Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Abstract

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 CO2 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 in vitro and in vivo, 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.

“FDA-approved carbonic anhydrase inhibitors reduce Amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness”

“…Additionally, while untreated TgSwDI mice showed significant vasoconstriction in DG and cortex, vessel width in CAI-treated mice was restored to WT levels. If on one hand these results corroborate the impact of CAA on EC degeneration and blood vessel dysfunction, as observed in AD subjects [52], on the other hand they confirm that CAIs may be able to regulate cerebral vessel tone, possibly by both reducing EC mitochondrial stress and ROS production [38][39][40]44],…”

“…Furthermore, arterial pulsation, which is important for multiple clearance mechanisms including IPAD [26, 136], can also be improved by CAIs [44, 56], suggesting that ATZ and MTZ could exert additional positive effects by improving vascular smooth muscle cell tone and function, which is currently the subject of further studies by our group.…”

Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations

“…CA inhibitors can be used for the development of anti-infective agents (CAs are responsible for the survival and virulence of certain pathogens) [ 38 ], for the treatment of glaucoma [ 39 ], cerebral ischemia [ 40 ], rheumatoid arthritis [ 41 ], obesity [ 42 ], neuropathic pain [ 43 ], epilepsy [ 44 ], or cancer [ 45 ]; in this context, it is important to highlight that CA IX and XII are overexpressed in numerous tumors, where they control the microenvironment pH (acidification of the extracellular medium) [ 46 ] and certain metabolic processes connected to tumor growth and metastasis [ 47 ]. Recent evidence also correlates CA inhibition with neuroprotective effects in Alzheimer’s disease [ 48 ].…”

Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H,5H-pyrano[3,2-c]chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors

“… 26 The unexpected and novel application of CAIs in synaptic transformation and attentional gating of memory is quite appreciating in the treatment of Alzheimer’s disease. 27 …”

“…CAs are committed as attractive targets for drug design to cure therapeutic diseases like acid–base disequilibria, epilepsy, glaucoma, cancer, osteoporosis and other neuromuscular disorders, edema, altitude sickness, and obesity. , Recent studies have shown the role of CA inhibitors (CAIs) as a therapeutic hit for other diseases like neuropathic pain, cerebral ischemia, and tumor . The unexpected and novel application of CAIs in synaptic transformation and attentional gating of memory is quite appreciating in the treatment of Alzheimer’s disease …”