title: Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram.
abstract: 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-alpha) 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-alpha 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-alpha riboprobe suggested that the cells responsible for TNF-alpha production in the brain were microglia. 4. Intraperitoneal administration of methylprednisolone inhibited the induction of TNF-alpha protein in a dose-dependent manner. A maximal inhibition of TNF-alpha 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-alpha protein in a dose-dependent manner. The maximal inhibition of TNF-alpha 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-alpha mRNA induced in rat brain by LPS challenge was reduced by intraperitoneal administration of methylprednisolone (2 x 15 mg kg(-1)) and of rolipram (3 x 3 mg kg(-1)). 7. We suggest that peripheral administration of LPS induces a time-dependent expression of TNF-alpha in rat brain, presumably in microglial cells, and that methylprednisolone and rolipram inhibit LPS-induced expression of TNF-alpha in these cells via a decrease of TNF-alpha mRNA stability and/or TNF-alpha gene transcription.
authors.affiliation: Novartis Ltd, Preclinical Research, Basel.
authors.forename: M
authors.initials: M
authors.lastname: Buttini
authors.forename: A
authors.initials: A
authors.lastname: Mir
authors.forename: K
authors.initials: K
authors.lastname: Appel
authors.forename: K H
authors.initials: KH
authors.lastname: Wiederhold
authors.forename: S
authors.initials: S
authors.lastname: Limonta
authors.forename: P J
authors.initials: PJ
authors.lastname: Gebicke-Haerter
authors.forename: H W
authors.initials: HW
authors.lastname: Boddeke
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D011760:Pyrrolidinones; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020889:Rolipram; D008775:Methylprednisolone