Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
30
Q. Wang et al.
seizures into ve stages: (1) mouth and facial movements, (2) head nodding, (3)
forelimb clonus, (4) standing, and (5) standing and falling, representing the transition from focal seizures to secondary generalized seizures [3].
The electrical stimulation kindling model allows specic exploration of brain
regions to understand their roles in the onset and occurrence of epilepsy. Additionally,
it serves as a valuable tool for screening anti-seizure drugs. This kindling process
induces progressive changes in the hippocampal neural circuitry [111]. Notably,
Goddard etal. [131, 136] reported that kindling-induced epileptic plasticity is similar to learning, implying that healthy brains learn pathological activity patterns during the kindling process.
1.4.3.2 Kindling Model
Both chemical and electrical stimulation can induce a decrease in the seizure threshold
in mice, known as the kindling phenomenon [132, 137]. Compared to electrical stimula-
tion, chemical kindling is more straightforward, requires no brain surgery or electrode
implantation and is less time-consuming [137]. As mentioned earlier, a single high-dose
(suprathreshold dose) injection of PTZ in rodents can induce acute seizures, while multiple low-dose (subthreshold dose) injections can decrease the seizure threshold [138].
Karler etal. [137] reported the kindling response induced by chronic PTZ injections in
CF-1 mice. In the PTZ-induced kindling model, a single low-dose injection of PTZ initiated mild epileptic seizures without convulsions [139, 140]. With an increasing number
of PTZ injections, the latency period for epileptic seizures decreases, the severity
increases, and ultimately, a single low- dose injection can trigger severe tonic–clonic
seizures [139, 140]. The commonly used intraperitoneal injection dose for PTZ kindling
in mice is 35mg/kg, and PTZ is administered daily or every other day, with consecutive
injections until the manifestation of tonic–clonic seizures [139, 140].
1.4.3.3 Optogenetic Kindling Model
Classic epilepsy models may cause tissue damage and lack the ability to discriminate between neuronal loss and epileptogenesis mechanisms [141, 142]. Moreover,
they can only be localized to specic brain areas and cannot activate or parse specic cell populations [141, 142]. The optogenetic kindling model seamlessly integrates the technical advantages of optogenetics with classic kindling practices. By
manipulating specic neuronal groups using light-sensitive proteins, such as
Channelrhodopsin-2 (ChR2), Halorhodopsin (NpHR), and Archaerhodopsin-3
(Arch) [142], a causal relationship between neuronal groups and epilepsy can be
established. ChR2 induces depolarization through cation inux upon exposure to
blue light, leading to neuronal activation. NpHR and Arch inhibit neuronal activity
by pumping chloride ions into and protons out of the neurons, respectively [143,
144]. Cela etal. [141] expressed ChR2in the mouse neocortex to develop an opto-
genetic kindling model. This model reproduces hallmark features of the classic
electrical stimulation kindling model, such as gradual increases in epileptic
1 Overview
31
electroencephalogram (EEG) and seizure severity over time and long-term susceptibility to seizures. Unlike the classic model, the optogenetic kindling model circumvents signicant brain damage and glial reactions [141].
1.4.4 Poststatus Epilepticus Models
Kindling models typically fail to induce chronic spontaneous seizures in animals.
Currently, epilepsy is generally speculated to encompass three stages: (1) initial
triggering events, (2) a latent period, and (3) chronic spontaneous seizures (Table1.5)
[145–149].
In the poststatus epilepticus model, status epilepticus (SE) is typically induced
by the injection of kainic acid (KA) or pilocarpine, resulting in the development of
chronic spontaneous recurrent seizures (SRSs) after an approximately one-month
latent period [151–153]. Kainic acid, which was isolated and extracted in 1953 from
the red alga Digenea simplex [154], stimulates ionotropic KA receptors, leading to
intense neuronal depolarization and eventual neuronal death. The hippocampal
damage caused by KA replicates the typical histopathological changes observed in
temporal lobe epilepsy (TLE) patients [152]. Administration methods for kainic
acid include systemic, intrahippocampal, or intra-amygdalar delivery, with intraamygdalar administration resulting in a lower survival rate. In rats, stereotaxic
injection of kainic acid into the hippocampus induces SE at doses of 0.4–2.0μg,
while systemic administration requires a high single injection dose of 6–15mg/kg
or multiple injections with a low dose of 5mg/kg [152, 155].
