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Background: The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P1 receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatment of multiple sclerosis. An emerging body of experimental evidence points to additional direct effects on cells of the central and peripheral nervous system. Furthermore, fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Here we investigated whether modulation of particular signaling aspects of S1P as well as LPA by fingolimod might propagate peripheral nerve regeneration in vivo and independent of its anti-inflammatory potency.Methods: Sciatic nerve crush was performed in wildtype C57BL/6, in immunodeficient Rag1 (-/-) and Foxn1 (-/-) mice. Analyses were based on walking track analysis and electrophysiology, histology, and cAMP formation. Quantification of different LPA species was performed by liquid chromatography coupled to tandem mass spectrometry. Furthermore, functional consequences of autotaxin inhibition by the specific inhibitor PF-8380 and the impact of fingolimod on early cytokine release in the injured sciatic nerve were investigated.Results: Clinical and electrophysiological measures indicated an improvement of nerve regeneration under fingolimod treatment that is partly independent of its anti-inflammatory properties. Fingolimod treatment correlated with a significant elevation of axonal cAMP, a crucial factor for axonal outgrowth. Additionally, fingolimod significantly reduced LPA levels in the injured nerve. PF-8380 treatment correlated with improved myelin thickness. Sciatic nerve cytokine levels were not found to be significantly altered by fingolimod treatment.Conclusions: Our findings provide in vivo evidence for direct effects of fingolimod on cells of the peripheral nervous system that may propagate nerve regeneration via a dual mode of action, differentially affecting axonal outgrowth and myelination by modulating relevant aspects of S1P and LPA signaling. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Although there is evidence for a pathogenic role of humoral factors in multifocal motor neuropathy (MMN), plasma exchange (PE) is assumed to be an ineffective treatment. We set out to elucidate possible reasons for this apparent contradiction. Methods: A retrospective analysis of seven patients with MMN, who underwent 4 to 18 sessions of PE. Clinical response, electrophysiological parameter and anti-ganglioside antibody titers were reviewed. Results: Two patients, who had anti-ganglioside antibodies, exhibited transient clinical responses to PE, manifested by improved neurological function. Whereas electrophysiological parameters continued to worsen in all patients, anti-ganglioside antibody titers declined during PE, but increased after PE. Conclusion: PE is of limited therapeutic value in patients with MMN, who do not respond to established treatment options. It may only be useful as an adjunctive treatment in a subset of patients. The transient decrease of anti-ganglioside-antibodies titers suggests that pathogenic humoral factors in MMN are only temporarily reduced. Further, PE treatment alone is insufficient to prevent axons from continuing degeneration, which may explain the failure of PE to substantially influence the disease course of patients with MMN. [Copyright &y& Elsevier]