Montine Thomas J, Milatovic Dejan, Gupta Ramesh C, Valyi-Nagy Tibor, Morrow Jason D, Breyer Richard M
Department of Pathology, Vanderbilt University, Nashville, Tennessee, USA.
J Neurochem. 2002 Oct;83(2):463-70. doi: 10.1046/j.1471-4159.2002.01157.x.
Increase in prostaglandin (PG) E2 levels and oxidative damage are associated with diseases of brain that involve activation of innate immunity. We tested the hypothesis that cerebral oxidative damage resulting from activation of innate immunity with intracerebroventricular (icv) lipopolysaccharide (LPS) is dependent on PGE2-mediated signaling. We measured two quantitative in vivo biomarkers of lipid peroxidation: F2-isoprostanes (IsoPs) that derive from arachidonic acid (AA) that is uniformly distributed in all cell types in brain, and F4-neuroprostanes (NeuroPs) that derive from docosahexaenoic acid (DHA) that is highly concentrated in neuronal membranes. LPS stimulated delayed elevations in cerebral F2-IsoPs and F4-NeuroPs that were completely suppressed by indomethacin or ibuprofen pre-treatment. LPS-induced cerebral oxidative damage was abolished by disruption of subtype 2 receptor for PGE2 (EP2). In contrast, initial oxidative damage from icv kainic acid (KA) was more rapid than with LPS also was completely suppressed by indomethacin or ibuprofen pre-treatment but was independent of EP2 receptor activation. The protective effect of deleting the EP2 receptor was not associated with changes in cerebral eicosaniod production, but was partially related to reduced induction of nitric oxide synthase (NOS) activity. These results suggest the EP2 receptor as a therapeutic target to limit oxidative damage from activation of innate immunity in cerebrum.
前列腺素（PG）E2水平升高和氧化损伤与涉及先天免疫激活的脑部疾病有关。我们检验了以下假设：脑室内（icv）注射脂多糖（LPS）激活先天免疫所导致的脑氧化损伤依赖于PGE2介导的信号传导。我们测量了脂质过氧化的两种体内定量生物标志物：源自花生四烯酸（AA，均匀分布于脑内所有细胞类型）的F2-异前列腺素（IsoPs），以及源自二十二碳六烯酸（DHA，高度浓缩于神经元膜）的F4-神经前列腺素（NeuroPs）。LPS刺激后，脑内F2-IsoPs和F4-NeuroPs延迟升高，吲哚美辛或布洛芬预处理可完全抑制这种升高。PGE2的2型受体（EP2）被破坏后，LPS诱导的脑氧化损伤被消除。相比之下，icv注射 kainic acid（KA）引起的初始氧化损伤比LPS更快，同样也被吲哚美辛或布洛芬预处理完全抑制，但与EP2受体激活无关。删除EP2受体的保护作用与脑内类二十烷酸生成的变化无关，但部分与一氧化氮合酶（NOS）活性诱导的降低有关。这些结果表明，EP2受体可作为一个治疗靶点，以限制大脑中先天免疫激活引起的氧化损伤。
