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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 improved proximal and distal nerve conduction.(A) Representative CMAP (compound motor action potentials) traces during EAN course at days −1 and 16 p.i. showing a conduction block for methylcellulose-treated rats at day 16 p.i. whereas for 45 mg/kg DMF-treated rats no conduction block was recorded. (B) Representative F-wave traces after distal stimulation showing prolonged F-waves latencies only for the methylcellulose-treated group at day 16 p.i. in comparison to day -1. Rats treated with 45mg/kg did not show any significant differences in the F-wave latencies between day -1 and 16 p.i. The black vertical line defines the motor (M) response and the F (F-wave) response latency. On the left of the red vertical line applies the M response regarding distance (horizontally, ms) and vertically (mV) and on the right of the red vertical line applies the F response data (ms, mV), (M: M response, F: F response, D: distance of one side of the dotted lined squares). (C) After proximal and distal stimulation of the sciatic nerve the conduction velocity was calculated. A statistical significant reduction of the MNCV (motor nerve conduction velocity) appeared for the control group and the 15mg/kg group (p<0,0001 ***, n = 10), but no difference in the MNCV was seen for the 45mg/kg DMF treated group indicating a protective role of DMF against demyelination. Mean values and SEM are depicted.
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pone.0143416.g002: Dimethyl fumarate improved proximal and distal nerve conduction.(A) Representative CMAP (compound motor action potentials) traces during EAN course at days −1 and 16 p.i. showing a conduction block for methylcellulose-treated rats at day 16 p.i. whereas for 45 mg/kg DMF-treated rats no conduction block was recorded. (B) Representative F-wave traces after distal stimulation showing prolonged F-waves latencies only for the methylcellulose-treated group at day 16 p.i. in comparison to day -1. Rats treated with 45mg/kg did not show any significant differences in the F-wave latencies between day -1 and 16 p.i. The black vertical line defines the motor (M) response and the F (F-wave) response latency. On the left of the red vertical line applies the M response regarding distance (horizontally, ms) and vertically (mV) and on the right of the red vertical line applies the F response data (ms, mV), (M: M response, F: F response, D: distance of one side of the dotted lined squares). (C) After proximal and distal stimulation of the sciatic nerve the conduction velocity was calculated. A statistical significant reduction of the MNCV (motor nerve conduction velocity) appeared for the control group and the 15mg/kg group (p<0,0001 ***, n = 10), but no difference in the MNCV was seen for the 45mg/kg DMF treated group indicating a protective role of DMF against demyelination. Mean values and SEM are depicted.

Mentions: The electrophysiological measurements of the sciatic nerve at the maximum of the clinical course (day 16 p.i.) showed a significant reduction of the MNCV in the methylcellulose-treated rats (mean MNCV on day 16 p.i. 31.9 m/s vs. day -1 p.i. 46.9 m/s, ***p<0.0001, n = 10) and the rats treated with 15 mg/kg DMF, a non-significant reduction of MNCV for the 30 mg/kg DMF treated group, whereas no difference was seen on day 16 p.i. as compared to the mean MNCV on day -1 for 45 mg/kg DMF-treated group (Fig 2).


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 improved proximal and distal nerve conduction.(A) Representative CMAP (compound motor action potentials) traces during EAN course at days −1 and 16 p.i. showing a conduction block for methylcellulose-treated rats at day 16 p.i. whereas for 45 mg/kg DMF-treated rats no conduction block was recorded. (B) Representative F-wave traces after distal stimulation showing prolonged F-waves latencies only for the methylcellulose-treated group at day 16 p.i. in comparison to day -1. Rats treated with 45mg/kg did not show any significant differences in the F-wave latencies between day -1 and 16 p.i. The black vertical line defines the motor (M) response and the F (F-wave) response latency. On the left of the red vertical line applies the M response regarding distance (horizontally, ms) and vertically (mV) and on the right of the red vertical line applies the F response data (ms, mV), (M: M response, F: F response, D: distance of one side of the dotted lined squares). (C) After proximal and distal stimulation of the sciatic nerve the conduction velocity was calculated. A statistical significant reduction of the MNCV (motor nerve conduction velocity) appeared for the control group and the 15mg/kg group (p<0,0001 ***, n = 10), but no difference in the MNCV was seen for the 45mg/kg DMF treated group indicating a protective role of DMF against demyelination. Mean values and SEM are depicted.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4664277&req=5

pone.0143416.g002: Dimethyl fumarate improved proximal and distal nerve conduction.(A) Representative CMAP (compound motor action potentials) traces during EAN course at days −1 and 16 p.i. showing a conduction block for methylcellulose-treated rats at day 16 p.i. whereas for 45 mg/kg DMF-treated rats no conduction block was recorded. (B) Representative F-wave traces after distal stimulation showing prolonged F-waves latencies only for the methylcellulose-treated group at day 16 p.i. in comparison to day -1. Rats treated with 45mg/kg did not show any significant differences in the F-wave latencies between day -1 and 16 p.i. The black vertical line defines the motor (M) response and the F (F-wave) response latency. On the left of the red vertical line applies the M response regarding distance (horizontally, ms) and vertically (mV) and on the right of the red vertical line applies the F response data (ms, mV), (M: M response, F: F response, D: distance of one side of the dotted lined squares). (C) After proximal and distal stimulation of the sciatic nerve the conduction velocity was calculated. A statistical significant reduction of the MNCV (motor nerve conduction velocity) appeared for the control group and the 15mg/kg group (p<0,0001 ***, n = 10), but no difference in the MNCV was seen for the 45mg/kg DMF treated group indicating a protective role of DMF against demyelination. Mean values and SEM are depicted.
Mentions: The electrophysiological measurements of the sciatic nerve at the maximum of the clinical course (day 16 p.i.) showed a significant reduction of the MNCV in the methylcellulose-treated rats (mean MNCV on day 16 p.i. 31.9 m/s vs. day -1 p.i. 46.9 m/s, ***p<0.0001, n = 10) and the rats treated with 15 mg/kg DMF, a non-significant reduction of MNCV for the 30 mg/kg DMF treated group, whereas no difference was seen on day 16 p.i. as compared to the mean MNCV on day -1 for 45 mg/kg DMF-treated group (Fig 2).

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