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40
Q. Wang et al.
that inhibiting presynaptic calcium channels reduces the release of excitatory neurotransmitters, which may be one of the mechanisms underlying the antiepileptic
activity of gabapentin-like calcium channel blockers, but the underlying mechanism
is still unclear [222]. Reports have shown that lamotrigine can block N- and P/Q- type calcium channels at presynaptic nerve terminals, thereby reducing the release
of glutamate to exert its anticonvulsant effect [223–225]. In addition, phenobarbital
and topiramate can block L-type and N-type calcium currents [215].
1.5.1.3 Voltage-Gated Potassium Channel Enhancement
Potassium ion channels exhibit high heterogeneity and represent a complex class of
ion channels. There are multiple subtypes throughout the nervous system, each of
which plays different roles in various types of neurons and different brain regions.
Therefore, developing drugs targeting specic subtypes is highly challenging.
Currently, the only clinically used antiseizure medication that enhances voltagegated potassium ion channels is retigabine, but many studies are underway to
develop novel potassium channel enhancers [226].
Retigabine, acting as a positive allosteric modulator (or opener) of potassium ion
channels, is the only clinically approved antiseizure medication that acts on KCNQ
channels [227]. It is used to treat focal-onset seizures in adults. Its mechanism of action
involves enhancing the voltage-gated potassium channels of the Kv7 subfamily, increasing their repolarization rate, and reducing their subsequent inactivation rate [228].
1.5.2 Blocking Excitatory Neurotransmission
A widespread feature of epilepsy is abnormal neuronal excitability, with glutamate
being the primary excitatory neurotransmitter in the adult human brain. Therefore,
in the study of antiseizure medications, researchers have shown signicant interest
in drugs affecting glutamate receptor ion channels, aiming to explore the possibility
of controlling seizures by blocking glutamate transmission [229, 230].
Glutamate exerts its excitatory effects through ligand-gated ion channels and
metabotropic receptor subtypes. Among the postsynaptic ligand-gated ion channels,
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors
(AMPARs) are crucial for fast excitatory neurotransmission, while N-methyl-Daspartate (NMDA) receptors (NMDARs) mediate many globally important slow
postsynaptic excitatory potentials [231]. However, the function of kainate receptors,
although capable of modulating excitability at both presynaptic and postsynaptic
sites, remains unclear [232, 233].
Perampanel is a noncompetitive AMPAR antagonist that reduces neuronal excitability and synchronous features of epileptic-like activity [234, 235]. It was the rst
drug specically approved for controlling seizures by blocking glutamate receptors
[236–238]. Perampanel binds to the extracellular region of AMPARs, distinct from
the glutamate recognition site, in a voltage-independent manner. Its binding induces
1 Overview
41
conformational changes in AMPAR subunits, restricting their ability to convert agonist (i.e., glutamate) binding into channel opening. The ultimate result is a reduction
in fast excitatory neurotransmission, limiting the generation of seizures and the spread
of epileptic discharges [239]. Experimental evidence has shown that perampanel
blocks only a small fraction of AMPAR currents, preserving the majority of normal
synaptic transmission while sufciently slowing epileptic-like discharges [240].
In addition to perampanel, several other antiseizure medications exert their
effects by modulating glutamatergic neurotransmission. Although the exact mechanism of action of felbamate is not fully understood, it is speculated to have several
potential modes. Its primary antiseizure activity is thought to involve the modulation of NMDA receptors, which reduce glutamate transmission. Other effects
include enhancing the action of gamma-aminobutyric acid (GABA) and inhibiting
voltage-gated sodium and calcium channels [215, 241, 242].
Topiramate (TPM) demonstrates broad efcacy in refractory partial and secondary generalized seizures. It can reduce the excitatory effects of glutamate through
AMPA receptors [243]. Additionally, TPM blocks sodium channels, enhances
GABA-A receptor-mediated inhibition, inhibits high-voltage calcium channels, and
inhibits carbonic anhydrase [244].
