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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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Dimethyl fumarate reduced inflammatory infiltrates of T cells and macrophages in sciatic nerves of EAN rats.(A) Rats were daily force fed with DMF or tap water and 16 days p.i. (at expected disease maximum), sciatic nerves were isolated and stained for CD3+ cells (a, b, c) and CD68+ cells (macrophages) (d, e, f). Representative photos of sciatic nerves in transverse sections of methylcellulose-treated animals (a and d), 15 mg/kg DMF-treated animals (b and e) and 45mg/kg DMF treated animals (c and f). Scale bars indicate 100μm. (B) Mean numbers of T cells per mm2 sciatic nerve sections and B. Mean numbers of macrophages (CD68+) per mm2 sciatic nerve sections as calculated by immunohistochemistry on day 16 p.i. from EAN rats (n = 6/group) receiving orally DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (** p<0,005, ***p<0,0001). The experiment was repeated 2 times with similar results.
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pone.0143416.g003: Dimethyl fumarate reduced inflammatory infiltrates of T cells and macrophages in sciatic nerves of EAN rats.(A) Rats were daily force fed with DMF or tap water and 16 days p.i. (at expected disease maximum), sciatic nerves were isolated and stained for CD3+ cells (a, b, c) and CD68+ cells (macrophages) (d, e, f). Representative photos of sciatic nerves in transverse sections of methylcellulose-treated animals (a and d), 15 mg/kg DMF-treated animals (b and e) and 45mg/kg DMF treated animals (c and f). Scale bars indicate 100μm. (B) Mean numbers of T cells per mm2 sciatic nerve sections and B. Mean numbers of macrophages (CD68+) per mm2 sciatic nerve sections as calculated by immunohistochemistry on day 16 p.i. from EAN rats (n = 6/group) receiving orally DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (** p<0,005, ***p<0,0001). The experiment was repeated 2 times with similar results.

Mentions: We next analysed if the therapeutic efficacy of DMF correlates with a reduction of inflammatory infiltration of the PNS. Histopathological data showing inflammation within the sciatic nerves are depicted in Fig 3. Administration of 45mg/kg DMF reduced significantly the degree of macrophage- and lymphocyte- infiltration at the peak of the disease (day 16 p.i.) compared to methylcellulose-treated group (Fig 3A, 3B and 3C ***p<0.001). The groups treated with 15mg/kg DMF showed a significant reduction of T cell infiltration, yet no reduction of the macrophage infiltrates was found at this dosage (Fig 3C).


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 reduced inflammatory infiltrates of T cells and macrophages in sciatic nerves of EAN rats.(A) Rats were daily force fed with DMF or tap water and 16 days p.i. (at expected disease maximum), sciatic nerves were isolated and stained for CD3+ cells (a, b, c) and CD68+ cells (macrophages) (d, e, f). Representative photos of sciatic nerves in transverse sections of methylcellulose-treated animals (a and d), 15 mg/kg DMF-treated animals (b and e) and 45mg/kg DMF treated animals (c and f). Scale bars indicate 100μm. (B) Mean numbers of T cells per mm2 sciatic nerve sections and B. Mean numbers of macrophages (CD68+) per mm2 sciatic nerve sections as calculated by immunohistochemistry on day 16 p.i. from EAN rats (n = 6/group) receiving orally DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (** p<0,005, ***p<0,0001). The experiment was repeated 2 times with similar results.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0143416.g003: Dimethyl fumarate reduced inflammatory infiltrates of T cells and macrophages in sciatic nerves of EAN rats.(A) Rats were daily force fed with DMF or tap water and 16 days p.i. (at expected disease maximum), sciatic nerves were isolated and stained for CD3+ cells (a, b, c) and CD68+ cells (macrophages) (d, e, f). Representative photos of sciatic nerves in transverse sections of methylcellulose-treated animals (a and d), 15 mg/kg DMF-treated animals (b and e) and 45mg/kg DMF treated animals (c and f). Scale bars indicate 100μm. (B) Mean numbers of T cells per mm2 sciatic nerve sections and B. Mean numbers of macrophages (CD68+) per mm2 sciatic nerve sections as calculated by immunohistochemistry on day 16 p.i. from EAN rats (n = 6/group) receiving orally DMF at different doses (15mg/kg, 45mg/kg/day) and methylcellulose-treated rats. Mean values and SEM are depicted (** p<0,005, ***p<0,0001). The experiment was repeated 2 times with similar results.
Mentions: We next analysed if the therapeutic efficacy of DMF correlates with a reduction of inflammatory infiltration of the PNS. Histopathological data showing inflammation within the sciatic nerves are depicted in Fig 3. Administration of 45mg/kg DMF reduced significantly the degree of macrophage- and lymphocyte- infiltration at the peak of the disease (day 16 p.i.) compared to methylcellulose-treated group (Fig 3A, 3B and 3C ***p<0.001). The groups treated with 15mg/kg DMF showed a significant reduction of T cell infiltration, yet no reduction of the macrophage infiltrates was found at this dosage (Fig 3C).

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