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The neuroprotective agents chlomethiazole and SB203580 inhibit IL‐1β signalling but not its biosynthesis in rat cortical glial cells
Author(s) -
Simi Anastasia,
PorsmyrPalmertz Margareta,
Hjertén Anna,
IngelmanSundberg Magnus,
Tindberg Niclas
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.01178.x
Subject(s) - neuroprotection , western blot , nitric oxide synthase , lipopolysaccharide , p38 mitogen activated protein kinases , microbiology and biotechnology , biology , microglia , nitric oxide , northern blot , interleukin , protein kinase a , kinase , chemistry , inflammation , biochemistry , messenger rna , pharmacology , immunology , cytokine , endocrinology , gene
Chlomethiazole and pyridinyl imidazole compounds, exemplified by SB203580, are structurally distinct p38 mitogen‐activated protein kinase inhibitors with neuroprotective properties in models of cerebral ischaemia. We have examined their effects in interleukin‐1β (IL‐1β) synthesis, release and signalling in rat cortical glial cells, given the important role of IL‐1β in cerebral ischaemia. We analysed (i) IL‐1β mRNA expression by northern blot, (ii) IL‐1β protein precursor levels within the cells by western blot, and (iii) the levels of the mature IL‐1β protein secreted into the medium by enzyme‐linked immunosorbent assay (ELISA) after treatment of rat cortical glial cells with lipopolysaccharide. While the induction of IL‐1β expression by lipopolysaccharide or by IL‐1β itself was very sensitive to nuclear factor kappa B (NF‐κB) inhibitors, chlomethiazole or SB203580 were nearly without effect, indicating a differential regulation as compared to peripheral cells, e.g. monocytes. In contrast, chlomethiazole and SB203580 potently inhibited the IL‐1β‐induced expression of c‐ fos and inducible nitric oxide synthase, as monitored by northern blot and quantitative RT–PCR, respectively. Because IL‐1β‐induced expression of c‐ fos and inducible nitric oxide synthase is believed to directly contribute to the pathology of cerebral ischaemic injury, the results suggest a direct mechanism for the neuroprotective effects of chlomethiazole and SB203580, and further establish the anti‐inflammatory properties of chlomethiazole.