Sathyanesan Monica, Girgenti Matthew J, Warner-Schmidt Jennifer, Newton Samuel S
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06519, USA.
Mol Brain. 2015 Oct 6;8:59. doi: 10.1186/s13041-015-0150-x.
Non-steroidal anti-inflammatory drugs such as indomethacin are widely used to treat inflammatory diseases and manage pain, fever and inflammation in several conditions, including neuropsychiatric disorders. Although they predominantly function by inhibiting cyclooxygenase (COX) activity, important COX-independent actions also occur. These actions could be responsible for the adverse side effects associated with chronic and/or high dose usage of this popular drug class.
We examined gene regulation in the hippocampus after peripheral administration of indomethacin by employing a microarray approach. Secondary confirmation and the brain expression pattern of regulated genes was examined by in situ hybridization and immunohistochemistry. Transglutaminase 2, serum glucocorticoid inducible kinase, Inhibitor of NF-kappa B and vascular endothelial growth factor were among genes that were prominently upregulated, while G-protein coupled receptor 56 and neuropeptide Y were among genes that were downregulated by indomethacin. Co-localization studies using blood vessel markers revealed that transglutaminase 2 was induced specifically in brain vasculature.
The data demonstrate that COX-inhibitors can differentially regulate gene transcription in multiple, functionally distinctly cell types in the brain. The results provide additional insight into the molecular actions of COX-inhibitors and indicate that their effects on vasculature could influence cerebral blood flow mechanisms.
非甾体抗炎药如吲哚美辛被广泛用于治疗炎症性疾病，并在包括神经精神疾病在内的多种病症中控制疼痛、发热和炎症。尽管它们主要通过抑制环氧化酶（COX）活性发挥作用，但也会出现重要的非COX依赖性作用。这些作用可能导致与长期和/或高剂量使用这类常用药物相关的不良副作用。
我们采用微阵列方法研究了外周给予吲哚美辛后海马体中的基因调控。通过原位杂交和免疫组织化学检查了调控基因的二次确认及脑内表达模式。转谷氨酰胺酶2、血清糖皮质激素诱导激酶、核因子κB抑制剂和血管内皮生长因子等基因显著上调，而G蛋白偶联受体56和神经肽Y等基因则被吲哚美辛下调。使用血管标志物的共定位研究表明，转谷氨酰胺酶2在脑血管中特异性诱导表达。
数据表明，COX抑制剂可在大脑中多种功能不同的细胞类型中差异性地调节基因转录。这些结果为COX抑制剂的分子作用提供了更多见解，并表明它们对脉管系统的影响可能会影响脑血流机制。
