Matute.

Ethics declarations

Funding

This study was funded by MINECO SAF2010-21547 and SAF2013-45084-R (C. M) and SAF2014-54070-JIN (A.M), FEDER, Department of Industry of Basque Government (IE14-385) and CIBERNED.

Conflict of interests

The authors declare no competing financial interests.

Ethical approval

Animal studies were approved by the animal ethics committee of CIC biomaGUNE and local authorities and were conducted in accordance with the Directives of the European Union on animal ethics and welfare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martín, A., Vázquez-Villoldo, N., Gómez-Vallejo, V. et al. In vivo imaging of system xc- as a novel approach to monitor multiple sclerosis. Eur J Nucl Med Mol Imaging 43, 1124–1138 (2016). https://doi.org/10.1007/s00259-015-3275-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-015-3275-3

Keywords

Navigation