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Anticonvulsant Effects of Carbonic Anhydrase Inhibitors: The Enigmatic Link Between Carbonic Anhydrases and Electrical Activity of the Brain

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Abstract

Acetazolamide (ACZ), a sulfonamide carbonic anhydrase (CA) inhibitor, was first introduced into medical use as a diuretic in the1950s. Shortly after its introduction, its antiglaucoma and anticonvulsant properties came to light. Subsequently, studies of ACZ have explored a plethora of neurophysiological functions of CAs in the CNS. In addition, topiramate (TPM) and zonisamide (ZNS), which were developed as antiepileptic drugs (AEDs) in the1990s, were found to have the ability to inhibit CAs. How CA inhibition prevents seizures is elusive. CA expression and activity are extensively detected in neurons, the choroid plexus, oligodendrocytes and astrocytes. TPM and ZNS appear to produce multimodal actions in the CNS as well as CA inhibition unlike ACZ. Nonetheless, CA inhibitors share some common denominators. They do not only affect the fine equilibrium among CO2, H+ and HCO3− in the extraneuronal and intraneuronal milieu, but also modulate the activity of ligand gated ion channels at the neuronal level such as GABA-A signaling through inhibiting CA-replenished HCO3− efflux. In addition, there are studies reporting their ability to alter Ca2+ kinetics through modulation of ligand gated Ca2+ channels, voltage gated Ca2+ channels (VGCC) or Ca2+-induced Ca2+ release channels (CICRC). The present study will review the involvement of CAs in the formation of epileptogenesis, and likely mechanisms by which CA inhibitors suppress the electrical activity of the brain. The common properties of CA inhibitors provide some clues for a possible link among metabolism, CAs, Ca2+ and GABA signaling.

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Ozsoy, H.Z. Anticonvulsant Effects of Carbonic Anhydrase Inhibitors: The Enigmatic Link Between Carbonic Anhydrases and Electrical Activity of the Brain. Neurochem Res 46, 2783–2799 (2021). https://doi.org/10.1007/s11064-021-03390-2

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