Nuclear receptor peroxisome proliferator-activated receptor-γ is activated in rat microglial cells by the anti-inflammatory drug HCT1026, a derivative of flurbiprofen
Nuclear receptor peroxisome proliferator-activated receptor-γ is activated in rat microglial cells by the anti-inflammatory drug HCT1026, a derivative of flurbiprofen
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DOI：
10.1111/j.1471-4159.2004.02932.x
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发表时间：
2005-02-01
影响因子：
4.7
通讯作者：
Minghetti, L
中科院分区：
文献类型：
--
作者：
Bernardo, A;Ajmone-Cat, MA;Minghetti, L
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）在大鼠小胶质细胞（脑内巨噬细胞的主要群体）的原代培养物中组成型表达，其配体依赖性激活导致几种小胶质细胞功能的抑制。一些非甾体抗炎药（NSAID），例如吲哚美辛和布洛芬，显示出PPAR-gamma激动特性。已经提出，PPAR-gamma激活有助于长期使用某些NSAID延迟阿尔茨海默病（AD）进展的潜在益处。先前的数据表明，NSAID HCT 1026 [2-氟-α-甲基（1，1 '-联苯）4-乙酸-4-（硝基氧基）丁酯]，一种释放一氧化氮（NO）的氟比洛芬衍生物，减少了各种模型中反应性小胶质细胞的数量。这一证据连同与布洛芬的化学类比使我们研究氟比洛芬和HCT 1026是否与PPAR-gamma相互作用并干扰小胶质细胞活化。我们发现，低浓度（1 μ M）的HCT 1026，而不是氟比洛芬，激活大鼠小胶质细胞的原代培养物中的PPAR-gamma，与合成激动剂环格列酮的动力学相似。PPAR-gamma拮抗剂GW 9662（2-氯-5-硝基苯甲酰苯胺）可防止HCT 1026激活PPAR-gamma。有趣的是，与在高于环加氧酶抑制所需浓度的浓度下激活PPAR-gamma的其它NSAID不同，HCT 1026在相同的低浓度（1 μ M）下激活PPAR-gamma并抑制前列腺素E-2合成。结果表明，HCT 1026可能通过PPAR-gamma激活发挥额外的抗炎作用，从而更有效地控制小胶质细胞激活和脑炎症。
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is constitutively expressed in primary cultures of rat microglia, the main population of brain resident macrophages, and its ligand-dependent activation leads to the repression of several microglial functions. A few non-steroidal anti-inflammatory drugs (NSAIDs), e.g. indomethacin and ibuprofen, show PPAR-gamma agonistic properties. It has been proposed that PPAR-gamma activation contributes to the potential benefits of the long-term use of certain NSAIDs in delaying the progression of Alzheimer's disease (AD). Previous data have shown that the NSAID HCT1026 [2-fluoro-alpha-methyl(1,1'-biphenyl)4-acetic acid-4-(nitrooxy)butyl ester], a derivative of flurbiprofen which releases nitric oxide (NO), reduces the number of reactive microglial cells in a variety of models. This evidence together with the chemical analogy with ibuprofen led us to investigate whether flurbiprofen and HCT1026 interact with PPAR-gamma and interfere with microglial activation. We found that a low concentration (1 muM) of HCT1026, but not flurbiprofen, activated PPAR-gamma in primary cultures of rat microglia, with kinetics similar to those of the synthetic agonist ciglitazone. The PPAR-gamma antagonist GW9662 (2-chloro-5-nitrobenzanilide) prevented the activation of PPAR-gamma by HCT1026. Interestingly, unlike other NSAIDs that activate PPAR-gamma at concentrations higher than those required for cyclooxygenase inhibition, HCT1026 activated PPAR-gamma and inhibited prostaglandin E-2 synthesis at the same low concentration (1 muM). The results suggest that HCT1026 may exert additional anti-inflammatory actions through PPAR-gamma activation, allowing a more effective control of microglial activation and brain inflammation.