Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling

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.

Plasma sphingosine 1-phosphate concentrations and cardiovascular autonomic neuropathy in individuals with type 2 diabetes

“…Preclinical studies reported that administration of a S1P receptor agonist improved neuronal electrophysiologic function and reduced demyelination 26 , 27 . Szepanowski et al 28 also reported that treatment with a S1P receptor agonist enhanced axonal outgrowth after nerve injury, suggesting a beneficial role of S1P during the nerve regeneration process. In addition, reduced levels of S1P may be implicated in degenerative disorders in the nervous system 8 .…”

Aligned Fingolimod-Releasing Electrospun Fibers Increase Dorsal Root Ganglia Neurite Extension and Decrease Schwann Cell Expression of Promyelinating Factors

“…Wang et al (2010) showed that highly aligned poly-L-lactic acid electrospun fibers with a diameter comparable to those used in this study enhanced neurite extension and Schwann cell migration compared with fibers of smaller diameter and reduced alignment. Here, to further enhance their regenerative propensity, we loaded aligned electrospun fibers with fingolimod, which has been associated with improved functional outcomes following peripheral nerve injury (Szepanowski et al, 2016).…”

Secretome analysis of nerve repair mediating Schwann cells reveals Smad‐dependent trophism

“…Moreover, treatment of DRG expiants with conditioned culture medium derived from FTY720P‐treated Schwann cells significantly induced neurite growth on both growth permissive and growth inhibitory substrates. The induction of the repair Schwann cell phenotype in juvenile and adult Schwann cells led to the conclusion that FTY720P may be used as a therapeutic option to promote nerve regeneration, further supported by the observation that FTY720P application in a mouse model of peripheral nerve injury improved nerve conduction velocities and myelin thickness (16).…”