Experimental Osteoarthritis in Rats Is Attenuated by ABC294640, a Selective Inhibitor of Sphingosine Kinase-2

Fitzpatrick, Leo R.; Green, Cecelia; Maines, Lynn W.; Smith, Charles D.

doi:10.1159/000323911

Cited by 33 publications

(27 citation statements)

References 41 publications

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“…In the MIA-induced knee OA model, ABC294640 57 , a selective inhibitor of sphingosine kinase-2; AS1892802 58, 59 , which rarely penetrates the central nervous tissue and is a selective Rho kinase inhibitor; and MEN16132 60 , a kinin B(2) receptor antagonist, significantly improved weight bearing of the injected limb and alleviated cartilage degradation. Systemic co-administration of the selective positive allosteric modulator NS-9283 enhanced the analgesic potency of the nicotinic acetylcholine receptor (nAChR) α4β2 agonist ABT-594 5-fold 61 .…”

Section: Peripheral Mechanismsmentioning

confidence: 99%

Osteoarthritis pain mechanisms: basic studies in animal models

Zhang

Ren

Dubner

2013

Osteoarthritis and Cartilage

137

112

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Osteoarthritis (OA) is a complex and painful disease of the whole joint. At present there are no satisfying agents for treating OA. The current standard of care mainly involves managing and alleviating its symptoms. Mechanisms of OA pain have been studied in rodent knee OA models produced by intra-knee injection of the chondrocyte glycolytic inhibitor mono-iodoacetate, surgery, or spontaneous development in some species. These models are clinically relevant in terms of histological damage and functional changes, and are used to study mechanisms underlying mechanical, thermal, ambulatory, body weight supporting-evoked, and ongoing OA pain. Recent peripheral, spinal, and supraspinal biochemical and electrophysiological studies in these models suggest that peripheral pro-inflammatory mediators and neuropeptides sensitize knee nociceptors. Spinal cytokines and neuropeptides promote OA-associated pain, and peripheral and spinal cannabinoids inhibit OA pain respectively through cannabinoid-1 (CB1) and CB1/CB2 receptors. TRPV1 and metalloproteinases contribute and supraspinal descending facilitation of 5-HT/5-HT 3 receptors may also contribute to OA pain. Conditioned place preference tests demonstrate that OA pain induces aversive behaviors suggesting brain involvement in OA pain. During OA, brain functional connectivity is enhanced, but at present it is unclear how this change is related to OA pain.

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Section: Peripheral Mechanismsmentioning

confidence: 99%

Osteoarthritis pain mechanisms: basic studies in animal models

Zhang

Ren

Dubner

2013

Osteoarthritis and Cartilage

137

112

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“…The TUNEL method was used to determine leukocyte apoptosis in the colonic lamina propria and submucosa. Generally, we used the method as described previously (Fitzpatrick et al, 2011a). This method has been used previously in conjunction with the TNBS colitis model (Wittig et al, 2000).…”

Section: Vidofludimus Improves Colitis In Rats Bymentioning

confidence: 99%

Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Fitzpatrick

Small

Doblhofer

et al. 2012

J Pharmacol Exp Ther

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Vidofludimus (Vido) is a novel oral immunomodulatory drug that inhibits dihydro-orotate dehydrogenase and lymphocyte proliferation in vitro. Vido inhibits interleukin (IL)-17 secretion in vitro independently of effects on lymphocyte proliferation. Our primary goal was to evaluate the in vivo effects of Vido on IL-17 secretion and the parameters of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. To further delineate the mechanism of action for Vido, rats were dosed concomitantly with uridine (Uri). Young Wistar rats received a 150-l enema of either phosphate-buffered saline (PBS) or TNBS on study day 1. The ex vivo effects of Vido on 24-h colonic IL-17 secretion were determined by using colonic strips from PBS-or TNBStreated rats. Some rats were dosed with vehicle, Vido, or Vido ϩ Uri for 6 days. On day 6, the parameters of colitis were determined from colonic tissue. These parameters included macroscopic, histological, and transcription factor measurements, IL-17 production, and numbers of CD3 ϩ T cells. Ex vivo Vido completely blocked IL-23 ϩ IL-1␤-stimulated secretion of IL-17 by colonic strips. In vivo Vido treatment alone most effectively reduced macroscopic and histological pathology and the numbers of CD3 ϩ T cells. In contrast, similarly reduced nuclear signal transducer and activator of transcription 3 (STAT3) binding and IL-17 levels were observed from animals treated with Vido alone and Vido ϩ Uri. Vido improves TNBS-induced colonic inflammation by a unique dual mode of action: 1) inhibiting expansion of colonic T lymphocytes, and 2) suppressing colonic IL-17 production, which is independent from the control of T-lymphocyte proliferation, by inhibition of STAT3 and nuclear factor-B activation.

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“…One compound, ABC294640, has a K I of 8 μM at SphK2 [16]. This adamantyl compound has been reported to be efficacious in several disease models including hepatic ischemia-reperfusion injury [17], osteoarthritis [18], Crohn’s disease [19], ulcerative colitis [20] and colon cancer [21] among others. However, ABC294640 was recently documented to bind to the estrogen receptor where it has tamoxifen-like properties [22].…”

mentioning

confidence: 99%

Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate

Kharel

Raje

Gao

et al. 2012

Biochemical Journal

109

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Sphingosine 1-phosphate (S1P) is a pleiotropic lipid mediator involved in numerous cellular and physiological functions. Notable among these are cell survival and migration as well as lymphocyte trafficking. S1P, which exerts its effects via five G protein coupled receptors (S1P1-5), is formed by the action of two sphingosine kinases (SphKs). While SphK1 is the more intensively studied isotype, SphK2 is unique in it nuclear localization and has been reported to oppose some of the actions ascribed to SphK1. While several scaffolds of SphK1 inhibitors have been described, there is a scarcity of selective SphK2 inhibitors that are necessary to evaluate the downstream effects of inhibition of this isotype. Herein we report a cationic amphiphilic small molecule that is a selective SphK2 inhibitor. In the course of characterizing this compound in wild type and SphK null mice we discovered that administration of the inhibitor to wild type mice resulted in a rapid increase in blood S1P, which is in contrast to our SphK1 inhibitor that drives circulating S1P levels down. Using a cohort of F2 hybrid mice, we confirmed, compared to wild type mice, that circulating S1P levels were higher in SphK2 null mice and lower in SphK1 null mice. Thus both SphK1 and SphK2 inhibitors recapitulate the blood S1P levels observed in the corresponding null mice. Moreover, circulating S1P levels mirror SphK2 inhibitor levels providing a convenient biomarker of target engagement.

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Experimental Osteoarthritis in Rats Is Attenuated by ABC294640, a Selective Inhibitor of Sphingosine Kinase-2

Cited by 33 publications

References 41 publications

Osteoarthritis pain mechanisms: basic studies in animal models

Osteoarthritis pain mechanisms: basic studies in animal models

Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action

Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate

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