The pilocarpine model also induces hippocampal damage and is used for
studying TLE [156]. Pilocarpine acts as an agonist for muscarinic acetylcholine
receptors, with the M1 muscarinic acetylcholine receptor speculated to play a
role in initiating epileptic seizures [156, 157]. The pilocarpine model induces
Table 1.5 Three hypothesized stages of epileptogenesis
Stage of
epileptogenesis Denitions Characterizations
Initial precipitating
injury or
epileptogenic event
Latent period A latent period between
Chronic epilepsy A period characterized
An acute insult to the
brain that triggers the
epileptogenic process
[146, 149]
the initial injury and the
emergence of the rst
spontaneous seizure
[146, 147]
by the emergence of
spontaneous recurrent
seizures [147, 149]
The initial precipitating injury or epileptogenic
event includes head trauma, infection, stroke,
and prolonged febrile seizures [146]
The latent period involves wide cellular and
molecular changes, from gene transcription to
patterns of neuronal connectivity, which
inuence the excitability of the neuronal
network [146–148, 150]. This period usually
lasts for weeks, months or even years [145, 147]
The cellular and molecular changes have
produced reorganized synaptic circuitry, mossy
ber sprouting, and a hyperexcitable state [145]
32
Q. Wang et al.
injuries in the dentate gyrus, thalamus, and amygdala and degeneration of CA1
and CA3 hippocampal neurons, with seizures originating in the hippocampus
and spreading to the amygdala and neocortex [112]. The intraperitoneal injection dose for inducing seizures with pilocarpine is 300–400mg/kg [156], and
coadministration of lithium (3mEq/kg) 24hours before pilocarpine injection
signicantly reduces the required pilocarpine dose for inducing seizures to
30mg/kg [156].
In addition to chemical stimulation, continuous electrical stimulation of
the hippocampus or amygdala can also induce SE, leading to spontaneous
recurrent seizures after a seizure-free latent period [32, 158]. Compared to
chemically induced poststatus epilepticus models, electrical stimulation
models offer advantages in testing antiepileptic drugs because they circumvent potential interactions between proconvulsant chemicals and test compounds [158].
1.4.5 Genetic Models
Genetics plays a crucial role in human epilepsy, with the identication of numerous epilepsy-related genes through comprehensive whole-genome association
studies and sequencing [159, 160]. Genetic models involving the introduction of
gene mutations leading to seizures in animals offer valuable insights into the
mechanisms of genetic epilepsy. This, in turn, facilitates the development of antiepileptic therapies and contributes to the progress of precision medicine. Rodents,
particularly mice and rats, are species prevalently employed in genetic epilepsy
research [110].
1.4.5.1 Rodent Animal Models
Absence Seizure Models
Absence seizures are a representative subtype of inherited generalized epilepsy
[159]. Given their hereditary and spontaneous characteristics, genetic models more
closely parallel absence epilepsy than experimentally induced seizure models [111].
The tottering (tg) mutant mouse, which was initially utilized for studying hereditary
ataxia, has spontaneous epileptic seizures characterized by synchronous burst spikewave discharges (SWDs) in cortical electroencephalogram recordings concomitant
with absence seizures and focal motor seizures [161]. The tottering mouse serves as
a valuable animal model due to its analogous electrographic patterns, behavioral
manifestations, and pharmacological response to human absence epilepsy [162].
These strains harbor a mutation in the Cacna1a gene, which encodes the CaV2.1
channel α subunit, resulting in reduced CaV2.1 calcium current density [163]. The
commonly used Tottering-6j mouse model frequently exhibits absence-like
1 Overview
33
epileptic seizures, with slow-wave discharges in the bilateral cortex and abrupt cessation of behavior and gaze xation, accompanied by severe ataxia, rendering this
model suitable for investigating the pathogenic mechanisms of CaV2.1 channelrelated epilepsy and drug screening [164].
