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Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram
Author(s) -
Buttini M.,
Mir A.,
Appel K.,
Wiederhold K. H.,
Limonta S.,
GebickeHaerter P. J.,
Boddeke H. W. G. M.
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701502
Subject(s) - rolipram , methylprednisolone , tumor necrosis factor alpha , lipopolysaccharide , in situ hybridization , endocrinology , medicine , intraperitoneal injection , pharmacology , phosphodiesterase inhibitor , microglia , glucocorticoid , alpha (finance) , phosphodiesterase , biology , messenger rna , inflammation , biochemistry , enzyme , construct validity , nursing , gene , patient satisfaction
1 We have investigated the effects of the phosphodiesterase (PDE) type IV inhibitor rolipram and of the glucocorticoid methylprednisolone on the induction of tumour necrosis factor alpha (TNF‐α) mRNA and protein in brains of rats after peripheral administration of lipopolysaccharide (LPS). 2 After intravenous administration of LPS, a similar time‐dependent induction of both TNF‐α mRNA and protein was observed in rat brain. Peak mRNA and protein levels were found 7 h after administration of LPS. 3 In situ hybridization experiments with a specific antisense TNF‐α riboprobe suggested that the cells responsible for TNF‐α production in the brain were microglia. 4 Intraperitoneal administration of methylprednisolone inhibited the induction of TNF‐α protein in a dose‐dependent manner. A maximal inhibition of TNF‐α protein production by 42.9±10.2% was observed at a dose regimen consisting of two injections of each 30 mg kg −1 methylprednisolone. 5 Intraperitoneal administration of rolipram also inhibited the induction of TNF‐α protein in a dose‐dependent manner. The maximal inhibition of TNF‐α protein production was 96.1±12.2% and was observed at a dose regimen of three separate injections of each 3 mg kg −1 rolipram. 6 In situ hybridization experiments showed that the level of TNF‐α mRNA induced in rat brain by LPS challenge was reduced by intraperitoneal administration of methylprednisolone (2×15 mg kg −1 ) and of rolipram (3×3 mg kg −1 ). 7 We suggest that peripheral administration of LPS induces a time‐dependent expression of TNF‐α in rat brain, presumably in microglial cells, and that methylprednisolone and rolipram inhibit LPS‐induced expression of TNF‐α in these cells via a decrease of TNF‐α mRNA stability and/or TNF‐α gene transcription.