Filipovich Talia, Fleisher-Berkovich Sigal
Department of Clinical Pharmacology, Ben-Gurion University, P.O.B 653, Beer-Sheva 84105, Israel.
Peptides. 2008 Dec;29(12):2250-6. doi: 10.1016/j.peptides.2008.09.002. Epub 2008 Sep 16.
Endothelins are well known as modulators of inflammation in the periphery, but little is known about their possible role in brain inflammation. Stimulation of astrocyte prostaglandin, an inflammatory mediator, synthesis was shown so far only by endothelin 3 (ET-3). By contrast, several studies showed no change or slight decrease of basal nitric oxide synthesis after treatment of astrocytes with endothelin 1 (ET-1) and ET-3. However, a significant increase in astrocytic and microglial nitric oxide synthase (NOS) was observed after exposure to ET-1 and ET-3 in a model of forebrain ischaemia. Here we demonstrate that all three endothelins (ET-1, ET-2, ET-3) significantly enhanced the synthesis of prostaglandin E(2) and nitric oxide in glial cells. Each of the selective antagonists for ETA and ETB receptors (BQ123 and BQ788 respectively), significantly inhibited endothelins-induced production of both nitric oxide and prostaglandin E(2). These results suggest a regulatory mechanism of endothelins, interacting with both endothelin receptors, on glial inflammation. Therefore, inhibition of endothelin receptors may have a therapeutic potential in pathological conditions of the brain, when an uncontrolled inflammatory response is involved.
内皮素作为外周炎症的调节因子已广为人知，但它们在脑炎症中可能发挥的作用却鲜为人知。迄今为止，仅内皮素3（ET-3）能刺激星形胶质细胞合成前列腺素（一种炎症介质）。相比之下，多项研究表明，用内皮素1（ET-1）和ET-3处理星形胶质细胞后，基础一氧化氮合成没有变化或略有下降。然而，在前脑缺血模型中，暴露于ET-1和ET-3后，观察到星形胶质细胞和小胶质细胞一氧化氮合酶（NOS）显著增加。在此我们证明，所有三种内皮素（ET-1、ET-2、ET-3）均能显著增强神经胶质细胞中前列腺素E2和一氧化氮的合成。ETA和ETB受体的每种选择性拮抗剂（分别为BQ123和BQ788）均能显著抑制内皮素诱导的一氧化氮和前列腺素E2的产生。这些结果表明内皮素与两种内皮素受体相互作用对神经胶质炎症具有调节机制。因此，在内皮素受体参与不受控制的炎症反应的脑部病理状况下，抑制内皮素受体可能具有治疗潜力。
