Peroxisome proliferator-activated receptor-γ ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo
Peroxisome proliferator-activated receptor-γ ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo
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DOI：
10.1523/jneurosci.20-18-06862.2000
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发表时间：
2000-09-15
影响因子：
5.3
通讯作者：
Feinstein, DL
中科院分区：
文献类型：
--
作者：
Heneka, MT;Klockgether, T;Feinstein, DL
诱导型一氧化氮合酶（iNOS）在脑中的表达可能有助于阿尔茨海默病（AD）的神经毒性。诱导型一氧化氮合酶的表达可以诱导在小脑颗粒细胞（CGCs）在体内以及在体外，使这些细胞被用来研究神经元诱导型一氧化氮合酶表达的调节。我们在这里报告，显微注射细菌脂多糖和干扰素γ到大鼠小脑诱导iNOS表达的CGCs和随后的细胞死亡的DNA片段染色评估。共注射三种结构不同的过氧化物酶体增殖物激活受体γ激动剂包括抗糖尿病噻唑烷二酮曲格列酮、非甾体抗炎药（NSAID）布洛芬和前列腺素类15-脱氧-Delta 12，14前列腺素J（2）在内的过氧化物酶体增殖物激活受体γ（PPAR γ）可减少iNOS表达和细胞死亡，而同时注射选择性环加氧酶抑制剂NS-398则没有效果。这些数据表明，PPAR γ激动剂可以调节脑中的炎症反应。由于持续使用NSAID降低了AD的风险并延迟了AD的发作，因此这些结果进一步表明NSAID通过与AD脑中存在的PPAR γ结合，从而防止iNOS表达和神经元细胞死亡而提供治疗价值。
Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD). Expression of iNOS can be induced in cerebellar granule cells (CGCs) in vivo as well as in vitro, allowing these cells to be used to study regulation of neuronal iNOS expression. We report here that microinjection of bacterial lipopolysaccharide and interferon gamma into rat cerebellum induced iNOS expression in CGCs and subsequent cell death assessed by staining for DNA fragmentation. Co-injection of three structurally distinct agonists of the peroxisome proliferator-activated receptor gamma (PPAR gamma), including the antidiabetic thiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and the pro-stanoid 15-deoxy-Delta 12,14 prostaglandin J(2), reduced both iNOS expression and cell death, whereas co-injection of the selective cyclo-oxygenase inhibitor NS-398 had no effect. These data demonstrate that PPAR gamma agonists can modulate inflammatory responses in brain. Because sustained medication with NSAIDs reduces the risk and delays the onset of AD, these results further suggest that NSAIDs provide therapeutic value by binding to PPAR gamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.