Tachikawa Masanori, Hosoya Ken-ichi, Terasaki Tetsuya
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Adv Pharmacol. 2014;71:337-60. doi: 10.1016/bs.apha.2014.06.006. Epub 2014 Aug 22.
Prostaglandin (PG) E2 and PGD2, which are biosynthesized from arachidonic acid generated by enzymatic cleavage of membrane phospholipid in response to various stimuli, play key roles in multiple brain pathophysiological processes, including modulation of synaptic plasticity, neuroinflammation, and sleep promotion. Concentrations of PGE2 and PGD2 in brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) are maintained at appropriate levels for normal brain function by regulatory systems. The blood-brain barrier (BBB) and the blood-CSF barrier (BCSFB) possess ISF/CSF-to-blood efflux transport systems that are the primary cerebral clearance pathways for PGE2 and PGD2. However, regulatory dysfunction at the brain barriers may seriously affect brain function. In a mouse inflammation model, significant reduction of PGE2 efflux transport at the BBB has been observed. Several kinds of cephalosporin antibiotics and nonsteroidal anti-inflammatory drugs inhibit the BBB- and BCSFB-mediated efflux transport of PGE2 and PGD2. Especially, drugs that inhibit multidrug resistance-associated protein 4 (MRP4)-mediated PGE2 transport are capable of reducing PGE2 efflux at the BBB. Thus, it might be important in the treatment of inflammatory and infectious diseases to use drugs that do not inhibit clearance of PGE2 at the brain barriers, in order to avoid unexpected adverse CNS effects. Further, considering that PGD2 in CSF is a natural sleep-promoting factor, changes in the activity of the PGD2 efflux transport system at the BCSFB may modify the PGD2 level in CSF, thus affecting physiological sleep. These findings indicate that the efflux transport systems at the brain barriers play key roles in the pathophysiology and pharmacology of PGE2 and PGD2.
前列腺素（PG）E2和PGD2由膜磷脂经酶促裂解产生的花生四烯酸生物合成，响应各种刺激，在多种脑病理生理过程中起关键作用，包括调节突触可塑性、神经炎症和促进睡眠。脑间质液（ISF）和脑脊液（CSF）中PGE2和PGD2的浓度通过调节系统维持在适当水平以实现正常脑功能。血脑屏障（BBB）和血脑脊液屏障（BCSFB）具有ISF/CSF到血液的外流转运系统，这是PGE2和PGD2的主要脑清除途径。然而，脑屏障处的调节功能障碍可能严重影响脑功能。在小鼠炎症模型中，已观察到BBB处PGE2外流转运显著减少。几种头孢菌素抗生素和非甾体抗炎药抑制BBB和BCSFB介导的PGE2和PGD2外流转运。特别是，抑制多药耐药相关蛋白4（MRP4）介导的PGE2转运的药物能够减少BBB处的PGE2外流。因此，在治疗炎症和感染性疾病时，使用不抑制脑屏障处PGE2清除的药物可能很重要，以避免意外的中枢神经系统不良反应。此外，考虑到CSF中的PGD2是一种天然的促睡眠因子，BCSFB处PGD2外流转运系统活性的变化可能会改变CSF中PGD2的水平，从而影响生理睡眠。这些发现表明，脑屏障处的外流转运系统在PGE2和PGD2的病理生理学和药理学中起关键作用。
