TY  - JOUR
AU  - Marković, Miloš
AU  - Miljković, Đorđe
AU  - Trajković, Vladimir
PY  - 2003
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6002
AB  - Among the numerous genes controlled by cyclic adenosine monophosphate (cAMP)/protein kinase A signalling machinery is the gene encoding the inducible nitric oxide synthase (iNOS), an enzyme catalyzing the synthesis of a highly reactive free radical nitric oxide (NO). While being a major microbicidal and tumoricidal molecule, iNOS-derived NO has also been implicated in tissue destruction, as well as in regulation of inflammatory/immune cell function in various disorders associated with excessive inflammation. A feasible way for cAMP-dependent therapeutic control of inflammation, including iNOS-mediated NO synthesis, could involve the administration of drugs that block the enzymatic activity of cAMP-degrading phosphodiesterases (PDE). Indeed, cAMP-elevating PDE inhibitors can influence iNOS activation in different cell types in vitro, and their potent anti-inflammatory effects in experimental disease models and clinical studies were frequently accompanied with profound modulation of NO production. A set of conflicting data has been generated over the years, ranging from strong suppression to marked enhancement of NO release by cAMP-increasing PDE inhibitors, depending on cell-type, iNOS stimuli, and/or the agents used. The present review summarizes the data on iNOS modulation by cAMP-elevating PDE inhibitors and possible mechanisms behind it, speculating on its contribution to the therapeutic effects of these drugs.
PB  - Bentham Science Publishers Ltd.
T2  - Current Drug Targets - Inflammation and Allergy
T1  - Regulation of inducible nitric oxide synthase by cAMP-elevating phospho-diesterase inhibitors
IS  - 1
VL  - 2
DO  - 10.2174/1568010033344471
SP  - 63
EP  - 67
ER  - 

@article{
author = "Marković, Miloš and Miljković, Đorđe and Trajković, Vladimir",
year = "2003",
abstract = "Among the numerous genes controlled by cyclic adenosine monophosphate (cAMP)/protein kinase A signalling machinery is the gene encoding the inducible nitric oxide synthase (iNOS), an enzyme catalyzing the synthesis of a highly reactive free radical nitric oxide (NO). While being a major microbicidal and tumoricidal molecule, iNOS-derived NO has also been implicated in tissue destruction, as well as in regulation of inflammatory/immune cell function in various disorders associated with excessive inflammation. A feasible way for cAMP-dependent therapeutic control of inflammation, including iNOS-mediated NO synthesis, could involve the administration of drugs that block the enzymatic activity of cAMP-degrading phosphodiesterases (PDE). Indeed, cAMP-elevating PDE inhibitors can influence iNOS activation in different cell types in vitro, and their potent anti-inflammatory effects in experimental disease models and clinical studies were frequently accompanied with profound modulation of NO production. A set of conflicting data has been generated over the years, ranging from strong suppression to marked enhancement of NO release by cAMP-increasing PDE inhibitors, depending on cell-type, iNOS stimuli, and/or the agents used. The present review summarizes the data on iNOS modulation by cAMP-elevating PDE inhibitors and possible mechanisms behind it, speculating on its contribution to the therapeutic effects of these drugs.",
publisher = "Bentham Science Publishers Ltd.",
journal = "Current Drug Targets - Inflammation and Allergy",
title = "Regulation of inducible nitric oxide synthase by cAMP-elevating phospho-diesterase inhibitors",
number = "1",
volume = "2",
doi = "10.2174/1568010033344471",
pages = "63-67"
}

Marković, M., Miljković, Đ.,& Trajković, V.. (2003). Regulation of inducible nitric oxide synthase by cAMP-elevating phospho-diesterase inhibitors. in Current Drug Targets - Inflammation and Allergy
Bentham Science Publishers Ltd.., 2(1), 63-67.
https://doi.org/10.2174/1568010033344471

Marković M, Miljković Đ, Trajković V. Regulation of inducible nitric oxide synthase by cAMP-elevating phospho-diesterase inhibitors. in Current Drug Targets - Inflammation and Allergy. 2003;2(1):63-67.
doi:10.2174/1568010033344471 .

