Treatment of Chronic Experimental Autoimmune Encephalomyelitis with Epigallocatechin-3-Gallate and Glatiramer Acetate Alters Expression of Heme-Oxygenase-1.

We previously demonstrated that epigallocatechin-3-gallate (EGCG) synergizes with the immunomodulatory agent glatiramer acetate (GA) in eliciting anti-inflammatory and neuroprotective effects in the relapsing-remitting EAE model. Thus, we hypothesized that mice with chronic EAE may also benefit from this combination therapy. We first assessed how a treatment with a single dose of GA together with daily application of EGCG may modulate EAE. Although single therapies with a suboptimal dose of GA or EGCG led to disease amelioration and reduced CNS inflammation, the combination therapy had no effects. While EGCG appeared to preserve axons and myelin, the single GA dose did not improve axonal damage or demyelination. Interestingly, the neuroprotective effect of EGCG was abolished when GA was applied in combination. To elucidate how a single dose of GA may interfere with EGCG, we focused on the anti-inflammatory, iron chelating and anti-oxidant properties of EGCG. Surprisingly, we observed that while EGCG induced a downregulation of the gene expression of heme oxygenase-1 (HO-1) in affected CNS areas, the combined therapy of GA+EGCG seems to promote an increased HO-1 expression. These data suggest that upregulation of HO-1 may contribute to diminish the neuroprotective benefits of EGCG alone in this EAE model. Altogether, our data indicate that neuroprotection by EGCG in chronic EAE may involve regulation of oxidative processes, including downmodulation of HO-1. Further investigation of the re-dox balance in chronic neuroinflammation and in particular functional studies on HO-1 are warranted to understand its role in disease progression.

The antioxidant idebenone fails to prevent or attenuate chronic experimental autoimmune encephalomyelitis in the mouse.

Oxidative stress and mitochondrial dysfunction appear to contribute to neurodegenerative processes during multiple sclerosis (MS). Thus, antioxidants may represent a therapeutic option for MS. The antioxidant idebenone was proven to be beneficial in Friedreich's ataxia and Leber's hereditary optic neuropathy, two disorders caused by mitochondrial alterations. Here we showed that idebenone protected neuronal HT22 cells from glutamate-induced death in vitro. However, in experimental autoimmune encephalomyelitis, idebenone failed to affect disease incidence or onset when applied preventively, or to reduce disease severity when applied therapeutically. Histopathological examination of CNS from idebenone treated mice showed no improvement in inflammation, demyelination, or axonal damage. Thus, we hypothesize that idebenone treatment will likely not benefit patients with MS.