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

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.

Voltage-Gated Potassium Channels as Regulators of Cell Death

Ion channels allow the flux of specific ions across biological membranes, thereby determining ion homeostasis within the cells. Voltage-gated potassium-selective ion channels crucially contribute to the setting of the plasma membrane potential, to volume regulation and to the physiologically relevant modulation of intracellular potassium concentration. In turn, these factors affect cell cycle progression, proliferation and apoptosis. The present review summarizes our current knowledge about the involvement of various voltage-gated channels of the Kv family in the above processes and discusses the possibility of their pharmacological targeting in the context of cancer with special emphasis on Kv1.1, Kv1.3, Kv1.5, Kv2.1, Kv10.1, and Kv11.1.

Minimum conditions for the induction of cortical spreading depression in brain slices

Cortical spreading depression (CSD) occurs during various forms of brain injury such as stroke, subarachnoid hemorrhage, and brain trauma, but it is also thought to be the mechanism of the migraine aura. It is therefore expected to occur over a range of conditions including the awake behaving state. Yet it is unclear how such a massive depolarization could occur under relatively benign conditions. Using a microfluidic device with focal stimulation capability in a mouse brain slice model, we varied extracellular potassium concentration as well as the area exposed to increased extracellular potassium to determine the minimum conditions necessary to elicit CSD. Importantly, we focused on potassium levels that are physiologically plausible (≤145 mM; the intracellular potassium concentration). We found a strong correlation between the threshold concentration and the slice area exposed to increased extracellular potassium: minimum area of exposure was needed with the highest potassium concentration, while larger areas were needed at lower concentrations. We also found that moderate elevations of extracellular potassium were able to elicit CSD in relatively small estimated tissue volumes that might be activated under noninjury conditions. Our results thus show that CSD may be inducible under the conditions that expected in migraine aura as well as those related to brain trauma.