Marković, Miloš, Miljković, Đorđe, Trajković, Vladimir, "Regulation of inducible nitric oxide synthase by cAMP-elevating phospho-diesterase inhibitors" in Current Drug Targets - Inflammation and Allergy, 2, no. 1 (2003):63-67,
https://doi.org/10.2174/1568010033344471 . .

TY  - JOUR
AU  - Miljković, Đorđe
AU  - Samardzić, Tatjana
AU  - Drakulić, Danijela
AU  - Stošić-Grujičić, Stanislava
AU  - Trajković, Vladimir
PY  - 2002
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6000
AB  - Mycophenolic acid (MPA) and A77 1726, the active components of the immunosuppressants mycophenolate mophetil and leflunomide, respectively, in a dose-dependent manner inhibited interferon (IFN)-gamma/LPS-induced interleukin (IL)-6 release in confluent cultures of mouse L929 fibrosarcoma cells. In addition, both drugs markedly reduced the production of the free radical gas nitric oxide (NO), without affecting the viability of L929 cells. The inhibitors of NO synthase, aminoguanidine and L-NMMA, but not L-NMMA inactive counterpart D-NMMA, mimicked the effects of A77 1726 and MPA on IL-6 generation in L929 fibroblasts. Furthermore, NO-releasing substance SNP completely reverted IL-6 accumulation in L929 cultures treated with A77 1726, while only partial recovery of IL-6 production was observed in the presence of MPA. MPA, but not A77 1726, significantly suppressed NO-independent IL-6 release triggered by cAMP-elevating agent rolipram. Thus, while A77 1726 effect on IL-6 production was mediated through concomitant reduction of NO synthesis, MPA action was mainly independent of the interference with NO generation. Finally, both agents inhibited IFN-gamma/LPS-triggered IL-6 production in mouse primary fibroblasts, but not in mouse peritoneal macrophages, indicating cell-specificity of this novel anti-inflammatory action of A77 1726 and MPA.
PB  - Elsevier
T2  - Cytokine
T1  - Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms
IS  - 4
VL  - 19
DO  - 10.1006/cyto.2002.0885
SP  - 181
EP  - 186
ER  - 

@article{
author = "Miljković, Đorđe and Samardzić, Tatjana and Drakulić, Danijela and Stošić-Grujičić, Stanislava and Trajković, Vladimir",
year = "2002",
abstract = "Mycophenolic acid (MPA) and A77 1726, the active components of the immunosuppressants mycophenolate mophetil and leflunomide, respectively, in a dose-dependent manner inhibited interferon (IFN)-gamma/LPS-induced interleukin (IL)-6 release in confluent cultures of mouse L929 fibrosarcoma cells. In addition, both drugs markedly reduced the production of the free radical gas nitric oxide (NO), without affecting the viability of L929 cells. The inhibitors of NO synthase, aminoguanidine and L-NMMA, but not L-NMMA inactive counterpart D-NMMA, mimicked the effects of A77 1726 and MPA on IL-6 generation in L929 fibroblasts. Furthermore, NO-releasing substance SNP completely reverted IL-6 accumulation in L929 cultures treated with A77 1726, while only partial recovery of IL-6 production was observed in the presence of MPA. MPA, but not A77 1726, significantly suppressed NO-independent IL-6 release triggered by cAMP-elevating agent rolipram. Thus, while A77 1726 effect on IL-6 production was mediated through concomitant reduction of NO synthesis, MPA action was mainly independent of the interference with NO generation. Finally, both agents inhibited IFN-gamma/LPS-triggered IL-6 production in mouse primary fibroblasts, but not in mouse peritoneal macrophages, indicating cell-specificity of this novel anti-inflammatory action of A77 1726 and MPA.",
publisher = "Elsevier",
journal = "Cytokine",
title = "Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms",
number = "4",
volume = "19",
doi = "10.1006/cyto.2002.0885",
pages = "181-186"
}

Miljković, Đ., Samardzić, T., Drakulić, D., Stošić-Grujičić, S.,& Trajković, V.. (2002). Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms. in Cytokine
Elsevier., 19(4), 181-186.
https://doi.org/10.1006/cyto.2002.0885

Miljković Đ, Samardzić T, Drakulić D, Stošić-Grujičić S, Trajković V. Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms. in Cytokine. 2002;19(4):181-186.
doi:10.1006/cyto.2002.0885 .