1.5.3 Modulation ofNeurotransmitter Release
Because neural functional conduction occurs through electrochemical means, selectively reducing the release of neurotransmitters (such as glutamate) from presynaptic nerve terminals can signicantly inhibit the excitability of neural activity. Some
antiepileptic drugs act through this pathway to control seizures.
Levetiracetam and brivaracetam primarily achieve their antiepileptic effects by
binding to the synaptic vesicle protein SV2A, reducing the release of neurotransmitters [245, 246]. The interaction of levetiracetam with SV2A can decrease the release
of synaptic vesicles in rapidly ring neurons during repetitive stimulation. Because
levetiracetam restricts the release of glutamate and GABA in an activity-dependent
manner, its impact on rapidly ring neurons is most signicant, consistent with the
selective inhibition of epileptic-like activity [246–249]. However, the exact mechanism by which SV2A inhibits vesicle release remains unclear, mainly due to the
uncertain physiological role of SV2A despite extensive research.
Brivaracetam is a selective, high-afnity ligand for SV2A with excellent antiepileptic properties and rapid onset of action. Experiments have shown that brivaracetam has a greater afnity for SV2A than does levetiracetam [250]. Animal studies
have demonstrated that, compared to levetiracetam, brivaracetam has a 15- to 100fold greater afnity for SV2A [250, 251]. Additionally, brivaracetam restricts the
release of neurotransmitters in an activity-dependent manner [250].
In addition to the abovementioned antiepileptic drugs that bind to SV2A,
lamotrigine can also inhibit the release of neurotransmitters from presynaptic terminals. However, further experimental data are needed to conrm whether this effect
is mediated by SV2A [252].
42
Q. Wang et al.
1.5.4 Improving Neuronal GABAergic Inhibitory Function
The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) plays a crucial
role in the control of neuronal excitability in the mammalian brain. Disruption of
GABAergic neurotransmission has been implicated in the pathogenesis or manifestation of various neurological disorders, including epilepsy.
GABA, an amino acid, serves as the primary inhibitory neurotransmitter in the
central nervous system. It induces hyperpolarizing inhibition in nearly all neurons,
leading to a reduction in neuronal excitability. GABA exerts its effects on GABA
receptors located postsynaptically to GABAergic neurons. These GABA receptors
are considered the principal inhibitory receptors in the central nervous system and
are classied as GABA-A, GABA-B, and GABA-C receptors [253, 254]. GABA-A
receptors are ligand-gated ion channels and are members of the classic “Cys-loop”
receptor family. GABA-A receptors mediate transient, fast-desensitizing currents
(phasic inhibition) [255]. In contrast to GABA-A receptors, GABA-B receptors
couple to potassium channels through G proteins, mediating slow hyperpolarization
of the postsynaptic membrane [256]. The most critical component in the regulation
of epileptic activity within the GABA system is the GABA-A receptor. Mutations in
genes, neurodegeneration causing GABA receptor damage, or the use of GABA
receptor antagonists can impair GABAergic transmission and induce seizures, while
drugs that enhance GABAergic transmission are used to treat epilepsy [257, 258].
Following GABA release, the extracellular GABA concentration is regulated by
GABA transporters. GABA transporters on the cell membrane help regulate the
extracellular GABA concentration by reabsorbing GABA.They transiently bind
with GABA in the extracellular matrix and transport the neurotransmitter to the
cytoplasm, reducing GABA levels in the synaptic cleft. Thus, factors affecting presynaptic GABA release, postsynaptic GABA receptor function, and GABA reuptake and clearance may contribute to neuronal excitation leading to epileptic
seizures, and the development of some antiepileptic drugs is targeted at these processes. After GABA is reabsorbed, it can be recycled into the readily releasable
neurotransmitter pool or converted to succinic semialdehyde by the mitochondrial
enzyme GABA transaminase, rendering it inactive.
In the mature brain, the binding of GABA to GABA-A receptors induces an
inward ow of Cl
level to a low intracellular level. Compared to those in the mature brain, the activation of GABA-A receptors in the immature brain is primarily depolarizing and
potentially epileptic due to the ow of chloride ions from a high intracellular level
to a low extracellular level [259].
