Cyclosporin A Suppresses the Induction of Nitric Oxide Synthesis in Interferon‐γ‐Treated L929 Fibroblasts

Trajković,; Badovinac, Vladimir P.; Janković,; Samardžić, Tatjana; D, Maksimović; Popadić, Dušan

doi:10.1046/j.1365-3083.1999.00468.x

Cited by 14 publications

(9 citation statements)

References 29 publications

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“…The previously reported mechanism of CSA action on T cells involves the inhibition of phosphatase calcineurin (22). However, there is ample evidence suggesting that CSA action is independent of calcineurin in non‐T cells (30, 31). To clarify whether the calcineurin pathway plays a role in CSA‐induced VEGF suppression in FLS, FK‐506, a well‐known calcineurin inhibitor, was tested for its effects on VEGF production.…”

Section: Resultsmentioning

confidence: 99%

Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts

Cho¹,

Cho²,

Min³

et al. 2002

Arthritis & Rheumatism

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Objective. To determine the antiangiogenic effect of cyclosporin A (CSA) in rheumatoid arthritis (RA).Methods. We investigated the effect of CSA on the production of vascular endothelial growth factor (VEGF) by rheumatoid synovial fibroblasts. Fibroblastlike synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and cultured in the presence of CSA. The production of VEGF by FLS was measured in culture supernatants by enzyme-linked immunosorbent assay. The VEGF messenger RNA (mRNA) expression and activator protein 1 (AP-1) binding activity for VEGF transcription were determined by polymerase chain reaction and electrophoretic mobility shift assay, respectively.Results. CSA dose-dependently inhibited both constitutive and transforming growth factor ␤-induced VEGF production at the protein and mRNA levels. The suppressive action of CSA on VEGF synthesis was calcineurin dependent, as evidenced by a comparable inhibition by FK-506. Agonists of cAMP, 3-isobutyl-1-methylxanthine and N-2-O-dibutyryl-cAMP, mimicked the effect of CSA on VEGF production, while a cAMP antagonist, 2,3-dideoxyadenosine, abrogated the effect of CSA. A gel mobility shift assay showed that the inhibitory effect of CSA was associated with decreased AP-1 binding activity to the VEGF promoter, in a cAMP-dependent manner.Conclusion. CSA may exert an antiangiogenic effect by inhibiting AP-1-mediated VEGF expression in rheumatoid synovial fibroblasts.

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Section: Resultsmentioning

confidence: 99%

Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts

Cho¹,

Cho²,

Min³

et al. 2002

Arthritis & Rheumatism

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“…This hypothesis is in agreement with the study of Wimalawansa (2000), which shows that nitric oxide donor, nitroglycerin, reverses the ovariectomy-induced osteopenia. On the other hand it has been suggested that cyclosporin-A suppresses nitric oxide synthesis in L929 cells independent of cacineurin inhibition and interfering with intracellular pathways involved in the nitric oxide synthase induction, rather than inhibiting its enzymatic activity (Trajkovic et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Role of Soy Diet and L‐Arginine in Cyclosporin‐A‐Induced Osteopenia in Rats

Clementi¹,

Fiore

Mangano³

et al. 2001

Pharmacology & Toxicology

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Our previous studies show that chronic administration of L-arginine decreases cyclosporin-A-induced bone loss. The present study was designed to investigate whether a soy diet could prevent cyclosporin A-induced osteopenia and eventually improve the protective effect of L-arginine. Rats on soy diet were treated with cyclosporin-A, L-arginine, cyclosporin-AπL-arginine or saline. Control groups received a normal diet and the same pharmacological treatment. Our results show that a soy diet prevents osteopenia only in the spinal cord (π30%) and confirm the protective effect of Larginine in cyclosporin-A-induced osteopenia in whole body, pelvis and spine of rats on a normal diet (π31%, π55%, π55%, respectively). Moreover these data show that the osteoprotective effect of L-arginine in the whole body, pelvis and spine improves in the case of soy diet (π60%, π72%, π89%, respectively). The results suggest that a soy diet exerts a positive effect in cyclosporin-A-induced osteopenia only in sites with high turn-over and improves the osteoprotective effect of L-arginine.

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“…prevents the activation of other enzymes like the cyclooxigenase that is also related to the inflammatory pathway [70]. Other studies have demonstrated that CsA is also able to inhibit the expression and activation of iNOS, an enzyme related to NO overproduction and inflammation [70,71]. mechanisms, and the neuroprotective action of this drug has already been demonstrated in various models of CNS damage, including cerebral ischemia traumatic brain injury and acute SC injury [17,18,30,31,81,82].…”

Section: Calcineurin-independent Mechanismsmentioning

confidence: 99%

“…Although the beneficial action of CsA upon LP could be in part explained by the inhibitory effect of this drug on immune response, it should be stressed that CsA may also exert this positive effect by inhibiting either the expression or the activity of NOS [70,71]. Previous studies have already demonstrated a significant increase in both the expression [102,103] and activity [104] of NOS isoforms, and NO overproduction plays a key role on tissue destruction.…”

Section: Csa Inhibits the Expression And The Activity Of Nitric Oxidementioning

confidence: 99%

Protective Effect of Cyclosporin-A in Spinal Cord Injury: An Overview

Ibarra¹,

Dı́az-Ruiz²

2006

CMC

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Cyclosporin-A (CsA) is a potent and selective immunosupressive agent that, due to its mechanism of action, may be used to inhibit both the inflammatory reaction and the synthesis of nitric oxide (NO), a well-known neurotoxic agent. By these means CsA may diminish overproduction of free radicals and secondarily, lipid peroxidation (LP), both observed after acute spinal cord (SC) injury. Studies performed on reliable experimental models, using a well-standardized CsA dosing scheme, showed that a low dose of this drug inhibits the expression and activity of constitutive and inducible nitric oxide synthases (NOS), two enzymes strongly involved in the production of NO after SCI. Likewise, this compound inhibits LP. This inhibition is equivalent to the one induced by methylprednisolone (MP) at a high dose, but without the deleterious effects of the latter upon the survival of the animals. Moreover, inhibition of LP by CsA significantly correlates with a decrease in the demyelination process at the epicenter of the lesion, a significant survival of neurons in the red nucleus and enhanced motor recovery in animals submitted to a severe SC contusion. CsA acts as a neuroprotector agent after SC injury; hence, this drug may be useful in the treatment of acute SCI. CsA deserves further study in experimental animal models and in humans.

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Cyclosporin A Suppresses the Induction of Nitric Oxide Synthesis in Interferon‐γ‐Treated L929 Fibroblasts

Cited by 14 publications

References 29 publications

Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts

Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts

Role of Soy Diet and L‐Arginine in Cyclosporin‐A‐Induced Osteopenia in Rats

Protective Effect of Cyclosporin-A in Spinal Cord Injury: An Overview

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