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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 induced Nrf2 at the peak of EAN course.(A) Representative photos of Nrf2 staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg (d-f), 45mg/kg (g-i) and methylcellulose-treated animals (a-c), showing an increase of Nrf2 positive cells for 45mg/kg DMF-treated rats. Pictures a, d and g show nuclear stain (DAPI), pictures b, e and h Nrf2 stain and pictures c, f and i indicate double staining. Scale bars indicate 100μm. (B) Percentage of Nrf2 positive staining per sciatic nerve section measured by immunofluorescent staining on day 16 p.i. from EAN rats (n = 6/group) receiving DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (*p<0,05).
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pone.0143416.g005: Dimethyl fumarate induced Nrf2 at the peak of EAN course.(A) Representative photos of Nrf2 staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg (d-f), 45mg/kg (g-i) and methylcellulose-treated animals (a-c), showing an increase of Nrf2 positive cells for 45mg/kg DMF-treated rats. Pictures a, d and g show nuclear stain (DAPI), pictures b, e and h Nrf2 stain and pictures c, f and i indicate double staining. Scale bars indicate 100μm. (B) Percentage of Nrf2 positive staining per sciatic nerve section measured by immunofluorescent staining on day 16 p.i. from EAN rats (n = 6/group) receiving DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (*p<0,05).

Mentions: Representative pictures from an immunofluorescent staining, showing Nrf2 positive cells in the sciatic nerves are depicted in Fig 5 and revealed a significantly increased expression of Nrf2 in the peripheral nerves of 45mg/kg DMF treated group at the peak of disease (*p<0,05, n = 6).


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 induced Nrf2 at the peak of EAN course.(A) Representative photos of Nrf2 staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg (d-f), 45mg/kg (g-i) and methylcellulose-treated animals (a-c), showing an increase of Nrf2 positive cells for 45mg/kg DMF-treated rats. Pictures a, d and g show nuclear stain (DAPI), pictures b, e and h Nrf2 stain and pictures c, f and i indicate double staining. Scale bars indicate 100μm. (B) Percentage of Nrf2 positive staining per sciatic nerve section measured by immunofluorescent staining on day 16 p.i. from EAN rats (n = 6/group) receiving DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (*p<0,05).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0143416.g005: Dimethyl fumarate induced Nrf2 at the peak of EAN course.(A) Representative photos of Nrf2 staining for sciatic nerve transverse sections of rats (n = 6/group) treated with DMF 15mg/kg (d-f), 45mg/kg (g-i) and methylcellulose-treated animals (a-c), showing an increase of Nrf2 positive cells for 45mg/kg DMF-treated rats. Pictures a, d and g show nuclear stain (DAPI), pictures b, e and h Nrf2 stain and pictures c, f and i indicate double staining. Scale bars indicate 100μm. (B) Percentage of Nrf2 positive staining per sciatic nerve section measured by immunofluorescent staining on day 16 p.i. from EAN rats (n = 6/group) receiving DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (*p<0,05).
Mentions: Representative pictures from an immunofluorescent staining, showing Nrf2 positive cells in the sciatic nerves are depicted in Fig 5 and revealed a significantly increased expression of Nrf2 in the peripheral nerves of 45mg/kg DMF treated group at the peak of disease (*p<0,05, n = 6).

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