In 1982, Vergnes and collaborators [165] introduced the Genetic Absence
Epileptic Rats of Strasbourg (GAERs). These rats exhibited spontaneous absence
seizures characterized by cortical EEG spike-wave discharges at 6–7Hz coupled
with immobility. Sodium valproate, diazepam, and trimethadione have proven
effective in suppressing the spontaneous seizures of this model [166]. Additionally,
the GAERs model also exhibits anxiety-like behavior, social impairment, diminished learning capabilities, and heightened contextual and conditioned fear
responses, along with decits in cross-modal recognition memory and visual
attention functions [167].
Similarly, Wistar Albino Glaxo strain inbred Rijswijk (WAG/Rij) rats display
spontaneous absence seizures, featuring characteristics such as rapid breathing,
unexpected eye blinking, whisker twitching, and facial muscle spasms [168]. The
spike-wave discharges in WAG/Rij rats can be inhibited by ethosuximide, levetiracetam, and valproic acid. Due to their behavioral, electroencephalographic, and
genetic similarities to humans, the WAG/Rij rat model has been widely applied in
the study of genetic absence epilepsy, particularly in the context of childhood
absence epilepsy [169].
Reex Seizure Models
Numerous animal models and certain human epilepsies can be experimentally
induced by controlled stimuli, referred to as reex epilepsy [170]. According to
Irmen etal. [171], reex seizures are part of a conceptual continuum with spontaneous seizures. The primary triggers for human reex epilepsy are visual stimuli,
whereas in most rodents, reex seizures are elicited by auditory stimuli [172].
Consequently, audiogenic seizure (AGS) models have been developed in rodents,
notably in Dilute Brown non-Agouti (DBA/2) mice and genetically epilepsyprone rats (GEPRs).
DBA/2 mice exhibit genetic susceptibility to generalized AGS, increased sensitivity to convulsive seizures, and increased responsiveness to electrically and chemically induced seizures, making them valuable for screening drugs targeting
generalized seizures [111]. The sensitivity of DBA/2 mice to audiogenic seizures is
greatest in the early life stages (12–17days of age), peaking between 19 and 24days
of age and gradually decreasing thereafter [172]. By adulthood (>80days old), they
become completely resistant to auditory stimulation [172].
There are two subtypes of GEPRs: GEPR-3s and GEPR-9s. In GEPR-3s, the
endpoint of seizures is generalized clonus involving all four limbs, whereas in
GEPR-9s, seizures culminate in tonic hindlimb extension [111]. These heritable
reex models serve as a fundamental foundation for delving into the intricate mechanisms associated with neuronal hyperexcitability in epilepsy.
34
Q. Wang et al.
1.4.5.2 Nonrodent Animal Models
In addition to rodents, earlier research utilized diverse species, such as cats, dogs,
and nonhuman primates, as epilepsy animal models [110]. Recent studies have
broadened this scope, incorporating species such as fruit ies, zebrash, birds, sea
lions, and baboons [32, 110].
Baboon Photosensitive Epilepsy Model
Killam etal. [173, 174] reported photomyoclonic syndrome in baboons (Papio papio).
In the Casamance region of Senegal, a substantial proportion (60% to 80%) of adolescent baboons displayed myoclonic responses to intermittent photic stimulation (25
ashes/second), starting with rapid bilateral eyelid clonus, expanding to facial and neck
twitching, followed by limb tonic extension, and potentially evolving into generalized
clonus [175]. EEG recordings consistently revealed paroxysmal discharges characterized by multiple spikes or spike-wave patterns, accompanying photosensitive myoclonic
seizures [176]. The baboon model of photosensitive epilepsy serves as a valuable tool
for replicating human photosensitive myoclonus. Notably, myoclonic responses can be
effectively suppressed by primidone, phenobarbital, and benzodiazepine drugs, whereas
phenytoin and carbamazepine exhibit limited efcacy [175].
