About five million people are diagnosed with epilepsy globally each year. Epilepsy occurs when the brain experiences excessive electrical activities between neurons, causing recurrent seizures. Anti-seizure medications prevent abnormal brain activity and restore neurotransmission balance.
Download this poster from Drug Discovery News to explore the mechanisms underlying seizures and how different anti-seizure treatments work in the brain.
Stopping power surges in the brain
How do seizures occur, and how do anti-seizure drugs work?
By Yuning Wang, PhD
Illustrated by Julie Davie
Electrical Activity
Neurons transmit electrical signals through membrane depolarization caused by a rapid flow of sodium ions into the cell through voltage-gated sodium channels. This depolarization opens voltage-activated calcium channels, allowing calcium ions to enter the cell and trigger neurotransmitter release from synaptic vesicles at the synaptic cleft. Once the depolarization is complete, the cell resets by expelling potassium ions through the voltage-gated potassium channel. The neurotransmitters released during this process have excitatory or inhibitory effects on the postsynaptic membrane.
What Causes Seizures?
Normal brain function relies on a precise balance between excitatory and inhibitory neurotransmission. Seizures typically occur when increased excitation or decreased inhibition disrupts the balance. Genetic mutations and physiological conditions that lead to dysfunctional channels, receptors, and signaling pathways associated with neurotransmission can all cause imbalances (1). As a result, large groups of neurons become overly active and fire excessively. More than 30 anti-seizure medications have been developed to restore the balance via different targets (2)
Excitatory
Neurotransmission Excitatory neurotransmitters such as glutamate bind to receptors on the postsynaptic cell membrane, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) ion channels, allowing sodium and calcium ions to enter and excite the cell to fire an action potential.
Drug Target 1: Sodium
Channel Blockade Many anti-seizure drugs work by preventing the return of sodium channels to an active state, thereby inhibiting membrane depolarization (3).
Drug Target 2: Calcium
Channel Blockade Scientists developed several calcium channel antagonists that block calcium channels to attenuate neuronal firing (3, 4).
Drug Target 3: Modulating
Synaptic Vesicle Proteins Some drugs bind to presynaptic vesicle proteins to inhibit the trafficking of synaptic vesicles, thus decreasing neurotransmitter release (3).
Drug Target 4: Inhibiting
Glutamate Receptors Researchers use NMDA or AMPA receptor blockers as therapeutics to prevent glutamate binding and inhibit excitatory neurotransmission (3)
Inhibitory Neurotransmission
Inhibitory synapses respond to γ-aminobutyric acid (GABA). GABA binds and opens GABA type A (GABAA) receptors, which are ligand-gated ion channels that are selectively permeable to chloride ions. Chloride ions enter the postsynaptic cell, diminishing the chance of an action potential.
Drug Target 5: Activating Potassium Channels
Potassium channels are promising targets for novel anti-seizure treatments such as potassium channel activators and gene therapy (5).
Drug Target 6: Enhancing GABA-Mediated Inhibition
Several drugs act on GABAA receptors as positive allosteric modulators to increase the channel opening frequency, resulting in enhanced inhibitory neurotransmission (3).
References
1. Stafstrom, C. E. & Carmant, L. Seizures and Epilepsy: An Overview for Neuroscientists. Cold Spring Harb Perspect Med 5, a022426 (2015).
2. Löscher, W. & Klein, P. The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond. CNS Drugs 35, 935–963 (2021).
3. Rogawski, M. A., Löscher, W. & Rho, J. M. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med 6, a022780 (2016).
4. Tringham, E. et al. T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures. Science Translational Medicine 4, 121ra19-121ra19 (2012).
5. Köhling, R. & Wolfart, J. Potassium Channels in Epilepsy. Cold Spring Harb Perspect Med 6, a022871 (2016).