In vivo imaging of system xc- as a novel approach to monitor multiple sclerosis
Eur J Nucl Med Mol Imaging. 2015-12-10; 43(6): 1124-1138
DOI: 10.1007/s00259-015-3275-3
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Martín A(1), Vázquez-Villoldo N(2)(3)(4), Gómez-Vallejo V(5)(6), Padro D(5)(7),
Soria FN(2)(3)(4), Szczupak B(5), Plaza-García S(5)(7), Arrieta A(5), Reese
T(5)(7), Llop J(5)(6), Domercq M(2)(3)(4), Matute C(8)(9)(10).
Author information:
(1)Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
.
(2)Department of Neurosciences, University of the Basque Country, Barrio Sarriena
s/n, 48940, Leioa, Spain.
(3)Achucarro Basque Center for Neuroscience, UPV/EHU, 48170, Zamudio, Spain.
(4)Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de
Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain.
(5)Molecular Imaging Unit, CIC biomaGUNE, P° Miramon 182, San Sebastian, Spain.
(6)Radiochemistry and Nuclear Imaging, CIC biomaGUNE, P° Miramon 182, San
Sebastian, Spain.
(7)Magnetic Resonance Imaging, CIC biomaGUNE, P° Miramon 182, San Sebastian,
Spain.
(8)Department of Neurosciences, University of the Basque Country, Barrio Sarriena
s/n, 48940, Leioa, Spain. .
(9)Achucarro Basque Center for Neuroscience, UPV/EHU, 48170, Zamudio, Spain.
.
(10)Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de
Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain.
.
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-[(18)F]Fluoro-2-deoxy-D-glucose
([(18)F]FDG),
[(11)C]-(R)-(1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarbox
amide ([(11)C]PK11195) and (4S)-4-(3-(18)F-fluoropropyl)-L-glutamate
([(18)F]FSPG) were carried out during the course of experimental autoimmune
encephalomyelitis (EAE) induction in rats.
RESULTS: [(18)F]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, [(18)F]FDG did not show significant changes in
glucose metabolism throughout central nervous system and [(11)C]PK11195 evidenced
a significant increase of microglial/macrophage activation in spinal cord and
cerebellum 2 weeks after EAE induction. Therefore, [(18)F]FSPG showed a major
capacity to discriminate regions of the central nervous system affected by the MS
in comparison to [(18)F]FDG and [(11)C]PK11195. Additionally, clodronate-treated
rats showed a depletion in microglial population and [(18)F]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.
DOI: 10.1007/s00259-015-3275-3
PMID: 26659901 [Indexed for MEDLINE]