Chang Yunyoung C, Kim Hyung-Wook, Rapoport Stanley I, Rao Jagadeesh S
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, 9000 Rockville Pike, Bldg. 9, 1S-126, Bethesda, MD, 20892, USA.
Neurochem Res. 2008 Nov;33(11):2318-23. doi: 10.1007/s11064-008-9731-8. Epub 2008 May 24.
Chronic N-Methyl-D: -aspartate (NMDA) administration, a model of excitotoxicity, and chronic intracerebroventricular lipopolysaccharide infusion, a model of neuroinflammation, are reported to upregulate arachidonic acid incorporation and turnover in rat brain phospholipids as well as enzymes involved in arachidonic acid metabolism. This suggests cross-talk between signaling pathways of excitotoxicity and of neuroinflammation, involving arachidonic acid. To test whether chronic NMDA administrations to rats can upregulate brain markers of neuroinflammation, NMDA (25 mg/kg i.p.) or vehicle (1 ml saline/kg i.p.) was administered daily to adult male rats for 21 days. Protein and mRNA levels of cytokines and other inflammatory markers were measured in the frontal cortex using immunoblot and real-time PCR. Compared with chronic vehicle, chronic NMDA significantly increased protein and mRNA levels of interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase. Chronic NMDA receptor overactivation results in increased levels of neuroinflammatory markers in the rat frontal cortex, consistent with cross-talk between excitotoxicity and neuroinflammation. As both processes have been reported in a number of human brain diseases, NMDA receptor inhibitors might be of use in treating neuroinflammation in these diseases.
据报道，慢性给予N-甲基-D-天冬氨酸（NMDA）（一种兴奋性毒性模型）和慢性脑室内注入脂多糖（一种神经炎症模型）可上调大鼠脑磷脂中花生四烯酸的掺入和周转以及参与花生四烯酸代谢的酶。这表明兴奋性毒性信号通路与神经炎症信号通路之间存在涉及花生四烯酸的相互作用。为了测试对大鼠慢性给予NMDA是否会上调神经炎症的脑标志物，每天对成年雄性大鼠腹腔注射NMDA（25mg/kg）或溶剂（1ml生理盐水/kg），持续21天。使用免疫印迹和实时PCR测量额叶皮质中细胞因子和其他炎症标志物的蛋白质和mRNA水平。与慢性给予溶剂相比，慢性给予NMDA显著增加了白细胞介素-1β、肿瘤坏死因子α、胶质纤维酸性蛋白和诱导型一氧化氮合酶的蛋白质和mRNA水平。慢性NMDA受体过度激活导致大鼠额叶皮质中神经炎症标志物水平升高，这与兴奋性毒性和神经炎症之间的相互作用一致。由于在许多人类脑部疾病中都报道了这两个过程，NMDA受体抑制剂可能有助于治疗这些疾病中的神经炎症。