Miljković, Đorđe, Samardzić, Tatjana, Drakulić, Danijela, Stošić-Grujičić, Stanislava, Trajković, Vladimir, "Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms" in Cytokine, 19, no. 4 (2002):181-186,
https://doi.org/10.1006/cyto.2002.0885 . .

TY  - JOUR
AU  - Trajković, Vladimir
AU  - Stošić-Grujičić, Stanislava
AU  - Samardzić, Tatjana
AU  - Marković, Miloš
AU  - Miljković, Đorđe
AU  - Ramić, Zorica
AU  - Mostarica Stojković, Marija
PY  - 2001
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5997
AB  - The effect of interleukin-17 (IL-17) on production of nitric oxide (NO) in rodent astrocytes was investigated. While IL-17 by itself did not induce NO production, it caused a dose-dependent enhancement of IFN-gamma-triggered NO synthesis in both mouse and rat primary astrocytes. In contrast, IL-17 was unable to stimulate NO synthesis in either murine or rat macrophages. IFN-gamma-triggered expression of mRNA for iNOS, but not for its transcription factor interferon regulatory factor-1 (IRF-1), was markedly elevated in IL-17-treated astrocytes. The induction of iNOS mRNA by IL-17 in IFN-gamma-pretreated astrocytes was abolished by antagonists of nuclear factor-kappaB (NF-kappaB) activation--a proteasome inhibitor MG132 and an antioxidant agent PDTC, as well as with specific p38 MAP kinase inhibitor SB203580. While IL-17 stimulated both IL-1beta and IL-6 production in astrocytes, only IL-1 was partly responsible for IL-17-induced NO release. Finally, IL-17 synergized with exogenous IL-1beta and TNF-alpha for astrocyte NO production. Having in mind a well-known neurotoxic action of NO, these results suggest a possible role for IL-17 in the inflammatory diseases of the CNS.
PB  - Amsterdam: Elsevier
T2  - Journal of Neuroimmunology
T1  - Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes
IS  - 2
VL  - 119
DO  - 10.1016/s0165-5728(01)00391-5
SP  - 183
EP  - 191
ER  - 

@article{
author = "Trajković, Vladimir and Stošić-Grujičić, Stanislava and Samardzić, Tatjana and Marković, Miloš and Miljković, Đorđe and Ramić, Zorica and Mostarica Stojković, Marija",
year = "2001",
abstract = "The effect of interleukin-17 (IL-17) on production of nitric oxide (NO) in rodent astrocytes was investigated. While IL-17 by itself did not induce NO production, it caused a dose-dependent enhancement of IFN-gamma-triggered NO synthesis in both mouse and rat primary astrocytes. In contrast, IL-17 was unable to stimulate NO synthesis in either murine or rat macrophages. IFN-gamma-triggered expression of mRNA for iNOS, but not for its transcription factor interferon regulatory factor-1 (IRF-1), was markedly elevated in IL-17-treated astrocytes. The induction of iNOS mRNA by IL-17 in IFN-gamma-pretreated astrocytes was abolished by antagonists of nuclear factor-kappaB (NF-kappaB) activation--a proteasome inhibitor MG132 and an antioxidant agent PDTC, as well as with specific p38 MAP kinase inhibitor SB203580. While IL-17 stimulated both IL-1beta and IL-6 production in astrocytes, only IL-1 was partly responsible for IL-17-induced NO release. Finally, IL-17 synergized with exogenous IL-1beta and TNF-alpha for astrocyte NO production. Having in mind a well-known neurotoxic action of NO, these results suggest a possible role for IL-17 in the inflammatory diseases of the CNS.",
publisher = "Amsterdam: Elsevier",
journal = "Journal of Neuroimmunology",
title = "Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes",
number = "2",
volume = "119",
doi = "10.1016/s0165-5728(01)00391-5",
pages = "183-191"
}

