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

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 5

Fullerene ABS-75 rescues the reduced expression of EAAT1 and GS that occurs in astrocytes under inflammatory conditions.

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Fullerene ABS-75 rescues the reduced expression of EAAT1 and GS that occ...
(A) Primary mouse astrocytes were stimulated with either TNF-α (50 ng/ml) or LPS (1 μg/ml) and IFN-γ (200 U/ml) for 24 h in the absence or presence of ABS-75 (1 μM) or MK801 (1 μM). GS and EAAT1 expression were assessed by western blot. Quantification was performed using densitometry analysis (ImageJ; NIH) for 2 independent experiments. We found that both ABS-75 and MK801 could reverse the reduced expression of EAAT1 and GS by astrocytes under inflammatory conditions. P < 0.01, ANOVA followed by post-hoc test, mean ± SD. (B) Immunohistochemistry performed on spinal cord sections analyzed after disease progression revealed increased GS expression within the white matter of fullerene ABS-75 group as compared with vehicle-treated animals. Quantification by ImageJ confirmed increased numbers of GS-expressing glial cells in the white matter of fullerene ABS-75–treated mice. P < 0.05, Student’s t test, mean ± SD. (C) Immunohistochemistry performed on spinal cord sections analyzed after disease progression revealed that the cells expressing GS within the white matter were either oligodendrocytes (CNPase positive) or astrocytes (GFAP positive). Original magnification, ×200 (B); ×630 (C).