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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

The combined application of GA and EGCG treatment does not alter the iron chelator activity but enhanced HO-1 expression compared to EGCG.A: Soluble iron content in blood serum was quantified day 26 after immunization by using a modification of the ferrozine-based assay. B: Relative mRNA expression of HO-1 in cerebellar and cerebral regions of the CNS of mice included in Fig 3 treated with EGCG alone, or in combination with GA. (t-test) *p<0.05.
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pone.0130251.g004: The combined application of GA and EGCG treatment does not alter the iron chelator activity but enhanced HO-1 expression compared to EGCG.A: Soluble iron content in blood serum was quantified day 26 after immunization by using a modification of the ferrozine-based assay. B: Relative mRNA expression of HO-1 in cerebellar and cerebral regions of the CNS of mice included in Fig 3 treated with EGCG alone, or in combination with GA. (t-test) *p<0.05.

Mentions: Evidence from EAE and MS suggests that oxidative stress and dysregulated iron metabolism contribute to neuronal damage. EGCG has the potential to impact these two processes by minimizing the amount of iron ions available to generate destructive oxygen radicals [10]. Therefore, to explore whether GA may interfere with the iron chelating activity of EGCG, soluble iron content in blood serum of the different treatment groups was quantified using a ferrozine-based assay. As shown in Fig 4A, there was no difference of total soluble iron detectable between the ECGC-treated and the EGCG+GA-treated groups.


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)

The combined application of GA and EGCG treatment does not alter the iron chelator activity but enhanced HO-1 expression compared to EGCG.A: Soluble iron content in blood serum was quantified day 26 after immunization by using a modification of the ferrozine-based assay. B: Relative mRNA expression of HO-1 in cerebellar and cerebral regions of the CNS of mice included in Fig 3 treated with EGCG alone, or in combination with GA. (t-test) *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130251.g004: The combined application of GA and EGCG treatment does not alter the iron chelator activity but enhanced HO-1 expression compared to EGCG.A: Soluble iron content in blood serum was quantified day 26 after immunization by using a modification of the ferrozine-based assay. B: Relative mRNA expression of HO-1 in cerebellar and cerebral regions of the CNS of mice included in Fig 3 treated with EGCG alone, or in combination with GA. (t-test) *p<0.05.
Mentions: Evidence from EAE and MS suggests that oxidative stress and dysregulated iron metabolism contribute to neuronal damage. EGCG has the potential to impact these two processes by minimizing the amount of iron ions available to generate destructive oxygen radicals [10]. Therefore, to explore whether GA may interfere with the iron chelating activity of EGCG, soluble iron content in blood serum of the different treatment groups was quantified using a ferrozine-based assay. As shown in Fig 4A, there was no difference of total soluble iron detectable between the ECGC-treated and the EGCG+GA-treated groups.

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