Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an antiinflammatory drug: implication in Alzheimer's disease

Brain inflammatory processes underlie the pathogenesis of Alzheimer's disea se, and nonsteroidal anti-inflammatory drugs have a protective effect in th e disease. The aim of this study was to characterize in vivo in the rat bra in the inflammatory reaction in response to excitotoxic insult and to inves tigate the efficacy of nimesulide treatment. Quisqualic acid was injected i nto the right nucleus basalis of rats. The excitotoxin induced cholinergic degeneration, an intense glial reaction and the production of inflammatory mediators. Three hours after injection, a five-fold elevation in the concen tration of interleukin-1 beta in the injected area was observed. This eleva tion was reduced by 50% by nimesulide (10 mg/kg, i.m.) pretreatment. Electr on microscope examination and immunocytochemical staining revealed an inten se activation of microglia and astrocytes at both 24h and 7 days after inje ction. Cyclooxygenase-2-immunoreactivity was induced in the blood vessels o f the injected hemisphere in perivascular microglial and endothelial cells 24h after injection. Seven days postinjection, a cyclooxygenase-2-positive signal was induced in the parenchymal microglia and large amounts of prosta glandin-E-2 were measured in the injected area. Twenty-four hours and 7 day s after injection, many inducible nitric oxide synthase-positive cells and a high level of nitrite were detected at the injection site, Seven days of nimesulide (10 mg/kg/day, i.m.) treatment strongly attenuated the microglia l reaction, reduced the number of inducible nitric oxide synthase-positive cells and completely abolished the increase in prostaglandin-Ea formation. These data provide valuable support in vivo for the potential efficacy of c yclooxygenase-2 inhibitors in Alzheimer's disease therapy.