Sphingosine 1-phosphate receptor modulation attenuate mechanical allodynia in mouse model of chronic complex regional pain syndrome by suppressing pathogenic astrocyte activation

Abstract

Background and objectivesFTY720 ((2-amino-2-)2-[4-octylphenyl]ethyl)-1,3-propanediol) is an Food and Drug Administration (FDA)-approved immunomodulatory drug for treating multiple sclerosis. It inhibits lymphocyte egression from lymphoid tissues by downregulating sphingosine-1 phosphate receptor (S1PR). To date, there has been no study on the effects of FTY720 on the chronic stage of the complex regional pain syndrome (CRPS) rodent model, despite its antiallodynic effect in previous studies. Thus, the aim of this study is to investigate the effect of FTY720 in a chronic stage of the CRPS mouse model.MethodThe authors used a mouse model of CRPS, involving tibia fracture/cast immobilization, to test the efficacy of intrathecal FTY720 (2.5 or 25 ng daily; 6 days) or vehicle during the chronic (7 weeks after fracture) stage of CRPS.ResultsIntrathecal recombinant FTY720 administration was antiallodynic in the chronic stage of the CRPS mouse model, and such an effect of FTY720 developed by modulating astrocyte activation in the spinal cord. Additionally, according to the in vitro data, the FTY720 treatment inhibited S1P-induced increase in the nitric oxide production and suppression of the NF-κB pathway, by inhibiting the phosphorylation of NF-κB/p65 in astrocytes without toxic effect on astrocytes.ConclusionCollectively, these results demonstrate that intrathecally administered FTY720 attenuates mechanical allodynia in the chronic stage of the CRPS mouse model.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…In contrast, FTY720-treated immortalized astrocytes displayed increased release of the astrocyte-secreted protein GM-CSF [89], whereas LPS-stimulated primary astrocytes decreased GM-CSF release following treatment with FTY720 [65]. No effect of FTY720 on astrocyte reactivity status has been found [46,64,[67][68][69][70] and even an increased number of GFAP-positive cells has been reported in in vivo models [66,90].…”

“…In vitro, interferon-gamma (IFN-γ)-stimulated rat astrocytes increased ADR-β2 and reduced MHC-II expression following FTY720-and pFTY720 treatment through a decrease in NFκB p65 (also named RelA) [98]. In addition, FTY720 inhibited the degree of phosphorylation of NFκB and p65 both after cellular stress by OGD and in unstimulated primary astrocyte cultures [65,90,92,93], and increased the inhibitor NFκB-alpha (Iκbα) levels in a mouse HD model [84], both leading to a reduced NFκB activation. The observed effects of FTY720 on pro-inflammatory cytokine production in astrocytes can be explained by these effects on NFκB, and are supported by its inhibitory effect on the production of the NFκB down-stream targets NLRP3 and IL-1β, which was not present in S1PR1 knock-out astrocytes [99].…”

The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain

“…Since the S1P receptor modulator FTY720 -Food and Drug Administration-approved for multiple sclerosis) has been reported to control disease severity and attenuate sciatic nerve damage in chronic experimental autoimmune neuritis [205], the ceramide to S1P pathway may be relevant for the development of CRPS and the pain associated with it. This assumption is supported by a first preclinical study where intrathecal injection of FTY720 inhibits S1P-induced increase in nitric oxide production and suppression of the NF-κB pathway in astrocytes; in the chronic stage of a mouse CRPS model, intrathecal FTY720 administration was antiallodynic and is suggested to be mediated by modulating astrocyte activation in the spinal cord [206].…”

<p>Effectiveness of Intravenous Immunoglobulin for Management of Neuropathic Pain: A Narrative Review</p>

“…Journal of Pain Research 2020:13 contributes a little more to the acute stage of CRPS than to the chronic stage. [23][24][25][26][27][28] The disease durations were 2.4 ± 0.9 and 1.6 ± 0.7 years in studies conducted in 2017 and 2010, respectively. 15,16 Therefore, the greater effect of IVIG in the study by Goebel et al in 2010 16 compared to 2017 15 may be explained by the enrollment of patients in a relatively early phase of CRPS.…”