−
, driven by its concentration gradient from a high extracellular
1.5.4.1 Modulation ofGABA-A Receptors
Some antiepileptic drugs that act on GABA-A receptors are primarily positive allosteric modulators. In the absence of GABA, they do not activate the receptor [260].
However, when synaptic release of GABA increases, these drugs can enhance
1 Overview
43
inhibitory neurotransmission. Benzodiazepines (such as clonazepam, clorazepate,
diazepam, and midazolam) and barbiturates are positive allosteric modulators of
GABA-A receptors. Upon binding to the GABA-A receptor, these drugs augment
the response to GABA, enhancing chloride ion inux. Barbiturates and benzodiazepines exhibit functional distinctions, with the former prolonging the duration of
chloride channel opening and the latter increasing the frequency of channel opening
[261]. There are reports suggesting that primidone is also a positive allosteric modulator of GABA-A receptors [262].
1.5.4.2 Increasing GABA Levels andInhibiting Reuptake andConversion
Löscher etal. reported that the most convincing mechanism through which primidone exerts its antiepileptic effects is by inuencing the content of GABA at synapses, either by increasing GABA neurotransmitter synthesis or release or inhibiting
its degradation [263]. Vigabatrin is an irreversible inhibitor of GABA transaminases. It increases brain GABA levels by inhibiting GABA transaminase, the major
enzyme responsible for degrading GABA, without signicantly affecting other
enzymes involved in GABA synthesis and metabolism [264]. Tiagabine is a GABA
uptake inhibitor. By selectively inhibiting the GAT-1 GABA transporter, this drug
blocks the reuptake of GABA by neurons and glial cells, with little activity against
GAT-2, GAT-3, or BGT-1 [265]. By slowing the reuptake of synaptic GABA, it
prolongs inhibitory postsynaptic potentials [266]. The temporary prolongation of
synaptic endogenous GABA release by blocking GABA uptake is a known mechanism of action for tiagabine in the treatment of seizures [267].
1.5.4.3 Carbonic Anhydrase Inhibitors
Carbonic anhydrase inhibitors (CAIs) are a class of drugs used to treat certain types
of seizures. These enzymes act by inhibiting the activity of carbonic anhydrase, an
enzyme involved in regulating acid–base balance in the body. CAIs are most commonly used to treat certain types of seizures, such as absence seizures and myoclonic seizures. The exact mechanism by which carbonic anhydrase inhibitors
control seizures is not fully understood [268–270].
Acetazolamide (ACZ) is a noncompetitive inhibitor of carbonic anhydrase.
Although it has achieved some success as an antiepileptic drug, especially in the
treatment of pediatric and chronic epilepsy, its use is limited due to tolerability
issues [271]. Acetazolamide induces acidication of intracellular and extracellular
environments, thereby activating acid-sensitive ion channels, which may contribute
to its antiepileptic effects [268–270]. Topiramate (TPM) and zonisamide (ZNS) are
effective antiepileptic drugs. Although their antiepileptic mechanisms are often
classied as blockades of voltage-gated sodium ion channels, they are also effective
nonspecic CA inhibitors. Therefore, their antiepileptic actions are strongly attributed to their carbonic anhydrase inhibition properties [269, 272, 273].
44
Q. Wang et al.
1.5.5 Other Mechanisms
The mechanisms of action of some clinically used antiepileptic drugs may involve
multiple pathways, or their mechanisms are not yet fully understood.
Everolimus is an inhibitor of mammalian target of rapamycin complex 1
(mTORC1) [274, 275]. As a protein kinase, mTOR plays a crucial role in cell
growth, differentiation, and metabolism. Everolimus interferes with the abnormal
growth and division of cells by inhibiting the activity of mTOR kinase. Therefore,
it is used in some cases for the treatment of epilepsy, particularly in patients with
tuberous sclerosis complex (TSC), helping to reduce the frequency of seizures in
TSC patients [274, 276, 277].
