Cyclosporin A induces hyperpermeability of the blood–brain barrier by inhibiting autocrine adrenomedullin-mediated up-regulation of endothelial barrier function

详细信息    查看全文

• 作者：Shinya Dohgu ; Noriko Sumi ; Tsuyoshi Nishioku ; Fuyuko Takata ; Takuya Watanabe ; Mikihiko Naito ; Hideki Shuto ; Atsushi Yamauchi ; Yasufumi Kataoka
• 关键词：Blood– ; brain barrier ; Cyclosporin A ; Adrenomedullin ; cAMP ; Adenylyl cyclase ; Permeability
• 刊名：European Journal of Pharmacology
• 出版年：2010
• 出版时间：10 October 2010
• 年：2010
• 卷：644
• 期：1-3
• 页码：5-9
• 全文大小：293 K

文摘

Cyclosporin A, a potent immunosuppressant, can often produce neurotoxicity in patients, although its penetration into the brain is restricted by the blood–brain barrier (BBB). Brain pericytes and astrocytes, which are periendothelial accessory structures of the BBB, can be involved in cyclosporin A-induced BBB disruption. However, the mechanism by which cyclosporin A causes BBB dysfunction remains unknown. Here, we show that in rodent brain endothelial cells, cyclosporin A decreased transendothelial electrical resistance (TEER) by inhibiting intracellular signal transduction downstream of adrenomedullin, an autocrine regulator of BBB function. Cyclosporin A stimulated adrenomedullin release from brain endothelial cells, but did not affect binding of adrenomedullin to its receptors. This cyclosporin A-induced decrease in TEER was attenuated by exogenous addition of adrenomedullin. Cyclosporin A dose-dependently decreased the total cAMP concentration in brain endothelial cells. A combination of cyclosporin A (1 μM) with an adenylyl cyclase inhibitor, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536; 10 μM), or a protein kinase A (PKA) inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89; 1 μM), markedly increased sodium fluorescein permeability in brain endothelial cells, whereas each drug alone had no effect. Thus, these data suggest that cyclosporin A inhibits the adenylyl cyclase/cyclic AMP/PKA signaling pathway activated by adrenomedullin, leading to impairment of brain endothelial barrier function.