Neuroimmunology Unit, Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, St. Bartholomew's and The London School of Medicine and Dentistry, 4, Newark Street, London, E12 AT, UK.
Fundam Clin Pharmacol. 2013 Oct;27(5):535-43. doi: 10.1111/j.1472-8206.2012.01050.x. Epub 2012 Jun 29.
Our previous studies have established that major changes in central nervous system (CNS) prostaglandin (PG) levels occur during the relapse phase of chronic relapsing experimental autoimmune encephalomyelitis (CR EAE), an animal model of the human demyelinating disease multiple sclerosis. PG production is controlled through a series of enzymic pathways that, in EAE, are influenced by neuroantigen-driven autoimmune events. In non-immune-based models of CNS disease, endogenous glucocorticoids have been proposed as instigators of PG synthesis via activation of the N-methyl-D-aspartate (NMDA) receptor. Glucocorticoids have an important regulatory role in the pathogenesis EAE and the NMDA receptor is intimately involved in many of the characteristic neuroinflammatory processes that govern the disease. Therefore, the alterations in prostanoid concentrations during the relapse stage of CR EAE may ultimately be governed by glucocorticoid-induced NMDA receptor activation. The current investigation has examined the proposed glucocorticoid-NMDA receptor link by determining the effects of the receptor antagonist, (+) MK-801, on CNS PGE 2 and PGD 2 levels in Biozzi mice with relapse symptoms of CR EAE. Prostanoid concentrations in the cerebral cortex were not altered by drug administration, and in cerebellar tissues, a vehicle effect negated any drug-induced changes. However, the level of PGD 2 in spinal cords from (+) MK-801-dosed mice was significantly lower, compared to controls, but PGE 2 concentrations remained unchanged. The results suggest that glucocorticoid-NMDA receptor-linked events are not primarily responsible for PG generation in the brain but may influence prostanoid production in discrete areas of the CNS.
我们之前的研究已经确立，在慢性复发实验性自身免疫性脑脊髓炎（CR EAE）的复发阶段，中枢神经系统（CNS）前列腺素（PG）水平会发生重大变化，CR EAE 是人类脱髓鞘疾病多发性硬化症的动物模型。PG 的产生是通过一系列酶途径来控制的，在 EAE 中，这些途径会受到神经抗原驱动的自身免疫事件的影响。在非基于免疫的 CNS 疾病模型中，内源性糖皮质激素已被提议通过激活 N-甲基-D-天冬氨酸（NMDA）受体来引发 PG 合成。糖皮质激素在 EAE 的发病机制中具有重要的调节作用，NMDA 受体密切参与许多控制疾病的特征性神经炎症过程。因此，CR EAE 复发阶段的前列腺素浓度变化最终可能受糖皮质激素诱导的 NMDA 受体激活的控制。目前的研究通过确定受体拮抗剂（+）MK-801 对具有 CR EAE 复发症状的 Biozzi 小鼠中枢神经系统 PGE 2 和 PGD 2 水平的影响，检查了拟议的糖皮质激素-NMDA 受体联系。药物给药并未改变大脑中的前列腺素浓度，而在小脑组织中，药物诱导的变化被载体效应抵消。然而，与对照组相比，（+）MK-801 给药小鼠脊髓中的 PGD 2 水平显著降低，但 PGE 2 浓度保持不变。结果表明，糖皮质激素-NMDA 受体相关事件并不是大脑中 PG 生成的主要原因，但可能会影响 CNS 特定区域的前列腺素产生。
