Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes
2001
Аутори:
Miljković, ĐorđeSamardžić, Tatjana
Mostarica Stojković, Marija
Stošić-Grujičić, Stanislava
Popadić, Dušan
Trajković, Vladimir
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2001 Elsevier Science B.V.
Метаподаци
Приказ свих података о документуАпстракт:
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.
Кључне речи:
Leflunomide; Astrocyte; Nitric oxide; iNOS; RatИзвор:
Brain Research, 2001, 889, 1-2, 331-338Финансирање / пројекти:
- Ministry of Science and Technology, Republic of Serbia, Yugoslavia
DOI: 10.1016/s0006-8993(00)03181-4
ISSN: 0006-8993
PubMed: 11166726