Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice

Imeri, Faik; Fallegger, Daniel; Živković, Aleksandra; Schwalm, Stephanie; Enzmann, Gaby; Blankenbach, Kira; Heringdorf, Dagmar Meyer zu; Homann, Thomas; Kleuser, Burkhard; Pfeilschifter, Josef; Engelhardt, Britta; Stark, Holger; Huwiler, Andrea

doi:10.1016/j.neuropharm.2014.05.012

Cited by 27 publications

(36 citation statements)

References 55 publications

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“…Previous studies also showed that FTY720 has positive efficacy on SCI in animal models after systemic administration. However, the side effects of FTY720 are dose-dependent [32,33]. The total dosage that we used (0.5 mg) is far less than that of the previous studies adopted (daily oral dosage of 1e3 mg/kg utilized for SCI at least 4 weeks).…”

Section: Discussionmentioning

confidence: 98%

Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis

Wang

Lü

et al. 2015

Biomaterials

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Section: Discussionmentioning

confidence: 98%

Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis

Wang

Lü

et al. 2015

Biomaterials

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“…They also have been reported in various central nervous system (CNS) injury including traumatic SCI, in which MMPs activation is responsible for the breakdown of BSCB 10. During the acute SCI, infiltrating neutrophils and other types of cell secrete MMPs, which further compromise the integrity of BSCB and result in neuro‐inflammation and cell death 7, 11. Among MMPs, the MMP‐9 plays a critical role in BSCB disruption and inflammation after acute SCI, suppressing MMP‐9 activity inhibits BSCB permeability and improve functional recovery 10, 12, 13.…”

Section: Introductionmentioning

confidence: 96%

Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP‐9 expression but not direct TJ proteins expression regulation

Zhang

Tang

Zheng

et al. 2017

J Cellular Molecular Medi

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Blood‐spinal cord barrier (BSCB) disruption is a major process for the secondary injury of spinal cord injury (SCI) and is considered to be a therapeutic target for SCI. Previously, we demonstrated that metformin could improve functional recovery after SCI; however, the effect of metformin on BSCB is still unknown. In this study, we found that metformin could prevent the loss of tight junction (TJ) proteins at day 3 after SCI in vivo, but in vitro there was no significant difference of these proteins between control and metformin treatment in endothelial cells. This indicated that metformin‐induced BSCB protection might not be mediated by up‐regulating TJ proteins directly, but by inhibiting TJ proteins degradation. Thus, we investigated the role of metformin on MMP‐9 and neutrophils infiltration. Neutrophils infiltration is the major source of the enhanced MMP‐9 in SCI. Our results showed that metformin decreased MMP‐9 production and blocked neutrophils infiltration at day 1 after injury, which might be related to ICAM‐1 down‐regulation. Also, our in vitro study showed that metformin inhibited TNF‐α‐induced MMP‐9 up‐regulation in neutrophils, which might be mediated via an AMPK‐dependent pathway. Together, it illustrated that metformin prevented the breakdown of BSCB by inhibiting neutrophils infiltration and MMP‐9 production, but not by up‐regulating TJ proteins expression. Our study may help to better understand the working mechanism of metformin on SCI.

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“…Multiple groups have synthesized various derivatives of FTY720 primarily for characterizing them in terms of S1P receptor affinity and the ability to induce lymphopenia (Clemens et al, 2005; Forrest et al, 2004; Foss et al, 2005; Hale et al, 2004b; Hanessian et al, 2007; Imeri et al, 2014; Mandala et al, 2002; Zhu et al, 2007), to evaluate the pro-apoptotic effects of sphingosine and FTY720 (Don et al, 2007), or as possible antiangiogenic agents (Nakayama et al, 2008). However, our group has focused on their value as potential barrier regulatory agents (Camp et al, 2009; Wang et al, 2014), in the hopes of designing a more optimal therapeutic agent.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphonate and enephosphonate analogs of FTY720, such as Tys, demonstrate similar but not identical barrier enhancing properties to S1P and FTY720 (Camp et al, 2009). Oxazolo-oxazole derivatives of FTY720 reduce EC permeability induced by LPS or TNFα in vitro (Imeri et al, 2014). Moreover, S1P, FTY720, and Tys attenuate lipopolysaccharide (LPS)-induced lung injury in vivo (Camp et al, 2009; McVerry et al, 2004; Peng et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Pulmonary Endothelial Cell Barrier Enhancement by Novel FTY720 Analogs: Methoxy-FTY720, Fluoro-FTY720, and β-Glucuronide-FTY720

Camp

Chiang

Sun

et al. 2015

Chemistry and Physics of Lipids

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Effective therapeutic agents are lacking for the prevention and reversal of vascular leak, a frequent pathophysiologic result of inflammatory processes such as acute respiratory distress syndrome (ARDS) and sepsis. We previously demonstrated the potent barrier-enhancing effects of related compounds sphingosine 1-phosphate (S1P), the pharmaceutical agent FTY720, and its analog (S)-FTY720 phosphonate (Tys) in models of inflammatory lung injury. In this study, we characterize additional novel FTY720 analogs for their potential to reduce vascular leak as well as utilize them as tools to better understand the mechanisms by which this class of agents modulates permeability. Transendothelial resistance (TER) and labeled dextran studies demonstrate that (R)-Methoxy-FTY720 ((R)-OMe-FTY), (R)/(S)-Fluoro-FTY720 (FTY-F), and β-Glucuronide-FTY720 (FTY-G) compounds display in vitro barrier-enhancing properties comparable or superior to FTY720 and S1P. In contrast, the (S)-Methoxy-FTY720 ((S)-OMe-FTY) analog disrupts lung endothelial cell (EC) barrier integrity in TER studies in association with actin stress fiber formation and robust intracellular calcium release, but independent of myosin light chain or ERK phosphorylation. Additional mechanistic studies with (R)-OMe-FTY, FTY-F, and FTY-G suggest that lung EC barrier enhancement is mediated through lipid raft signaling, Gi-linked receptor coupling to downstream tyrosine phosphorylation events, and S1PR1-dependent receptor ligation. These results provide important mechanistic insights into modulation of pulmonary vascular barrier function by FTY720-related compounds and highlight common signaling events that may assist the development of novel therapeutic tools in the prevention or reversal of the pulmonary vascular leak that characterizes ARDS.

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Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice

Cited by 27 publications

References 55 publications

Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis

Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis

Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP‐9 expression but not direct TJ proteins expression regulation

Pulmonary Endothelial Cell Barrier Enhancement by Novel FTY720 Analogs: Methoxy-FTY720, Fluoro-FTY720, and β-Glucuronide-FTY720

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