Cannabidiol (CBD, marketed as Epidiolex) is a major component of cannabinoids. It was approved by the US Food and Drug Administration (FDA) as a novel
antiepileptic drug in 2018 and is used for the treatment of certain severe pediatric
epilepsy syndromes, such as Dravet syndrome, Lennox-Gastaut syndrome, and seizures associated with TSC [278–281]. Despite being the rst cannabinoid preparation approved by the FDA for epilepsy treatment, its exact mechanism of action
remains unclear.
Studies have indicated that cannabinoids exert their effects by stimulating
two receptors in the endocannabinoid system, cannabinoid receptor type 1
(CB1) and type 2 (CB2). CBD reportedly primarily binds to CB1 receptors on
presynaptic neurons. This binding leads to the activation of presynaptic T-type
calcium channels and subsequent inhibition of neurotransmitter release [282].
Although most recent studies have suggested that cannabinoids act through CB1
receptors for their antiepileptic effects, recent research has reported that CB2
receptors, which are expressed at lower levels in the central nervous system
under normal conditions, can be induced to have higher expression under epileptic conditions. Therefore, CB2 receptors might also be a target for antiepileptic drugs [283].
The recently FDA-approved drug cenobamate (CNB) is considered a highly
effective treatment for focal-onset seizures, achieving seizure control in more than
20% of drug-resistant epilepsy patients. Because CNB was discovered based on
phenotype screening, its mechanism of action is not well-understood. However, it is
speculated to have a dual mechanism of action, acting as both a voltage-gated
sodium channel inhibitor by blocking sodium ion currents [284] and a positive allosteric modulator of GABA-A receptors, independent of the benzodiazepine binding
site [285]. It effectively enhances (tonic) inhibition of hippocampal neurons, which
may be a potential molecular mechanism for stabilizing the hippocampal neural
circuit in epilepsy. Due to CNB’s terminal half-life of 50–60hours, it can be taken
once daily, reducing the frequency of administration and improving patient compliance [286].
Ganaxolone (Ztalmy) is a synthetic neuroactive steroid used to treat seizures in
patients with cyclin-dependent kinase-like 5 (CDKL5) deciency disorder (CDD).
Its mechanism of action involves serving as a positive allosteric modulator of
1 Overview
45
GABA-A receptors [287]. Ganaxolone operates similarly to the endogenous neurosteroid allopregnanolone, binding to a unique recognition site on GABAA receptors
distinct from the binding sites of benzodiazepine drugs and barbiturate drugs. Upon
binding, ganaxolone produces antiepileptic effects by increasing the inhibitory
effect of GABA [287, 288].
1.5.6 Conclusion
In this chapter, we have summarized and determined the mechanisms of action of
antiepileptic drugs currently applied in clinical settings. In the early history of
human use of antiepileptic drugs, relatively few drug options were available, making the selection process less challenging. However, with the continuous development of novel antiepileptic drugs, there are now more than 30 drugs used in
clinical practice. While the emergence of new drugs provides more choices for the
treatment of epilepsy patients, it also increases the difculty for clinicians in
selecting appropriate medications. Therefore, understanding the mechanisms of
action for each drug, interactions between drugs, how to control side effects, and
individualized drug formulation for patients with different etiologies is crucial.
Additionally, despite the continuous development of novel antiepileptic drugs,
with reduced drug toxicity and improved patient compliance, neither the rate of
seizure control nor the proportion of drug-resistant patients has signicantly
decreased [289–291].
The reasons for the onset and development of epilepsy are not yet clear, and most
antiepileptic drugs are identied through screening in epilepsy animal models.
There is currently no treatment that can prevent or terminate epilepsy and its related
complications. Therefore, achieving a cure for epilepsy through the application of
antiepileptic drugs remains unattainable. Complete control of seizures or addressing
the root cause of epilepsy is the ultimate goal of treatment. To achieve this goal, the
development of effective and safe antiepileptogenic (AEG), disease-modifying
(DM), and/or seizure-preventative treatment drugs has been recognized as a high
priority in epilepsy research [292, 293].
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