Trajković, V., Stošić-Grujičić, S., Samardzić, T., Marković, M., Miljković, Đ., Ramić, Z.,& Mostarica Stojković, M.. (2001). Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes. in Journal of Neuroimmunology
Amsterdam: Elsevier., 119(2), 183-191.
https://doi.org/10.1016/s0165-5728(01)00391-5

Trajković V, Stošić-Grujičić S, Samardzić T, Marković M, Miljković Đ, Ramić Z, Mostarica Stojković M. Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes. in Journal of Neuroimmunology. 2001;119(2):183-191.
doi:10.1016/s0165-5728(01)00391-5 .

Trajković, Vladimir, Stošić-Grujičić, Stanislava, Samardzić, Tatjana, Marković, Miloš, Miljković, Đorđe, Ramić, Zorica, Mostarica Stojković, Marija, "Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes" in Journal of Neuroimmunology, 119, no. 2 (2001):183-191,
https://doi.org/10.1016/s0165-5728(01)00391-5 . .

TY  - JOUR
AU  - Trajković, Vladimir
AU  - Marković, Miloš
AU  - Samardzić, Tatjana
AU  - Miljković, Đorđe
AU  - Popadić, Dušan
AU  - Mostarica Stojković, Marija
PY  - 2001
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5996
AB  - Because the neurotoxic effects of the antifungal drug amphotericin B
(AMB) closely resemble those ascribed to the highly reactive gaseous free radical nitric
oxide (NO), we investigated the effect of AMB on NO production in rodent astrocytes.
AMB caused a dose-dependent increase of NO generation in interferon-g (IFN-g)-stimulated rat and mouse astrocytes, as well as in IFN-g 1 tumor necrosis factor-a (TNFa)-activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN-g-triggered expression of mRNA for iNOS, but not for its
transcription factor IRF-1. The activation of transcription factor NF-kB was apparently
required for AMB-induced iNOS mRNA expression, as the latter was abolished by
NF-kB inhibitors: pyrrolidine dithiocarbamate and MG132. AMB-mediated enhancement of astrocyte NO production was partly dependent on endogenous IL-1, as shown by
partial inhibition of AMB effect with IL-1 receptor antagonist. IFN-g 1 AMB treatment
led to reduction of astrocyte mitochondrial respiration (measured by MTT assay) that
has been completely reverted by selective iNOS inhibitor aminoguanidine. AMB toxicity
toward IFN-g-stimulated astrocytes was dependent on both AMB and NO action, since
AMB and NO-releasing substance SNP synergized in inducing astrocyte mitochondrial
dysfunction. These results suggest that the enhancement of cytokine-induced iNOS
activation in astrocytes and the subsequent release of high amounts of NO might be at
least partly responsible for AMB neurotoxicity.
PB  - Hoboken: Wiley
T2  - Glia
T1  - Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes
IS  - 3
VL  - 35
DO  - 10.1002/glia.1083
SP  - 180
EP  - 188
ER  - 