Zebrash Epilepsy Model
The zebrash, a straightforward vertebrate model organism, presents notable advantages in replicating genetic forms of epilepsy due to its simplied breeding and maintenance requirements, along with a greater reproductive capacity in comparison to rodent
models [110, 177]. The monitoring of zebrash seizure locomotor activity requires
automated behavioral tracking systems, and the characterization of brain activity is
accomplished by immobilizing zebrash in low-melting point agarose and implanting
microelectrodes into the optic tectum or forebrain for high- throughput local eld potential (LFP) recordings [178–180]. Therefore, the zebrash epilepsy model is ideal for
high-throughput antiseizure drug screening [179, 180]. Baraban and colleagues [181]
utilized zebrash with mutations in the voltage-gated sodium channel Scn1a gene
(scn1Lab mutant zebrash) as a model for Dravet syndrome to screen the effects of stiripentol, an inhibitor of zebrash seizures [181]. Their ndings revealed the action of
stiripentol on serotonin receptors, leading to the subsequent screening of topiramate and
clonazepam, which target the serotonin signaling pathway and may hold potential for
clinical treatment in patients with refractory Dravet syndrome [178]. In addition to
scn1Lab mutant zebrash, diverse mutant zebrash strains targeting other epilepsyrelated genes have been generated. Examples include UBE3A-mutant zebrash associated with Angelman syndrome, OCRL1-decient zebrash linked to Lowe syndrome,
UGP2-mutant zebrash associated with epileptic encephalopathy, and GABRG2knockout zebrash associated with light-induced reex seizures [182–185].
1 Overview
35
1.4.6 Trauma, Stroke, andInfection Models
The most common causes of acquired epilepsy in adults include traumatic brain
injury, stroke, and central nervous system infections [32]. These etiologies differ,
impacting patient responsiveness to antiepileptic drugs in clinical treatment [32].
Therefore, it is necessary to develop epilepsy animal models that replicate distinct
causes [32].
1.4.6.1 Posttraumatic Epilepsy Models
Traumatic brain injury (TBI) is a prevalent cause of refractory epilepsy in temporal
lobe epilepsy patients [186]. Common posttraumatic epilepsy (PTE) models include
the uid percussion injury (FPI) model, the controlled cortical impact (CCI) model,
and the impact-acceleration model. In comparison to experimentally induced seizure models, posttraumatic epilepsy models exhibit broader brain injuries, accompanied by cognitive and neuropsychiatric symptoms [186, 187].
Fluid Percussion Injury Model
The uid percussion injury model induces TBI by exposing the intact dura mater
to uid pressure pulses through craniotomy, resulting in neuronal damage and
epilepsy [188]. The FPI model primarily induces secondary generalized seizures
rather than partial seizures [189]. D’Ambrosio et al. [190] described chronic
spontaneous recurrent seizures in rats following uid percussion-induced traumatic brain injury. The brain damage caused by uid percussion injury is similar
to that caused by temporal lobe epilepsy, including neuronal loss in the hippocampus and mossy ber sprouting [20, 158, 191]. However, the FPI model has limitations, including a low frequency of spontaneous seizures, a need for prolonged
EEG monitoring for spontaneous seizure events, and an apparent lack of predictive validity [189, 192].
Controlled Cortical Impact Model
In 1988, Lighthall and colleagues [193] described controlled cortical impact injury
using ferrets as test animals. In the 1990s, the CCI model was adapted for use in
various animals, including rats, mice, and primates [189]. The CCI model induces
varying degrees of brain injury by compressing the exposed brain using pneumatic
or electromagnetic impactors, mimicking various injuries associated with traumatic
brain injury, such as cortical tissue loss, acute subdural hematoma, axonal injury,
concussion, and blood–brain barrier dysfunction [192]. In addition to seizures, CCI
model rats also exhibit cognitive and motor impairments, with motor dysfunction
36
Q. Wang et al.
typically resolving within a few months post-CCI induction, while cognitive decits
may persist for an extended period, correlating with brain atrophy and a gradual
reduction in cerebral blood ow [112]. Similar to the FPI model, the CCI model has
a low frequency of spontaneous seizures [189], but it can exhibit unprovoked seizures and hippocampal pathological changes early after trauma (CCI: 10weeks
postinjury; FPI: several months) [192].
