Lemon Nicole, Canepa Elisa, Ilies Marc A, Fossati Silvia
Alzheimer's Center at Temple (ACT), Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.
Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Temple University, Philadelphia, PA, United States.
Front Aging Neurosci. 2021 Nov 16;13:772278. doi: 10.3389/fnagi.2021.772278. eCollection 2021.
The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells and , in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.
神经血管单元（NVU）是中枢神经系统（CNS）重要的多细胞结构，参与脑血流量（CBF）调节、氧气和营养物质输送、免疫监视、清除、屏障功能及CNS内环境稳定。中风和阿尔茨海默病（AD）是两种存在广泛NVU功能障碍的病症。缺血性损伤后及AD病理发展过程中，NVU的细胞类型在结构和功能上均发生变化。中风和AD有诸如心血管疾病等共同风险因素，在分子水平上也有相似之处。在这两种疾病中，代谢支持的破坏、线粒体功能障碍、氧化应激增加、炎症信号分子释放及血脑屏障破坏均导致NVU功能障碍，进而导致细胞死亡和神经退行性变。AD和中风均需要改进治疗策略。碳酸酐酶（CAs）是其他疾病的知名靶点，最近其在脑血管病理发展中的功能正受到研究。CAs催化CO水合生成碳酸氢盐和一个质子。该反应对pH稳态、脑脊液翻转、CBF调节及其他生理功能很重要。人类表达15种具有不同分布模式的CA同工型。最近的研究提供证据表明，在中风和AD病理模型中，CA抑制对NVU细胞具有保护作用。CA抑制剂已获美国食品药品监督管理局（FDA）批准用于治疗青光眼、高原病及其他适应症。大多数FDA批准的CA抑制剂是泛CA抑制剂；然而，特定的CA同工型可能调节NVU功能。本综述将总结关于在中风和AD模型中使用泛CA和特定CA抑制剂以及对特定CA同工型进行基因操作的文献，以阐明CAs在NVU中的功能。尽管泛CA抑制剂具有保护作用且安全，但我们推测靶向特定的CA同工型将提高CA抑制的疗效并减少副作用。进一步确定特定CA同工型功能及疾病状态变化的更多研究对于开发针对中风和AD中出现的脑血管病理的新疗法至关重要。