@article{
author = "Trajković, Vladimir and Marković, Miloš and Samardzić, Tatjana and Miljković, Đorđe and Popadić, Dušan and Mostarica Stojković, Marija",
year = "2001",
abstract = "Because the neurotoxic effects of the antifungal drug amphotericin B
(AMB) closely resemble those ascribed to the highly reactive gaseous free radical nitric
oxide (NO), we investigated the effect of AMB on NO production in rodent astrocytes.
AMB caused a dose-dependent increase of NO generation in interferon-g (IFN-g)-stimulated rat and mouse astrocytes, as well as in IFN-g 1 tumor necrosis factor-a (TNFa)-activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN-g-triggered expression of mRNA for iNOS, but not for its
transcription factor IRF-1. The activation of transcription factor NF-kB was apparently
required for AMB-induced iNOS mRNA expression, as the latter was abolished by
NF-kB inhibitors: pyrrolidine dithiocarbamate and MG132. AMB-mediated enhancement of astrocyte NO production was partly dependent on endogenous IL-1, as shown by
partial inhibition of AMB effect with IL-1 receptor antagonist. IFN-g 1 AMB treatment
led to reduction of astrocyte mitochondrial respiration (measured by MTT assay) that
has been completely reverted by selective iNOS inhibitor aminoguanidine. AMB toxicity
toward IFN-g-stimulated astrocytes was dependent on both AMB and NO action, since
AMB and NO-releasing substance SNP synergized in inducing astrocyte mitochondrial
dysfunction. These results suggest that the enhancement of cytokine-induced iNOS
activation in astrocytes and the subsequent release of high amounts of NO might be at
least partly responsible for AMB neurotoxicity.",
publisher = "Hoboken: Wiley",
journal = "Glia",
title = "Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes",
number = "3",
volume = "35",
doi = "10.1002/glia.1083",
pages = "180-188"
}

Trajković, V., Marković, M., Samardzić, T., Miljković, Đ., Popadić, D.,& Mostarica Stojković, M.. (2001). Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes. in Glia
Hoboken: Wiley., 35(3), 180-188.
https://doi.org/10.1002/glia.1083

Trajković V, Marković M, Samardzić T, Miljković Đ, Popadić D, Mostarica Stojković M. Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes. in Glia. 2001;35(3):180-188.
doi:10.1002/glia.1083 .

Trajković, Vladimir, Marković, Miloš, Samardzić, Tatjana, Miljković, Đorđe, Popadić, Dušan, Mostarica Stojković, Marija, "Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes" in Glia, 35, no. 3 (2001):180-188,
https://doi.org/10.1002/glia.1083 . .

TY  - JOUR
AU  - Drulović, Jelena
AU  - Dujmović, Irena
AU  - Stojsavljević, Nebojša
AU  - Mesaroš, Šarlota
AU  - Anđelković, Slobodanka
AU  - Miljković, Đorđe
AU  - Perić, Vesna
AU  - Dragutinović, Gradimir
AU  - Marinković, Jelena
AU  - Lević, Zvonimir
AU  - Mostarica Stojković, Marija
PY  - 2001
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5995
AB  - The levels of uric acid (UA), a natural peroxynitrite scavenger, were measured in sera from 240 patients with multiple sclerosis (MS) and 104 sex- and age-matched control patients with other neurological diseases (OND). The mean serum UA concentration was lower in the MS than in the OND group, but the difference did not reach the level of statistical significance (P = 0.068). However, the mean serum UA level from patients with active MS (202.6 + 67.1 mumol/l) was significantly lower than that in inactive MS patients (226.5 + 78.6 mumol/l; P = 0.046) and OND controls (P = 0.007). We found a significant inverse correlation of serum UA concentration with female gender (P = 0.0001), disease activity (P = 0.012) and duration (P = 0.017), and a trend towards an inverse correlation with disability as assessed by EDSS score, which did not reach statistical significance (P = 0.067). Finally, multivariate linear regression analyses showed that UA concentration was independently correlated with gender (P = 0.0001), disease activity (P = 0.014) and duration of the disease (P = 0.043) in MS patients. These findings suggest that serum UA might serve as a possible marker of disease activity in MS. They also provide support to the potential beneficial therapeutic effect of radical-scavenging substances in MS.
PB  - Heidelberg: Springer
T2  - Journal of Neurology
T1  - Uric acid levels in sera from patients with multiple sclerosis
IS  - 2
VL  - 248
DO  - 10.1007/s004150170246
SP  - 121
EP  - 126
ER  - 

