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Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis
Alexandre S. Basso, … , Michael Gozin, Howard L. Weiner
Alexandre S. Basso, … , Michael Gozin, Howard L. Weiner
Published March 13, 2008
Citation Information: J Clin Invest. 2008;118(4):1532-1543. https://doi.org/10.1172/JCI33464.
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Research Article Neuroscience Article has an altmetric score of 11

Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis

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Abstract

Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75–treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, CD11b+ infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75–treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.

Authors

Alexandre S. Basso, Dan Frenkel, Francisco J. Quintana, Frederico A. Costa-Pinto, Sanja Petrovic-Stojkovic, Lindsay Puckett, Alon Monsonego, Amnon Bar-Shir, Yoni Engel, Michael Gozin, Howard L. Weiner

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Figure 1

Fullerene ABS-75 treatment reduces disease progression in secondary progressive EAE.

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Fullerene ABS-75 treatment reduces disease progression in secondary prog...
(A) Fullerene ABS-75 consists of the C60 fullerene core (i) attached to 4 adamantyl groups (ii) by oligoethyleneglycol bridges (iii). (B) Chronic progressive EAE was induced in 10-week-old NOD mice by subcutaneous immunization with 150 μg of MOG35–55 peptide in 4 mg/ml CFA. Pertussis toxin was given i.v. (150 ng per mouse) at the time of immunization and 48 h later. Fullerene ABS-75 (30 μg/kg, i.p.) was given daily beginning on day 20. n = 10 animals per group. Vehicle consisted of 2% DMSO. (C) Fullerene ABS-75 (30 μg/kg, i.p.) and memantine (1.5 mg/kg) were given daily beginning on day 19. n = 9–10 animals per group. Vehicle consisted of 2% DMSO. (D) Left: EAE was induced in 8-week-old SJL mice by s.c. immunization with 50 μg of PLP131–151 peptide in 4 mg/ml CFA. Pertussis toxin was given i.v. (150 ng per mouse) at the time of immunization and 48 h later. Fullerene ABS-75 (30 μg/kg, i.p.) and memantine (1.5 mg/kg) were given daily beginning on day 17. n = 15 animals per group. Arrows indicate relapses following the first attack. Right: Fullerene ABS-75 treatment (30 μg/kg, i.p.) begun 1 day before MOG immunization and done on a daily basis until the end of disease course was not able to ameliorate acute EAE in C57BL/6J mice. n = 8 animals per group. Disease score measured as follows: 0, no signs of disease; 1, loss of tone in the tail; 2, hindlimb paresis; 3, hindlimb paralysis; 4, tetraplegia; 5, moribund.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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