Demyelination arrest and remyelination induced by glatiramer acetate treatment of experimental autoimmune encephalomyelitis

Abstract

The interplay between demyelination and remyelination is critical in the progress of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). In the present study, we explored the capacity of glatiramer acetate (GA, Copaxone) to affect the demyelination process and/or lead to remyelination in mice inflicted by chronic EAE, using both scanning electron microscopy and immunohistological methods. Spinal cords of untreated EAE mice revealed substantial demyelination accompanied by tissue destruction and axonal loss. In contrast, in spinal cords of GA-treated mice, in which treatment started concomitantly with disease induction (prevention), no pathology was observed. Moreover, when treatment was initiated after the appearance of clinical symptoms (suppression) or even in the chronic disease phase (delayed suppression) when substantial demyelination was already manifested, it resulted in a significant decrease in the pathological damage. Detection of oligodendrocyte progenitor cells (OPCs) expressing the NG2 or O4 markers via colocalization with the proliferation marker BrdU indicated their elevated levels in spinal cords of GA-treated mice. The mode of action of GA in this system is attributed to increased proliferation, differentiation, and survival of OPCs along the oligodendroglial maturation cascade and their recruitment into injury sites, thus enhancing repair processes in situ.multiple sclerosis ͉ neuroprotection ͉ oligodendrocyte ͉ myelin repair

Altered Expression of Oligodendrocyte and Neuronal Marker Genes Predicts the Clinical Onset of Autoimmune Encephalomyelitis and Indicates the Effectiveness of Multiple Sclerosis–Directed Therapeutics

“…It inhibits Th17 and Th1 responses (54) and boosts CD4 + CD25 + regulatory T cells in the EAE model (16). It also promotes several other beneficial effects in the inflamed CNS, such as remyelination, oligodendrogenesis (32,55), neuroaxonal protection, and neurogenesis (56)(57)(58). Previous gene-expression studies in PBMCs obtained from untreated versus GA-treated MS patients showed that GA reduced the expression of proinflammatory cytokines, such as TNF (59).…”

“…To investigate whether the gene panel could be useful for evaluating the effectiveness of experimental therapies, we measured differential expression of the selected genes during development of MOG-induced EAE in mice that had been treated prophylactically with GA. We chose to use GA because it is effective in ameliorating MOG-induced EAE in both prophylactic and therapeutic protocols, shows protective properties in CNS tissues (32), and is an established drug for the treatment of MS (33). Most mice treated prophylactically with GA by s.c. injection every 7 d, starting from 7 d preimmunization with MOG, showed reduced disease incidence, delayed onset, and significantly milder clinical scores compared with those in the nontreated group (Fig.…”

Roles of NG2 glial cells in diseases of the central nervous system

“…On the one hand, lovastatin (HMG-CoA reductase inhibitor) [40] , glamorgan acetate [41] , guanosine or guanine [42] , ciliary neurotrophic factor [43] , thymosin β4 [44] , and endogenous leukemia inhibitory factor [45] , through different cascades of signal transduction, increase the numbers of NG2 cells and oligodendrocytes, and put an end to the demyelination process. The expression of platelet-derived growth factor α receptors (PDGFαRs) increases during the proliferation of NG2 cells, and NG2 proteoglycan expression disappears as NG2 cells differentiate into mature oligodendrocytes [46] .…”

Mechanisms and Patterns of Axonal Loss in Multiple Sclerosis

“…Early animal studies on the neuroprotective effects of GA show promise. Spinal cords of glatiramer acetate-treated EAE mice show significantly reduced demyelination and enhanced remyelination compared to controls (Aharoni et al, 2008). Moreover, when treatment was initiated at the time of manifestation of clinical symptoms, or even in the chronic disease phase when extensive demyelination had already accumulated, GA dramatically reduced pathological damage.…”