@article{
author = "Drulović, Jelena and Dujmović, Irena and Stojsavljević, Nebojša and Mesaroš, Šarlota and Anđelković, Slobodanka and Miljković, Đorđe and Perić, Vesna and Dragutinović, Gradimir and Marinković, Jelena and Lević, Zvonimir and Mostarica Stojković, Marija",
year = "2001",
abstract = "The levels of uric acid (UA), a natural peroxynitrite scavenger, were measured in sera from 240 patients with multiple sclerosis (MS) and 104 sex- and age-matched control patients with other neurological diseases (OND). The mean serum UA concentration was lower in the MS than in the OND group, but the difference did not reach the level of statistical significance (P = 0.068). However, the mean serum UA level from patients with active MS (202.6 + 67.1 mumol/l) was significantly lower than that in inactive MS patients (226.5 + 78.6 mumol/l; P = 0.046) and OND controls (P = 0.007). We found a significant inverse correlation of serum UA concentration with female gender (P = 0.0001), disease activity (P = 0.012) and duration (P = 0.017), and a trend towards an inverse correlation with disability as assessed by EDSS score, which did not reach statistical significance (P = 0.067). Finally, multivariate linear regression analyses showed that UA concentration was independently correlated with gender (P = 0.0001), disease activity (P = 0.014) and duration of the disease (P = 0.043) in MS patients. These findings suggest that serum UA might serve as a possible marker of disease activity in MS. They also provide support to the potential beneficial therapeutic effect of radical-scavenging substances in MS.",
publisher = "Heidelberg: Springer",
journal = "Journal of Neurology",
title = "Uric acid levels in sera from patients with multiple sclerosis",
number = "2",
volume = "248",
doi = "10.1007/s004150170246",
pages = "121-126"
}

Drulović, J., Dujmović, I., Stojsavljević, N., Mesaroš, Š., Anđelković, S., Miljković, Đ., Perić, V., Dragutinović, G., Marinković, J., Lević, Z.,& Mostarica Stojković, M.. (2001). Uric acid levels in sera from patients with multiple sclerosis. in Journal of Neurology
Heidelberg: Springer., 248(2), 121-126.
https://doi.org/10.1007/s004150170246

Drulović J, Dujmović I, Stojsavljević N, Mesaroš Š, Anđelković S, Miljković Đ, Perić V, Dragutinović G, Marinković J, Lević Z, Mostarica Stojković M. Uric acid levels in sera from patients with multiple sclerosis. in Journal of Neurology. 2001;248(2):121-126.
doi:10.1007/s004150170246 .

Drulović, Jelena, Dujmović, Irena, Stojsavljević, Nebojša, Mesaroš, Šarlota, Anđelković, Slobodanka, Miljković, Đorđe, Perić, Vesna, Dragutinović, Gradimir, Marinković, Jelena, Lević, Zvonimir, Mostarica Stojković, Marija, "Uric acid levels in sera from patients with multiple sclerosis" in Journal of Neurology, 248, no. 2 (2001):121-126,
https://doi.org/10.1007/s004150170246 . .

TY  - JOUR
AU  - Miljković, Đorđe
AU  - Samardžić, Tatjana
AU  - Mostarica Stojković, Marija
AU  - Stošić-Grujičić, Stanislava
AU  - Popadić, Dušan
AU  - Trajković, Vladimir
PY  - 2001
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5994
AB  - Highly reactive gaseous free radical nitric oxide (NO), generated by astrocytes and infiltrating macrophages is implicated in
inflammatory destruction of brain tissue, including that occurring in multiple sclerosis. Therefore, the influence of immunosuppressive
drug leflunomide on inducible nitric oxide synthase (iNOS)-dependent NO production in rat astrocytes and macrophages was investigated.
Under the same cultivating conditions, leflunomide’s active metabolite A77 1726 caused a dose-dependent decrease of NO production in
IFN-g1LPS-stimulated primary astrocytes, but not in macrophages. While A77 1726 did not alter iNOS enzymatic activity, it markedly
suppressed IFN-g1LPS-triggered expression of iNOS mRNA in astrocytes. In the presence of transcription inhibitor actinomycin D, A77
1726 failed to inhibit astrocyte NO production, suggesting transcriptional regulation of iNOS by leflunomide. This assumption was further
supported by the ability of A77 1726 to inhibit IFN-g1LPS-induced expression of mRNA for an important iNOS transcription factor
IRF-1. PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK/MEK), but not genistein, an unselective
protein tyrosine kinase inhibitor, completely mimicked cell type-specific inhibition of NO synthesis by A77 1726. Therefore, previously
described inhibition of MEK/MAP pathway by leflunomide could present a possible mechanism for A77 1726-mediated suppression of
iNOS activation in astrocytes. Accordingly to results obtained with primary astrocytes, both A77 1726 and PD98059 significantly reduced
IFN-g1LPS-induced NO synthesis in the cultures of rat astrocytoma cell line C6. The ability to suppress iNOS induction in astrocytes
supports potential use of leflunomide in the treatment of multiple sclerosis and other NO-dependent inflammatory brain disorders.
PB  - Elsevier Science B.V.
T2  - Brain Research
T1  - Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes
IS  - 1-2
VL  - 889
DO  - 10.1016/s0006-8993(00)03181-4
SP  - 331
EP  - 338
ER  - 

