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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 application of GA in combination with EGCG interferes with the anti-inflammatory and neuroprotective effects of EGCG single therapy.A: Quantification of inflammation, B: neurodegeneration C: and degree of demyelination in the spinal cord from control, GA, EGCG and combination therapy group included in Fig 1. Histopathological changes were assessed semi-quantitatively as percentage of spinal cord quadrants that showed pathological changes related to all investigated tissue quadrants. Representative Hematoxylin and Eosin staining to monitor inflammation of transverse spinal cord sections of control (D), GA treated mice (G), EGCG treated mice (J) and mice treated with the combination therapy (M) are shown. Bielschowsky staining was used to assess axonal damage. Representative spinal cord sections of control (E), GA treated mice (H), EGCG treated mice (K) and mice treated with the combination therapy (N) are shown. The degree of demyelination was determined by Luxol Fast Blue staining. Representative LFB spinal cord sections of control group (F), GA treated group (I), EGCG treated group (L) and group treated with EGCG and GA (O) are shown. (Kruskal-Wallis) *p<0.05, **p<0.01.
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pone.0130251.g002: The application of GA in combination with EGCG interferes with the anti-inflammatory and neuroprotective effects of EGCG single therapy.A: Quantification of inflammation, B: neurodegeneration C: and degree of demyelination in the spinal cord from control, GA, EGCG and combination therapy group included in Fig 1. Histopathological changes were assessed semi-quantitatively as percentage of spinal cord quadrants that showed pathological changes related to all investigated tissue quadrants. Representative Hematoxylin and Eosin staining to monitor inflammation of transverse spinal cord sections of control (D), GA treated mice (G), EGCG treated mice (J) and mice treated with the combination therapy (M) are shown. Bielschowsky staining was used to assess axonal damage. Representative spinal cord sections of control (E), GA treated mice (H), EGCG treated mice (K) and mice treated with the combination therapy (N) are shown. The degree of demyelination was determined by Luxol Fast Blue staining. Representative LFB spinal cord sections of control group (F), GA treated group (I), EGCG treated group (L) and group treated with EGCG and GA (O) are shown. (Kruskal-Wallis) *p<0.05, **p<0.01.

Mentions: To further examine potential mechanisms of drug interference in the chronic EAE model, we performed histopathological analysis of spinal cord sections from the mice included in the experiment shown in Fig 1. We focused attention on the effects of the different therapy regimes on inflammation, demyelination and neurodegeneration. Staining with hematoxylin and eosin revealed that both GA and EGCG single treatments led to significant reductions in spinal cord inflammation, compared to the vehicle control group (Fig 2A). However, mice treated with the combination therapy showed no significant reduction in inflammation compared to controls (Fig 2A). Interestingly, EGCG single treatment also preserved axons and myelin during chronic EAE, as reflected by the staining of neurofilaments assessed by Bielschowsky silver staining (Fig 2B), and myelin determined by LFB staining (Fig 2C). The single suboptimal application of GA was not sufficient to preserve axons and myelin. Moreover, the EGCG-mediated protection from both axonal damage and demyelination was abolished by the single application of GA (Fig 2B and 2C).


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 application of GA in combination with EGCG interferes with the anti-inflammatory and neuroprotective effects of EGCG single therapy.A: Quantification of inflammation, B: neurodegeneration C: and degree of demyelination in the spinal cord from control, GA, EGCG and combination therapy group included in Fig 1. Histopathological changes were assessed semi-quantitatively as percentage of spinal cord quadrants that showed pathological changes related to all investigated tissue quadrants. Representative Hematoxylin and Eosin staining to monitor inflammation of transverse spinal cord sections of control (D), GA treated mice (G), EGCG treated mice (J) and mice treated with the combination therapy (M) are shown. Bielschowsky staining was used to assess axonal damage. Representative spinal cord sections of control (E), GA treated mice (H), EGCG treated mice (K) and mice treated with the combination therapy (N) are shown. The degree of demyelination was determined by Luxol Fast Blue staining. Representative LFB spinal cord sections of control group (F), GA treated group (I), EGCG treated group (L) and group treated with EGCG and GA (O) are shown. (Kruskal-Wallis) *p<0.05, **p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130251.g002: The application of GA in combination with EGCG interferes with the anti-inflammatory and neuroprotective effects of EGCG single therapy.A: Quantification of inflammation, B: neurodegeneration C: and degree of demyelination in the spinal cord from control, GA, EGCG and combination therapy group included in Fig 1. Histopathological changes were assessed semi-quantitatively as percentage of spinal cord quadrants that showed pathological changes related to all investigated tissue quadrants. Representative Hematoxylin and Eosin staining to monitor inflammation of transverse spinal cord sections of control (D), GA treated mice (G), EGCG treated mice (J) and mice treated with the combination therapy (M) are shown. Bielschowsky staining was used to assess axonal damage. Representative spinal cord sections of control (E), GA treated mice (H), EGCG treated mice (K) and mice treated with the combination therapy (N) are shown. The degree of demyelination was determined by Luxol Fast Blue staining. Representative LFB spinal cord sections of control group (F), GA treated group (I), EGCG treated group (L) and group treated with EGCG and GA (O) are shown. (Kruskal-Wallis) *p<0.05, **p<0.01.
Mentions: To further examine potential mechanisms of drug interference in the chronic EAE model, we performed histopathological analysis of spinal cord sections from the mice included in the experiment shown in Fig 1. We focused attention on the effects of the different therapy regimes on inflammation, demyelination and neurodegeneration. Staining with hematoxylin and eosin revealed that both GA and EGCG single treatments led to significant reductions in spinal cord inflammation, compared to the vehicle control group (Fig 2A). However, mice treated with the combination therapy showed no significant reduction in inflammation compared to controls (Fig 2A). Interestingly, EGCG single treatment also preserved axons and myelin during chronic EAE, as reflected by the staining of neurofilaments assessed by Bielschowsky silver staining (Fig 2B), and myelin determined by LFB staining (Fig 2C). The single suboptimal application of GA was not sufficient to preserve axons and myelin. Moreover, the EGCG-mediated protection from both axonal damage and demyelination was abolished by the single application of GA (Fig 2B and 2C).

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