MICA: ET-1-mediated reduction of cerebral blood flow in Alzheimer's disease: therapeutic potential of zibotentan

阿尔茨海默氏病（AD）患者的脑血流量减少。这种减少发生在痴呆症发作之前。在已经患有AD的人中，通过大脑的血流减少越明显，他们的痴呆症就越严重。AD患者确实倾向于发展脑中血管的结构变化-退行性小血管病（SVD）和脑淀粉样血管病（CAA）。然而，AD患者脑血流量减少的分布与脑血管结构改变的分布不同，越来越多的证据表明，AD患者脑血流量减少主要是由血管功能异常而非结构异常介导的。AD患者的脑损伤和记忆障碍被认为是由一种称为淀粉样蛋白β（Abeta）的物质在脑中积累所致。这主要有两种形式，一种是较短的（Abeta 40），另一种是较长的（Abeta 42）。在AD中，较长形式（Abeta 42）的Abeta比例增加。较长形式的Abeta导致神经细胞产生更多的称为ACE的酶，反过来，产生化学物质Ang II。此外，这两种形式的Abeta增加了另一种化学物质内皮素-1（ET-1）的产生：Abeta 42通过作用于神经细胞中合成ET-1的酶（称为ECE）来实现这一点，而Abeta 40通过刺激大脑血管内膜中ET-1的产生来实现。ET-1和Ang II都会导致血管收缩，使管腔变窄。这减少了AD患者大脑中的血流量，从而损害了向神经细胞输送氧气和营养物质，减缓了废物的清除，对神经细胞功能产生不利影响。此外，实验研究表明，血液供应的减少可能会增加Abeta的产生，从而加速AD的进展。在AD的大鼠模型中，其他研究人员表明，注射ET-1导致更多的Abeta积累，更明显的继发性退行性变化和记忆测试中的表现受损。ET-1通过作用于血管壁中的特定受体（ET-A受体）来介导其血流量的减少。Ang II通过作用于其他受体（Ang II受体）来介导其作用。通过阻断其中一组或两组受体，应该可以改善大脑的血流。我们现在希望探索（i）zibotentan（由AstraZeneca生产的特异性ET-A阻断剂）和（ii）losartan（许可的Ang II受体阻断剂）在大鼠模型中用于改善通过脑的血流量的效用，所述大鼠模型结合了ET-1介导的血流量减少和脑中Abeta积聚。大鼠研究将使我们能够非常详细地检查zibotentan，losartan以及两者组合的作用，包括当血压或大脑活动发生变化时，这些药物如何影响血流的维持，以及对Abeta代谢的影响（包括欧洲经委会和欧洲环境委员会的活动，这两种药物都有助于大脑清除Abeta）。当老年人长期服用齐博腾坦和氯沙坦时，耐受性都很好。这些研究将阐明它们在恢复AD患者血流方面的单独和联合潜力，并可能因此改善记忆力和减缓痴呆症的进展。

Blood flow through the brain is reduced in patients with Alzheimer's disease (AD). The reduction occurs before the onset of dementia. In people who already have AD, the more marked the reduction in blood flow through the brain the more severe their dementia. Patients with AD do tend to develop structural changes to the blood vessels in the brain - degenerative small vessel disease (SVD) and cerebral amyloid angiopathy (CAA). However, the distribution of the reduction in cerebral blood flow differs from that of the structural changes to cerebral blood vessels in AD, and there is increasing evidence that it is largely mediated by functional rather than structural abnormalities of the vessels.The brain damage and memory disturbances that occur in AD are thought to result from the accumulation of a substance known as amyloid beta (Abeta) in the brain. This occurs in two main forms, a shorter one (Abeta40) and a longer one (Abeta42). In AD there is an increase in the proportion of Abeta that is of the longer form (Abeta42). The longer form of Abeta causes nerve cells to produce more of an enzyme called ACE that, in turn, produces the chemical Ang II. In addition, both forms of Abeta increase the production of another chemical called endothelin-1 (ET-1): Abeta42 does so by acting on an enzyme (called ECE) that synthesizes ET-1 in nerve cells, and Abeta40 by stimulating the production of ET-1 in the lining of blood vessels in the brain. Both ET-1 and Ang II cause blood vessels to constrict, narrowing their lumen. This reduces blood flow through the brain in patients with AD, and thereby impairs the delivery of oxygen and nutrients to nerve cells and slows the removal of waste products, adversely affecting nerve cell function. In addition, experimental studies suggest that the reduction in blood supply may increase the production of Abeta and thereby accelerate the progression of the AD. In a rat model of AD, other researchers showed that injection of ET-1 led to more accumulation of Abeta, more marked secondary degenerative changes and impaired performance in memory tests.ET-1 mediates its reduction in blood flow by acting on specific receptors in the vessel walls (ET-A receptors). Ang II mediates its effects by acting on other receptors (Ang II receptors). By blocking either or both sets of receptors, it should be possible to improve blood flow through the brain. We now wish to explore the utility of (i) zibotentan, a specific ET-A blocker produced by AstraZeneca, and (ii) losartan, a licensed Ang II receptor blocker, for improving blood flow through the brain in a rat model that combines ET-1-mediated reduction in blood flow and Abeta accumulation in the brain. The rat studies will allow us to examine the effects of zibotentan, losartan and a combination of the two in great detail, including how these drugs affect maintenance of flow when there are changes in blood pressure or brain activity, and what the effects are on Abeta metabolism (including on the activity of ECE and ACE, both of which help the brain to remove Abeta).Both zibotentan and losartan are well tolerated when given over long periods of time to elderly people. These studies will clarify their separate and combined potential for restoring blood flow in AD - and potentially therefore improving memory and slowing the progression of dementia.