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

Janssen A, Fiebiger S, Bros H, Hertwig L, Romero-Suarez S, Hamann I, Chanvillard C, Bellmann-Strobl J, Paul F, Millward JM, Infante-Duarte C - PLoS ONE (2015)

Bottom Line: 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.Interestingly, the neuroprotective effect of EGCG was abolished when GA was applied in combination.These data suggest that upregulation of HO-1 may contribute to diminish the neuroprotective benefits of EGCG alone in this EAE model.

View Article: PubMed Central - PubMed

Affiliation: Institute for Medical Immunology, Charité-Universitätmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center, joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Addition EGCG therapy leads to decreased expression of heme oxygenase-1 (HO-1).A: Relative mRNA expression of HO-1 in cerebral and cerebellar regions as well as spinal cords of mice treated with vehicle control, EGCG alone, or in combination with GA. (ANOVA). B: Relative expression of HO-1 in mice treated with EGCG compared to mice treated with EGCG+GA C: Relative expression of HO-1 in mice treated with EGCG compared to control vehicle treated animals (t-test).
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pone.0130251.g005: Addition EGCG therapy leads to decreased expression of heme oxygenase-1 (HO-1).A: Relative mRNA expression of HO-1 in cerebral and cerebellar regions as well as spinal cords of mice treated with vehicle control, EGCG alone, or in combination with GA. (ANOVA). B: Relative expression of HO-1 in mice treated with EGCG compared to mice treated with EGCG+GA C: Relative expression of HO-1 in mice treated with EGCG compared to control vehicle treated animals (t-test).

Mentions: Thus far, we observed alteration of HO-1 expression in EAE mice treated with EGCG alone compared to EAE mice treated with EGCG+GA. To elucidate how EGCG regulates HO-1 compared to control EAE mice in vivo, we conducted an additional experiment with 3 treatment groups, vehicle treated, EGCG treated and EGCG+GA-treated animals. As in the experiments shown above, treatment started when mice developed a clinical score ≥ 1. Mice were treated for a period of 12 days. Here, we examined HO-1 expression in cerebrum, cerebellum and spinal cord (Fig 5A). Multiple group comparisons indicated that treatment with EGCG+GA appeared to increase expression of HO-1 in cerebellum and spinal cord relative to mice treated with EGCG alone, although this was at the edge of statistical significance. Consistent with our previous results, there was no difference in HO-1 expression in the cerebrum. Upon analyzing the data with a two-group comparison, we could confirm that treatment with EGCG+GA increased HO-1 expression in cerebellum and spinal cord when compared with EGCG alone (Fig 5B). Furthermore, these data showed that EGCG reduced HO-1 expression in the cerebellum and spinal cord as compared with the vehicle treated control group (Fig 5C).


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

Janssen A, Fiebiger S, Bros H, Hertwig L, Romero-Suarez S, Hamann I, Chanvillard C, Bellmann-Strobl J, Paul F, Millward JM, Infante-Duarte C - PLoS ONE (2015)

Addition EGCG therapy leads to decreased expression of heme oxygenase-1 (HO-1).A: Relative mRNA expression of HO-1 in cerebral and cerebellar regions as well as spinal cords of mice treated with vehicle control, EGCG alone, or in combination with GA. (ANOVA). B: Relative expression of HO-1 in mice treated with EGCG compared to mice treated with EGCG+GA C: Relative expression of HO-1 in mice treated with EGCG compared to control vehicle treated animals (t-test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482710&req=5

pone.0130251.g005: Addition EGCG therapy leads to decreased expression of heme oxygenase-1 (HO-1).A: Relative mRNA expression of HO-1 in cerebral and cerebellar regions as well as spinal cords of mice treated with vehicle control, EGCG alone, or in combination with GA. (ANOVA). B: Relative expression of HO-1 in mice treated with EGCG compared to mice treated with EGCG+GA C: Relative expression of HO-1 in mice treated with EGCG compared to control vehicle treated animals (t-test).
Mentions: Thus far, we observed alteration of HO-1 expression in EAE mice treated with EGCG alone compared to EAE mice treated with EGCG+GA. To elucidate how EGCG regulates HO-1 compared to control EAE mice in vivo, we conducted an additional experiment with 3 treatment groups, vehicle treated, EGCG treated and EGCG+GA-treated animals. As in the experiments shown above, treatment started when mice developed a clinical score ≥ 1. Mice were treated for a period of 12 days. Here, we examined HO-1 expression in cerebrum, cerebellum and spinal cord (Fig 5A). Multiple group comparisons indicated that treatment with EGCG+GA appeared to increase expression of HO-1 in cerebellum and spinal cord relative to mice treated with EGCG alone, although this was at the edge of statistical significance. Consistent with our previous results, there was no difference in HO-1 expression in the cerebrum. Upon analyzing the data with a two-group comparison, we could confirm that treatment with EGCG+GA increased HO-1 expression in cerebellum and spinal cord when compared with EGCG alone (Fig 5B). Furthermore, these data showed that EGCG reduced HO-1 expression in the cerebellum and spinal cord as compared with the vehicle treated control group (Fig 5C).

Bottom Line: 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.Interestingly, the neuroprotective effect of EGCG was abolished when GA was applied in combination.These data suggest that upregulation of HO-1 may contribute to diminish the neuroprotective benefits of EGCG alone in this EAE model.

View Article: PubMed Central - PubMed

Affiliation: Institute for Medical Immunology, Charité-Universitätmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center, joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus