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

阿尔茨海默病（AD）患者的脑部血流量减少。这种减少发生在痴呆症发病之前。对于已经患有阿尔茨海默氏症的人来说，通过大脑的血流量减少越明显，他们的痴呆症就越严重。AD患者确实倾向于发生脑血管的结构改变——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，这主要是由血管的功能异常而不是结构异常介导的。阿尔茨海默症的脑损伤和记忆障碍被认为是由一种被称为淀粉样蛋白（Abeta）的物质在大脑中的积累引起的。这主要有两种形式，较短的（Abeta40）和较长的（Abeta42）。在AD中，较长形式的Abeta42的比例有所增加。较长形式的β使神经细胞产生更多的一种叫做ACE的酶，这种酶反过来又产生化学物质Ang II。此外，两种形式的Abeta都增加了另一种叫做内皮素-1 （ET-1）的化学物质的产生：Abeta42是通过作用于一种在神经细胞中合成ET-1的酶（称为ECE）来实现的，而Abeta40是通过刺激大脑血管内壁中ET-1的产生来实现的。ET-1和Ang - II都会导致血管收缩，使管腔变窄。这减少了阿尔茨海默病患者脑部的血流量，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了不利影响。此外，实验研究表明，血液供应的减少可能会增加β的产生，从而加速AD的进展。在阿尔茨海默病的大鼠模型中，其他研究人员发现，注射ET-1会导致更多的β积累，更明显的继发性退行性变化，以及记忆测试中的表现受损。ET-1通过作用于血管壁的特定受体（ET-A受体）介导其血流减少。Ang II通过作用于其他受体（Ang II受体）介导其作用。通过阻断其中一种或两种受体，应该有可能改善大脑的血液流动。我们现在希望探索(i) zibotentan（一种由阿斯利康生产的特异性ET-A阻滞剂）和（ii）氯沙坦（一种获得许可的Ang - ii受体阻滞剂）在大鼠模型中改善脑血流量的效用，该模型结合了et -1介导的血流量减少和脑内Abeta积累。大鼠研究将使我们能够非常详细地检查齐博坦、氯沙坦以及两者联合使用的效果，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，以及它们对β代谢的影响（包括对ECE和ACE的活性的影响，这两种药物都有助于大脑去除β）。zibotentan和氯沙坦在老年人长期服用时耐受性良好。这些研究将阐明它们在恢复阿尔茨海默氏症患者血液流动方面的单独和联合潜力，从而有可能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.