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 4

Fullerene ABS-75 protects neurons from oxidative injury and NMDA-dependent glutamate-induced injury but does not impair mouse memory function.

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Fullerene ABS-75 treatment halts oxidative injury, blocks CCL2 productio...
Rat cortical neurons (11 DIV) were challenged with either 60 μM H2O2 or 50 μM glutamate for 24 h in the absence or presence of ABS-75 (1 μM) or MK801 (1 μM). Glutamate- and H2O2-induced injuries were assessed by (A) MAP-2 staining and (B) LDH activity. The results showed reduced neuronal damage in fullerene ABS-75– and MK801-treated cultures. P < 0.01, control versus ABS-75 and MK801, and ABS-75 versus MK801. P < 0.01, control versus ABS-75, and control versus MK801 (H2O2-induced injury). ANOVA followed by post-hoc test, mean ± SD. (C) Fullerene ABS-75 and MK801 effects on memory function were assessed on a plus maze apparatus. On the first day (acquisition trial), animals were placed at the edge of an open arm and the latency to the first entry in the central area was recorded. On the second day (retention trial), all animals were returned to the arena and the latency to the first transfer onto the central area was recorded. Drugs were administered i.p. 30 min before the retention trial. All animals moved to the central area in the acquisition trial. In the retention trial, only animals treated with 0.15 mg/kg MK801 had similar results to those of vehicle mice in the acquisition trial. Animals treated with PBS, 2% DMSO, or ABS-75 arrived at the central area faster in the retention trial than in the acquisition trial, indicating that, unlike MK801, fullerene ABS-75 does not impair memory function. P < 0.05, Kruskal-Wallis test followed by Dunn’s multiple comparisons test. n = 10 animals per group. Median (line through each box) ± SD (error bars) are shown. Original magnification, ×130.