Abstract
BackgroundThe 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.MethodsSciatic 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.ResultsClinical 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.ConclusionsOur 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.
Highlights
The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions
forkhead box protein N1 (Foxn1)−/− mice, which are devoid of T- but not B-lymphocytes, did show an improvement of nerve regeneration under fingolimod treatment (Fig. 1a, c)
The mean increase in nerve conduction velocity in both fingolimod-treated and control Foxn1−/− mice implies a potentially positive role of T-lymphocyte deficiency on nerve regeneration, only fingolimod-treated Foxn1−/− mice showed a significant improvement compared to C57BL/6 controls and performed better in the functional analysis (Fig. 1a, c)
Summary
The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. 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. 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. Sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) and their signaling pathways have been best characterized. Lysophospholipid signaling appears to have a large range of physiological and pathophysiological functions [2, 3] in the adult organism and plays important roles during embryonic development, especially in the development of the nervous system and vascular development [4,5,6]. In contrast to S1P2–5, S1P1 is thought to exclusively couple with Gi/o, affecting cyclic adenosine monophosphate (cAMP) levels and Ca2+ mobilization, among others [10, 12]
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