Effect of dexamethasone, indomethacin, ibuprofen, and probenecid on carrageenan-induced brain inflammation.
A model of brain inflammation has recently been developed in mice using intraventricular injection of carrageenan (CAR). This model is characterized by increased brain water and vascular permeability, by neutrophil extravasation, and by evidence of increased pro-inflammatory arachidonic acid metabolites. The purpose of the current experiments was to determine the mechanism(s) by which CAR induces brain inflammation and to determine the utility of the CAR model in testing systemically administered therapeutic agents for their capacity to inhibit brain inflammation. Dexamethasone inhibited the increased brain water but not the increased vascular permeability produced by CAR. Indomethacin, an inhibitor of prostaglandin formation, suppressed peripheral inflammation produced by local injection of CAR but not brain inflammation produced by intraventricular CAR injection. Subsequent studies with carbon-14-labeled indomethacin showed that indomethacin penetrates peripheral tissues but is excluded from normal brain or brains inflamed by injection of CAR. Ibuprofen, another prostaglandin synthesis inhibitor, also had no effect on brain inflammation. Probenecid, an organic acid transport inhibitor, completely inhibited CAR-induced brain inflammation and also slowed brain elimination of intraventricularly administered prostaglandins. These experiments suggest, but do not conclusively prove, that increased prostaglandin formation contributes to brain inflammation. Also, the results with indomethacin and CAR-induced brain inflammation indicate that CAR-induced inflammation may be a useful model for screening for the ability of anti-inflammatory agents to cross the blood-brain barrier and exert their effect on brain inflammation.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001929:Brain Edema / Q000139:chemically induced / Q000188:drug therapy; D002199:Capillary Permeability / Q000187:drug effects; D002351:Carrageenan; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003907:Dexamethasone / Q000627:therapeutic use; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy*; D006614:Hindlimb / Q000098:blood supply; D007052:Ibuprofen / Q000627:therapeutic use; D007213:Indomethacin / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011339:Probenecid / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D002351:Carrageenan; D011339:Probenecid; D007052:Ibuprofen; D007213:Indomethacin