Scali C, Prosperi C, Vannucchi M G, Pepeu G, Casamenti F
Department of Pharmacology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy.
Eur J Neurosci. 2000 Jun;12(6):1900-12. doi: 10.1046/j.1460-9568.2000.00075.x.
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.
脑内炎症过程是阿尔茨海默病发病机制的基础，非甾体类抗炎药对该疾病具有保护作用。本研究的目的是在大鼠脑内体内表征对兴奋性毒性损伤的炎症反应，并研究尼美舒利治疗的疗效。将quisqualic酸注射到大鼠右侧基底核。兴奋性毒素诱导胆碱能变性、强烈的神经胶质反应和炎症介质的产生。注射后3小时，注射区域白细胞介素-1β浓度升高了5倍。尼美舒利（10mg/kg，肌肉注射）预处理可使这种升高降低50%。电子显微镜检查和免疫细胞化学染色显示，注射后24小时和7天，小胶质细胞和星形胶质细胞均被强烈激活。注射后24小时，注射半球血管周围的小胶质细胞和内皮细胞中诱导出环氧化酶-2免疫反应性。注射后7天，实质小胶质细胞中诱导出环氧化酶-2阳性信号，并且在注射区域检测到大量前列腺素-E2。注射后24小时和7天，在注射部位检测到许多诱导型一氧化氮合酶阳性细胞和高水平的亚硝酸盐。尼美舒利（10mg/kg/天，肌肉注射）治疗7天可强烈减弱小胶质细胞反应，减少诱导型一氧化氮合酶阳性细胞数量，并完全消除前列腺素-E2生成的增加。这些数据在体内为环氧化酶-2抑制剂在阿尔茨海默病治疗中的潜在疗效提供了有价值的支持。
