The Clinically-tested S1P Receptor Agonists, FTY720 and BAF312, Demonstrate Subtype-Specific Bradycardia (S1P1) and Hypertension (S1P3) in Rat

Fryer, Ryan M.; Muthukumarana, Akalushi; Harrison, Paul C.; Mazurek, Suzanne Nodop; Chen, Rong Rhonda; Harrington, Kyle E.; Dinallo, Roger M.; Horan, Joshua C.; Patnaude, Lori; Modis, Louise K.; Reinhart, Glenn A.

doi:10.1371/journal.pone.0052985

Cited by 77 publications

(68 citation statements)

References 40 publications

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“…The CNS is therefore an important site for mechanism of action of not only FTY720 but also of other S1PR 1 modulators, including CYM-5442 (6,57,71). In our studies, the maximal efficacy regarding the reduction of mechano-hypersensitivity was detected with doses of FTY720 at least 10-fold lower than those shown to cause lymphopenia (6) or bradycardia (72) and for NIBR-14/15 to cause pulmonary vascular leakage (40). Furthermore, we did not observe any changes in differential white blood cell counts following a 6-day infusion of FTY720 that provided near-tomaximal inhibition of CIPN.…”

Section: Discussionmentioning

confidence: 46%

The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

Janes

Little

et al. 2014

Journal of Biological Chemistry

133

159

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Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a critical dose-limiting side effect of many chemotherapeutic agents, including paclitaxel. Results: Spinal activation of the S1P-to-S1PR 1 axis contributes to the development and maintenance of paclitaxel-induced neuropathic pain through enhanced neuroinflammatory processes. Conclusion: Inhibition of S1PR 1 blocks and reverses paclitaxel-induced neuropathic pain without interfering with anticancer effects. Significance: Targeting the S1PR 1 signaling pathway could be an effective approach for the treatment of CIPN.

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Section: Discussionmentioning

confidence: 46%

The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

Janes

Little

et al. 2014

Journal of Biological Chemistry

133

159

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“…This promiscuity may be responsible for adverse affects, such as acute bradycardia (decreased heart rate) and hypertension, seen in fi ngolimod-treated patients ( 32,33 ). Initial results from rodent studies indicated that FTY720 phosphate activation of S1P 3 was responsible for both bradycardia and hypertension; however, treatment of humans with more selective agonists indicated that S1P 1 agonism was responsible for reduced heart rate, whereas S1P 3 signaling contributed to the development of hypertension (34)(35)(36)(37). The divergent utilization of S1P 1 and S1P 3 in rodents versus primates for the regulation of these coordinated .…”

Section: Vascular and Lymphatic Systemsmentioning

confidence: 99%

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

446

403

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This article is available online at http://www.jlr.org during development and ageing. S1P 1 , S1P 2 , and S1P 3 are essentially ubiquitously expressed, whereas expression of S1P 4 and S1P 5 are highly restricted to distinct cell types ( 4 ).Production of S1P can be initiated by external or internal signals, which lead to activation of the biosynthetic pathway beginning with metabolism of membrane SM to ceramide by SMases ( 5, 6 ). Ceramide, an important signaling molecule itself, can be metabolized by ceramidase to sphingosine (Sph) ( 7 ). Sph is then phosphorylated by one of two Sph kinases (Sphks), Sphk1 or Sphk2, resulting in S1P genesis ( 8-10 ) ( Fig. 1 ).Although there are proposed intracellular roles for S1P, it is often transported out of the cell where it can act in an autocrine or paracrine manner on S1PRs ( 11, 12 ). Transport out of the cell may occur via several transporters; however, the only bona fi de transporter to date is spinster 2, which is also capable of FTY720 (fi ngolimod/Gilenya; Novartis) export (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Once outside of the cell, S1P can bind to two known carriers, albumin or ApoM ( 6, 23, 24 ) ( Fig. 1 ). Approximately 35% of plasma S1P is bound to albumin and 65% to ApoM, which is found on a small percentage ( ‫ف‬ 5%) of HDL particles ( 24 ). This ApoM+HDL-bound S1P has been proposed as a primary contributor to the vasoprotective properties of HDLs ( 25-27 ). How albumin or ApoM deliver S1P to specifi c S1PRs has yet to be characterized. AGONISTS AND ANTAGONISTSThere are several well-characterized agonists and antagonists of S1PRs; however, most compounds have been diAbstract Sphingosine 1-phosphate (S1P) is a membranederived lysophospholipid that acts primarily as an extracellular signaling molecule. Signals initiated by S1P are transduced by five G protein-coupled receptors, named S1P 1-5 . Cellular and temporal expression of the S1P receptors (S1PRs) determine their specifi c roles in various organ systems, but they are particularly critical for regulation of the cardiovascular, immune, and nervous systems, with the most well-known contributions of S1PR signaling being modulation of vascular barrier function, vascular tone, and regulation of lymphocyte traffi cking. However, our knowledge of S1PR biology is rapidly increasing as they become attractive therapeutic targets in several diseases, such as chronic infl ammatory pathologies, autoimmunity, and cancer. Understanding how the S1PRs regulate interactions between biological systems will allow for greater effi cacy in this novel therapeutic strategy as well as characterization of complex physiological networks. Because of the rapidly expanding body of research, this review will focus on the most recent advances in S1PRs. Sphingosine 1-phosphate [2 S -amino-1-(dihydrogen phosphate)-4E-octadecene-1,3 R -diol] (S1P) is a simple membrane-derived lysophospholipid with regulatory roles in almost all facets of mammalian biology ( 1 ). Concentrations of S1P in blood and lymph plasmas are high, in the high...