@article{
author = "Miljković, Đorđe and Samardžić, Tatjana and Mostarica Stojković, Marija and Stošić-Grujičić, Stanislava and Popadić, Dušan and Trajković, Vladimir",
year = "2001",
abstract = "Highly reactive gaseous free radical nitric oxide (NO), generated by astrocytes and infiltrating macrophages is implicated in
inflammatory destruction of brain tissue, including that occurring in multiple sclerosis. Therefore, the influence of immunosuppressive
drug leflunomide on inducible nitric oxide synthase (iNOS)-dependent NO production in rat astrocytes and macrophages was investigated.
Under the same cultivating conditions, leflunomide’s active metabolite A77 1726 caused a dose-dependent decrease of NO production in
IFN-g1LPS-stimulated primary astrocytes, but not in macrophages. While A77 1726 did not alter iNOS enzymatic activity, it markedly
suppressed IFN-g1LPS-triggered expression of iNOS mRNA in astrocytes. In the presence of transcription inhibitor actinomycin D, A77
1726 failed to inhibit astrocyte NO production, suggesting transcriptional regulation of iNOS by leflunomide. This assumption was further
supported by the ability of A77 1726 to inhibit IFN-g1LPS-induced expression of mRNA for an important iNOS transcription factor
IRF-1. PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK/MEK), but not genistein, an unselective
protein tyrosine kinase inhibitor, completely mimicked cell type-specific inhibition of NO synthesis by A77 1726. Therefore, previously
described inhibition of MEK/MAP pathway by leflunomide could present a possible mechanism for A77 1726-mediated suppression of
iNOS activation in astrocytes. Accordingly to results obtained with primary astrocytes, both A77 1726 and PD98059 significantly reduced
IFN-g1LPS-induced NO synthesis in the cultures of rat astrocytoma cell line C6. The ability to suppress iNOS induction in astrocytes
supports potential use of leflunomide in the treatment of multiple sclerosis and other NO-dependent inflammatory brain disorders.",
publisher = "Elsevier Science B.V.",
journal = "Brain Research",
title = "Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes",
number = "1-2",
volume = "889",
doi = "10.1016/s0006-8993(00)03181-4",
pages = "331-338"
}

Miljković, Đ., Samardžić, T., Mostarica Stojković, M., Stošić-Grujičić, S., Popadić, D.,& Trajković, V.. (2001). Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes. in Brain Research
Elsevier Science B.V.., 889(1-2), 331-338.
https://doi.org/10.1016/s0006-8993(00)03181-4

Miljković Đ, Samardžić T, Mostarica Stojković M, Stošić-Grujičić S, Popadić D, Trajković V. Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes. in Brain Research. 2001;889(1-2):331-338.
doi:10.1016/s0006-8993(00)03181-4 .

Miljković, Đorđe, Samardžić, Tatjana, Mostarica Stojković, Marija, Stošić-Grujičić, Stanislava, Popadić, Dušan, Trajković, Vladimir, "Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes" in Brain Research, 889, no. 1-2 (2001):331-338,
https://doi.org/10.1016/s0006-8993(00)03181-4 . .