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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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Related in: MedlinePlus

Dimethyl fumarate did not induce Nrf2 in Schwann cells at the peak of EAN course.Representative photos of double (merge) Nrf2 positive Schwann cells (S100 positive) staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg, 45mg/kg and methylcellulose. No statistical significant increase between Nrf2 positive Schwann cells for DMF-treated vs. methylcellulose-treated rats on day 16 p.i. was detected (insets depict details of staining). Scale bars indicate 50μm.
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pone.0143416.g006: Dimethyl fumarate did not induce Nrf2 in Schwann cells at the peak of EAN course.Representative photos of double (merge) Nrf2 positive Schwann cells (S100 positive) staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg, 45mg/kg and methylcellulose. No statistical significant increase between Nrf2 positive Schwann cells for DMF-treated vs. methylcellulose-treated rats on day 16 p.i. was detected (insets depict details of staining). Scale bars indicate 50μm.

Mentions: In order to investigate the structures expressing Nrf2 in the peripheral nerves we performed double staining for Nrf2-S100 (Fig 6) and for Nrf2-NF200 (Fig 7A), which revealed that axons and not Schwann cells showed an induction of Nrf2 after dimethyl fumarate treatment on day 16 p.i. (Fig 7B, **p<0.05). A possible protective role of DMF on Schwann cells was investigated with a double staining TUNEL-S-100 staining, which did not show any significant reduction of Schwann cell death in the DMF treated groups (data not shown).


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)

Dimethyl fumarate did not induce Nrf2 in Schwann cells at the peak of EAN course.Representative photos of double (merge) Nrf2 positive Schwann cells (S100 positive) staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg, 45mg/kg and methylcellulose. No statistical significant increase between Nrf2 positive Schwann cells for DMF-treated vs. methylcellulose-treated rats on day 16 p.i. was detected (insets depict details of staining). Scale bars indicate 50μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664277&req=5

pone.0143416.g006: Dimethyl fumarate did not induce Nrf2 in Schwann cells at the peak of EAN course.Representative photos of double (merge) Nrf2 positive Schwann cells (S100 positive) staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg, 45mg/kg and methylcellulose. No statistical significant increase between Nrf2 positive Schwann cells for DMF-treated vs. methylcellulose-treated rats on day 16 p.i. was detected (insets depict details of staining). Scale bars indicate 50μm.
Mentions: In order to investigate the structures expressing Nrf2 in the peripheral nerves we performed double staining for Nrf2-S100 (Fig 6) and for Nrf2-NF200 (Fig 7A), which revealed that axons and not Schwann cells showed an induction of Nrf2 after dimethyl fumarate treatment on day 16 p.i. (Fig 7B, **p<0.05). A possible protective role of DMF on Schwann cells was investigated with a double staining TUNEL-S-100 staining, which did not show any significant reduction of Schwann cell death in the DMF treated groups (data not shown).

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