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“…The phosphorylated (active) form of fingolimod was administered at doses of 0.10, 0.30, and 1.00 mg/kg per 30 minutes, and inhibitor 31 was administered at doses of 0.18, 0.61, and 1.8 mg/kg per 30 minutes. The fingolimod doses were selected from published results in a similar model (Fryer et al, 2012), and the doses for inhibitor 31 were selected to achieve blood concentrations that demonstrated pharmacologic activity by reducing lymphocytes (see Results).…”

Section: Methodsmentioning

confidence: 99%

“…Significant reduction in HR was observed with the 0.1, 0.3, and 1.0 mg/kg doses, and no fingolimod phosphate-related changes in MAP were observed. This demonstrates the model is sensitive to the well-characterized reduction in HR from fingolimod-phosphate treatment (Fryer et al, 2012).…”

mentioning

confidence: 94%

“…Studies with both receptor knockout animals and with selective agonists demonstrate that S1PR1 activation in rodents results in lymphocyte sequestration and that S1PR3 activation induces bradycardia (Forrest et al, 2004;Sanna et al, 2004;Fryer et al, 2012). Yet S1PR3-sparing S1PR1 agonists reduce HR and elevate blood pressure in human trials (Mori and Kuwabara, 2014).…”

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confidence: 99%

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Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats

Harris¹,

Mittelstadt²,

Banfor

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Inhibition of the sphingosine-1-phosphate (S1P)-catabolizing enzyme S1P lyase (S1PL) elevates the native ligand of S1P receptors and provides an alternative mechanism for immune suppression to synthetic S1P receptor agonists. S1PL inhibition is reported to preferentially elevate S1P in lymphoid organs. Tissue selectivity could potentially differentiate S1PL inhibitors from S1P receptor agonists, the use of which also results in bradycardia, atrioventricular block, and hypertension. But it is unknown if S1PL inhibition would also modulate cardiac S1P levels or cardiovascular function. The S1PL inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile was used to determine the relationship in rats between drug concentration, S1P levels in select tissues, and circulating lymphocytes. Repeated oral doses of the S1PL inhibitor fully depleted circulating lymphocytes after 3 to 4 days of treatment in rats. Full lymphopenia corresponded to increased levels of S1P of 100-to 1000-fold in lymph nodes, 3-fold in blood (but with no change in plasma), and 9-fold in cardiac tissue. Repeated oral dosing of the S1PL inhibitor in telemeterized, conscious rats resulted in significant bradycardia within 48 hours of drug treatment, comparable in magnitude to the bradycardia induced by 3 mg/kg fingolimod. These results suggest that S1PL inhibition modulates cardiac function and does not provide immune suppression with an improved cardiovascular safety profile over fingolimod in rats.

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The Clinically-tested S1P Receptor Agonists, FTY720 and BAF312, Demonstrate Subtype-Specific Bradycardia (S1P1) and Hypertension (S1P3) in Rat

Cited by 77 publications

References 40 publications

The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

An update on the biology of sphingosine 1-phosphate receptors

Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats

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