Carbonic Anhydrase Inhibitors and Epilepsy: State of the Art and Future Perspectives.

Lidia Ciccone,Susanna Nencetti,Elisabetta Orlandini,Chiara Cerri

doi:10.3390/molecules26216380

Lidia Ciccone, Susanna Nencetti + Show 2 more

Open Access

https://doi.org/10.3390/molecules26216380

Copy DOI

Abstract

Carbonic anhydrases (CAs) are a group of ubiquitously expressed metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3. Thus, they are involved in those physiological and pathological processes in which cellular pH buffering plays a relevant role. The inhibition of CAs has pharmacologic applications for several diseases. In addition to the well-known employment of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently been demonstrated that CAIs could be considered as valid therapeutic agents against obesity, cancer, kidney dysfunction, migraine, Alzheimer’s disease and epilepsy. Epilepsy is a chronic brain disorder that dramatically affects people of all ages. It is characterized by spontaneous recurrent seizures that are related to a rapid change in ionic composition, including an increase in intracellular potassium concentration and pH shifts. It has been reported that CAs II, VII and XIV are implicated in epilepsy. In this context, selective CAIs towards the mentioned isoforms (CAs II, VII and XIV) have been proposed and actually exploited as anticonvulsants agents in the treatment of epilepsy. Here, we describe the research achievements published on CAIs, focusing on those clinically used as anticonvulsants. In particular, we examine the new CAIs currently under development that might represent novel therapeutic options for the treatment of epilepsy.

Highlights

According to the International League Against Epilepsy (ILAE), epilepsy is a chronic brain disorder operationally defined by the occurrence of two unprovoked seizures more than 24 h apart, or one unprovoked seizure when the risk for another is known to be high (>60%) [1]
In addition to the well-known employment of Carbonic anhydrases (CAs) inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently been demonstrated that CAIs could be considered as valid therapeutic agents against obesity, cancer, kidney dysfunction, migraine, Alzheimer’s disease and epilepsy
We describe the known CAI clinically used in epilepsy therapy: acetazolamide (ACZ), see Figure 1, zonisamide (ZNS), methazolamide (MZA) and topiramate (TPM) [9]

Summary

Introduction

According to the International League Against Epilepsy (ILAE), epilepsy is a chronic brain disorder operationally defined by the occurrence of two unprovoked seizures more than 24 h apart, or one unprovoked seizure when the risk for another is known to be high (>60%) [1]. (3) It has been clearly shown that alkalosis generally potentiates seizures by increasing neuronal excitability, while acidosis has an opposite effect [52] Since their role is in the regulation of the CO2/ HCO3− buffer system, CAs are crucially involved in the control of neural excitability [17]. It has been reported that overproduction of reactive oxygen species (ROS) provokes the progressive disruption of Ca2+ homeostasis essential for neuronal survival In this context, it has been proposed that CAs, in particular CA VII might have a role in the cell defence against oxidative damage thanks to its cysteine residues [69]. What is certain is that CAs represent molecular targets for epilepsy and that the interference with their activity, through specific inhibitors (CAIs), has an anticonvulsive outcome

CA Inhibitors Clinically Employed in Epilepsy Therapy

Anticonvulsant CAIs Design Strategy

Findings

Conclusions