Scali C, Giovannini M G, Prosperi C, Bellucci A, Pepeu G, Casamenti F
Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
Neuroscience. 2003;117(4):909-19. doi: 10.1016/s0306-4522(02)00839-4.
Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and non-steroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this work was to study in vivo whether attenuation of brain inflammatory response to excitotoxic insult by the selective cyclooxygenase-2 inhibitor, rofecoxib, may prevent neurodegeneration, as a contribution to a better understanding of the role inflammation plays in the pathology of Alzheimer's disease. We investigated, by immunohistochemical methods, glia reaction, the activation of p38 mitogen-activated protein kinase (p38MAPK) pathway with an antibody selective for the phosphorylated form of the enzyme and the number of choline acetyltransferase-positive neurons and, by in vivo microdialysis, cortical extracellular levels of acetylcholine following the injection of quisqualic acid into the right nucleus basalis of adult rats. Seven days after injection, a marked reduction in the number of choline acetyltransferase-positive neurons was found, along with an intense glia reaction, selective activation of p38MAPK at the injection site and a significant decrease in the extracellular levels of acetylcholine in the cortex ipsilateral to the injection site. The loss of cholinergic neurons persisted for at least up to 28 days. Rofecoxib (3 mg/kg/day, starting 1 h prior to injection of quisqualic acid) treatment for 7 days significantly attenuated glia activation and prevented the loss of choline acetyltransferase-positive cells and a decrease in cortical acetylcholine release. The prevention of cholinergic cell loss by rofecoxib occurred concomitantly with the inhibition of p38MAPK phosphorylation. Our findings suggest an important role of brain inflammatory reaction in cholinergic degeneration and demonstrate a neuroprotective effect of rofecoxib, presumably mediated through the inhibition of p38MAPK phosphorylation.
脑内炎症过程是阿尔茨海默病发病机制的基础，非甾体抗炎药对该疾病具有保护作用。本研究的目的是在体内研究选择性环氧化酶-2抑制剂罗非昔布是否可减轻脑内对兴奋性毒性损伤的炎症反应，从而预防神经退行性变，以更好地理解炎症在阿尔茨海默病病理过程中的作用。我们采用免疫组化方法研究了胶质细胞反应、用针对磷酸化形式酶的抗体检测p38丝裂原活化蛋白激酶（p38MAPK）途径的激活情况以及胆碱乙酰转移酶阳性神经元的数量，并通过体内微透析法检测了成年大鼠右侧基底核注射喹啉酸后皮质细胞外乙酰胆碱水平。注射7天后，发现胆碱乙酰转移酶阳性神经元数量显著减少，同时伴有强烈的胶质细胞反应、注射部位p38MAPK的选择性激活以及注射部位同侧皮质细胞外乙酰胆碱水平的显著降低。胆碱能神经元的丢失至少持续了28天。罗非昔布（3mg/kg/天，在注射喹啉酸前1小时开始给药）治疗7天可显著减轻胶质细胞激活，预防胆碱乙酰转移酶阳性细胞的丢失以及皮质乙酰胆碱释放的减少。罗非昔布对胆碱能细胞丢失的预防作用与p38MAPK磷酸化的抑制同时发生。我们的研究结果表明脑内炎症反应在胆碱能神经元变性中起重要作用，并证明了罗非昔布的神经保护作用，推测其通过抑制p38MAPK磷酸化介导。
