Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug: implication in Alzheimer's disease.
Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and nonsteroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this study was to characterize in vivo in the rat brain the inflammatory reaction in response to excitotoxic insult and to investigate the efficacy of nimesulide treatment. Quisqualic acid was injected into 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 concentration of interleukin-1beta in the injected area was observed. This elevation was reduced by 50% by nimesulide (10 mg/kg, i.m.) pretreatment. Electron microscope examination and immunocytochemical staining revealed an intense activation of microglia and astrocytes at both 24 h and 7 days after injection. Cyclooxygenase-2-immunoreactivity was induced in the blood vessels of the injected hemisphere in perivascular microglial and endothelial cells 24 h after injection. Seven days postinjection, a cyclooxygenase-2-positive signal was induced in the parenchymal microglia and large amounts of prostaglandin-E2 were measured in the injected area. Twenty-four hours and 7 days 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 microglial reaction, reduced the number of inducible nitric oxide synthase-positive cells and completely abolished the increase in prostaglandin-E2 formation. These data provide valuable support in vivo for the potential efficacy of cyclooxygenase-2 inhibitors in Alzheimer's disease therapy.
Scali
C
C
Department of Pharmacology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy.
Prosperi
C
C
Vannucchi
M G
MG
Pepeu
G
G
Casamenti
F
F
D000109:Acetylcholine / Q000032:analysis; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000032:analysis; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000276:immunology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005911:Gliosis / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000276:immunology*; D009474:Neurons / Q000737:chemistry / Q000201:enzymology / Q000648:ultrastructure; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018690:Excitatory Amino Acid Agonists; D007375:Interleukin-1; D007527:Isoenzymes; D009573:Nitrites; D013449:Sulfonamides; D005680:gamma-Aminobutyric Acid; D016318:Quisqualic Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D002795:Choline O-Acetyltransferase; D015232:Dinoprostone; D000109:Acetylcholine; C012655:nimesulide