Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram.
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.
Buttini
M
M
Novartis Ltd, Preclinical Research, Basel.
Mir
A
A
Appel
K
K
Wiederhold
K H
KH
Limonta
S
S
Gebicke-Haerter
P J
PJ
Boddeke
H W
HW
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
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