Basso, A.S., Frenkel, D., Quintana, F.J., Costa-Pinto, F.A., et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J. Clin. Invest., 118, 1532 (April, 2008).
A new avenue has opened for developing drugs to combat the progressive stage of multiple sclerosis (MS). An international team of scientists created a water-soluble fullerene, modified by oligoethyleneglycol bridges to which were attached the NMDA receptor antagonist amantadine. This unique molecule, dubbed ABS-75, offers both the protection against free radicals, typical of fullerenes, and the anti-excitatory capacity of a glutamate receptor antagonist.
ABS-75 was first tested in an animal model of MS, experimental autoimmune encephalitis or EAE, induced in myelin-oligodendrocyte glycoprotein-immunized NOD mice. Immunization of adult animals caused the onset of the acute phase of EAE by days 11-12, with symptoms peaking between days 16 and 18. Therapy with ABS-75 was initiated on day 20, at the approximate time that the progressive phase of the disease begins, and continued through the end of the experiment, on day 70. The treated mice had a significantly lower rate of disease progression than vehicle injected or memantine treated animals. However, pretreatment with ABS-75 had no effect on the acute phase of EAE. (Disease scores were assessed by observation of the following traits: loss of tone in the tail, hindlimb paresis, hindlimb paralysis, tetraplegia, and moribund.)
The general observational scores of the treated and control mice correlated well with disease progression as measured by axonal loss and demyelination in the lumbar spinal cord. ABS-75 also stopped CD11b infiltration into the white matter of the spinal cord by reducing astrocyte expression of the chemokine CCL2, and it blocked oxidative injury, characterized by protein tyrosine nitration via nitric oxide. The cytoprotective effects were associated with normal expression of key components of the glutamate-deactivating pathway, a glutamate transporter and glutamine synthetase, in astrocytes under inflammatory conditions. Finally, it should be noted that ABS-75 had no effect on adaptive responses of the immune system (i.e. T cell proliferation and cytokine production upon antigen-specific stimulation).
The beneficial effects of ABS-75 were dependent upon the presence of amantadine. However, memory and learning impairments often seen with NMDA receptor antagonists were not observed with the fullerene hybrid.
In all, the results provide a sound basis for pursuing fullerene-NMDA receptor hybrids as a therapy for secondary progressive MS. Indeed, such molecules may eventually become the first treatment to halt progression of this debilitating disease.
Message posted by: Keith Markey
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