A New Kid on the Block? Carbonic Anhydrases as Possible New Targets in Alzheimer’s Disease

Abstract

The increase in the incidence of neurodegenerative diseases, in particular Alzheimer’s Disease (AD), is a consequence of the world′s population aging but unfortunately, existing treatments are only effective at delaying some of the symptoms and for a limited time. Despite huge efforts by both academic researchers and pharmaceutical companies, no disease-modifying drugs have been brought to the market in the last decades. Recently, several studies shed light on Carbonic Anhydrases (CAs, EC 4.2.1.1) as possible new targets for AD treatment. In the present review we summarized preclinical and clinical findings regarding the role of CAs and their inhibitors/activators on cognition, aging and neurodegeneration and we discuss future challenges and opportunities in the field.

1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy

“…Out of 16 isoforms of CA, almost all are represented in the CNS 37 . For example, CA I is widely distributed in the motor neurons in spinal cord 38 . CA II, which is ubiquitous and physiologically dominant isoform of CA, has been identified in the myelin sheaths, myelinated tracts, oligodendrocytes, astrocytes and in the choroid plexus of mammalian brain 38 .…”

“…For example, CA I is widely distributed in the motor neurons in spinal cord 38 . CA II, which is ubiquitous and physiologically dominant isoform of CA, has been identified in the myelin sheaths, myelinated tracts, oligodendrocytes, astrocytes and in the choroid plexus of mammalian brain 38 . Numerous studies, both on animal models and on humans, consistently confirm the role of CAs in cognition.…”

“…Likewise, clinical studies indicate that CAs are involved in memory and learning processes. During a randomised, double-blind, placebo-controlled clinical trial, subjects receiving acetazolamide experienced deficits in cognitive functions, attention, concentration and short-term memory 38 . Importantly, epileptic patients receiving topiramate, that apart from its anticonvulsant effect, also acts as CA I inhibitor, showed significant cognitive impairments 42 .…”

Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics

“…Modifying the function of carbonic anhydrase in animal models improved learning abilities, and possible perception, processing and storing of temporally associated signals 74 . Some early reports have also speculated the role of zinc homeostasis being related to cognitive impairment in Alzheimer’s disease 75–77 . While results of the present study suggest that inhibition of carbonic anhydrase activity may enhance cognition, pharmacologic evidence to date has supported the opposite conclusion.…”

Coumarin carbonic anhydrase inhibitors from natural sources

“…Furthermore, some CAIs are in various stages of clinical development for the management of metastatic, hypoxic tumours [31][32][33][34] . It should be also noted that recently, some types of CAIs showed promising activity for the management of conditions such as neuropathic pain 35,36 , cerebral ischaemia 37 , arthritis [38][39][40] , idiopathic intracranial hypertension 41 , and some neurodegenerative disorders 42,43 . On the other hand, the CA activators (CAAs) show pharmacological applications for memory therapy 44 and in the modulation of emotional memory, which opens the possibility to apply them in areas with few therapeutic options at this moment, such as phobias, post-traumatic stress, generalised anxiety, and obsessive-compulsive disorders 45,46 .…”