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Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection.

Pitarokoili K, Ambrosius B, Meyer D, Schrewe L, Gold R - PLoS ONE (2015)

Bottom Line: In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves.This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate.We conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, St. Josef Hospital, Ruhr- University of Bochum, Bochum, Germany.

ABSTRACT

Background: Dimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system.

Methods and findings: Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.

Conclusions: We conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.

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Clinical EAN course under dimethyl fumarate treatment.EAN was induced in Lewis rats by immunisation on day 0 with P2 peptide 53–78 plus CFA. Rats received DMF diluted in 0,08% methylcellulose in tap water at doses of 15 mg/kg, 30mg/kg and 45mg/kg twice daily from day 0 to day 23-post immunisation by oral gavage. Control rats received 0,08% methylcellulose in tap water only. Mean values and SEM are depicted, ROC Area under curve (AUC) 45mg/kg vs. methylcellulose, n = 8 * p<0,05. The experiment was repeated 2 times with similar results.
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pone.0143416.g001: Clinical EAN course under dimethyl fumarate treatment.EAN was induced in Lewis rats by immunisation on day 0 with P2 peptide 53–78 plus CFA. Rats received DMF diluted in 0,08% methylcellulose in tap water at doses of 15 mg/kg, 30mg/kg and 45mg/kg twice daily from day 0 to day 23-post immunisation by oral gavage. Control rats received 0,08% methylcellulose in tap water only. Mean values and SEM are depicted, ROC Area under curve (AUC) 45mg/kg vs. methylcellulose, n = 8 * p<0,05. The experiment was repeated 2 times with similar results.

Mentions: After immunization with P2 protein peptide 53–78, clinical signs of EAN started around day 11 p.i.. The incidence of EAN for the control group was 100% and the groups receiving DMF showed an incidence of 100% (15 mg/kg), 100% (30 mg/kg) or 87.5% (45 mg/kg) respectively (n = 8). Treatment with 15 and 30 mg/kg had no statistically significant effect on the clinical course of EAN. Treatment with 45 mg/kg DMF delayed the onset of clinical EAN by 2–3 days and reduced significantly the clinical signs of EAN when compared with methylcellulose-treated control rats (Fig 1, ROC AUC, area under curve, *p<0,05). A further experiment was performed with a group treated with 100mg/kg DMF (n = 8). This high dosage showed no clinical effects and no overt signs of toxicity (data not shown). There was a non-significant reduction of body weight of sham-treated controls during the course of active EAN as compared to rats treated with 45 mg/kg DMF (data not shown), in accord with our experience with this disease model [11].


Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection.

Pitarokoili K, Ambrosius B, Meyer D, Schrewe L, Gold R - PLoS ONE (2015)

Clinical EAN course under dimethyl fumarate treatment.EAN was induced in Lewis rats by immunisation on day 0 with P2 peptide 53–78 plus CFA. Rats received DMF diluted in 0,08% methylcellulose in tap water at doses of 15 mg/kg, 30mg/kg and 45mg/kg twice daily from day 0 to day 23-post immunisation by oral gavage. Control rats received 0,08% methylcellulose in tap water only. Mean values and SEM are depicted, ROC Area under curve (AUC) 45mg/kg vs. methylcellulose, n = 8 * p<0,05. The experiment was repeated 2 times with similar results.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4664277&req=5

pone.0143416.g001: Clinical EAN course under dimethyl fumarate treatment.EAN was induced in Lewis rats by immunisation on day 0 with P2 peptide 53–78 plus CFA. Rats received DMF diluted in 0,08% methylcellulose in tap water at doses of 15 mg/kg, 30mg/kg and 45mg/kg twice daily from day 0 to day 23-post immunisation by oral gavage. Control rats received 0,08% methylcellulose in tap water only. Mean values and SEM are depicted, ROC Area under curve (AUC) 45mg/kg vs. methylcellulose, n = 8 * p<0,05. The experiment was repeated 2 times with similar results.
Mentions: After immunization with P2 protein peptide 53–78, clinical signs of EAN started around day 11 p.i.. The incidence of EAN for the control group was 100% and the groups receiving DMF showed an incidence of 100% (15 mg/kg), 100% (30 mg/kg) or 87.5% (45 mg/kg) respectively (n = 8). Treatment with 15 and 30 mg/kg had no statistically significant effect on the clinical course of EAN. Treatment with 45 mg/kg DMF delayed the onset of clinical EAN by 2–3 days and reduced significantly the clinical signs of EAN when compared with methylcellulose-treated control rats (Fig 1, ROC AUC, area under curve, *p<0,05). A further experiment was performed with a group treated with 100mg/kg DMF (n = 8). This high dosage showed no clinical effects and no overt signs of toxicity (data not shown). There was a non-significant reduction of body weight of sham-treated controls during the course of active EAN as compared to rats treated with 45 mg/kg DMF (data not shown), in accord with our experience with this disease model [11].

Bottom Line: In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves.This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate.We conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, St. Josef Hospital, Ruhr- University of Bochum, Bochum, Germany.

ABSTRACT

Background: Dimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system.

Methods and findings: Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.

Conclusions: We conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.

Show MeSH
Related in: MedlinePlus