Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram
Novartis Ltd, Preclinical Research S-360.402, CH-4002 Basel.
- 1We 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).
- 2After 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.
- 3In situ hybridization experiments with a specific antisense TNF-α riboprobe suggested that the cells responsible for TNF-α production in the brain were microglia.
- 4Intraperitoneal 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.
- 5Intraperitoneal 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.
- 6In 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).
- 7We 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.