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

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 6

Fullerene ABS-75 treatment does not interfere with the adaptive compartment of the immune system.

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Fullerene ABS-75 treatment does not interfere with the adaptive compartm...
(A–C) Splenocytes from vehicle- and ABS-75–treated animals (4 per group) were harvested by the end of disease course and cultivated in the presence of MOG for (A) T cell proliferation, (B) IL-2, and (C) IFN-γ production. No differences were observed. (D) Serum collected from vehicle- and ABS-75–treated animals at the end of disease course was tested for MOG-specific IgG2b levels. No differences were observed. (E and F) NOD mice were treated once a day with fullerene ABS-75 (30 μg/kg i.p.) from day –1 to day 10 after immunization, when draining lymph nodes were harvested to evaluate T cell recall response upon MOG stimulation. No differences were found for (E) T cell proliferation and (F) IFN-γ production. (G and H) NOD mice were immunized with MOG, and after 10 days, cells harvested from the draining lymph nodes were stimulated with antigen in the presence or absence of 1 μM fullerene ABS-75. In vitro 1 μM fullerene ABS-75 did not interfere with (G) T cell proliferation and (H) IFN-γ production upon antigen-specific stimulation.