Impact Acceleration Model
The impact acceleration model represents a diffuse traumatic brain injury model
[189]. Animals are placed in a stereotactic frame, and a specic weight is dropped
from a designated height onto the exposed bare dura mater, also known as the
weight-drop model [112, 189]. The severity of brain injury induced by this model
can be controlled by adjusting the weight and height of the fall [194]. Despite the
simplicity and cost-effectiveness of the impact acceleration model, its shortcomings
are conspicuous, including high mortality rates, low reproducibility, and the incapacity to develop spontaneous seizures [189, 192, 194].
1.4.6.2 Poststroke Epilepsy Models
Poststroke epilepsy is a common clinical complication following stroke. Widely
used models for poststroke epilepsy include the middle cerebral artery occlusion
(MCAO) model and the photothrombotic model [195]. The MCAO model appears
to primarily simulate early-stage seizures, with only 1 out of 26 injured rats developing late-stage spontaneous seizures [195]. The photothrombotic model, which is
induced by intravenous injection of Rose Bengal dye to induce cortical photothrombosis, results in approximately half of the rats experiencing seizures after 1–2months
[195]. Posttraumatic epilepsy models and poststroke epilepsy models are less commonly used in preclinical pharmacological research, as only 20–50% of the model
animals develop seizures, rendering drug screening challenging [32, 195].
1.4.6.3 Postinfection Epilepsy Models
The Theiler’s murine encephalomyelitis virus (TMEV) model involves infecting
C57BL/6 mice with TMEV, which induces seizures through viral encephalitis [32,
196]. The seizures manifest in two stages: frequent acute seizures during the early
infection phase and less frequent late-stage seizures several months after brain
inammation, leading to long-term alterations in seizure susceptibility [32, 196].
The TMEV model alters long-term susceptibility to seizures [196]. This model
responds to anti-inammatory compounds such as minocycline and certain traditional antiseizure medications (e.g., phenytoin and gabapentin), providing a platform to evaluate new compounds for their anti-inammatory, antiseizure, or
1 Overview
37
combined mechanisms [196]. Another model in which acute seizures are induced
through infection utilizes a mature cerebral malaria mouse model in which infected
red blood cells are injected intraperitoneally to induce experimental cerebral malaria
[186, 197]. Due to the mice succumbing or dying within 1–2weeks after infection,
only early-stage seizures can be analyzed [186, 197]. Additionally, infection with
tetanus toxin in a rat motor cortex injection model can lead to long-term seizures
characterized by interrupted motor activity, rhythmic facial twitches, and sudden
cessation of movement [198]. Limitations of the tetanus toxin model include the
absence of typical hippocampal sclerosis and neuronal loss, as well as the limited
occurrence of spontaneous seizures [198].
To meet the demands of high-throughput research, epilepsy models have progressively expanded from intact animals to in vitro organotypic preparations,
referred to as invitro models. These models utilize exvivo brain tissue slices, primary neuronal cultures, human embryonic stem cells (hESCs), or induced pluripotent stem cell (iPSC)-derived neurons or organoids and are increasingly employed
for epilepsy modeling and drug screening purposes [199, 200]. iPSC-induced neuronal models are often coupled with multiple electrode array (MEA) technology to
assess spontaneous discharge activity, epileptiform burst discharge, and other
epilepsy- like phenotypes, enabling high-throughput testing of drug responses [200].
From early acute seizure models to chronic kindling models and further to poststatus epilepticus models, genetic models, and trauma-induced models, animal
models have replicated distinctive features of epilepsy. However, to date, there is no
model that perfectly meets the criteria of face validity, construct validity, and predictive validity. Due to the complexity of epilepsy, the choice of animal model can
be tailored based on specic practical needs. With the continuous advancement of
new technologies, the future of epilepsy animal models remains promising from
face validity to construct validity and potentially expanding to predictive validity.
This progression aims to provide valuable insights into the mechanisms underlying
epilepsy and the development of new therapies, ultimately enhancing the quality of
life for individuals with epilepsy.
1.5 Antiseizure Medication Mechanisms ofAction
Epilepsy is one of the most common and disabling chronic neurological disorders.
There are 50 to 70 million people with epilepsy worldwide, and the disease traverses the entire lifespan [201]. Antiseizure medications (ASMs) are currently the
main treatment modality. They act on various mechanisms and molecular targets
involved in neuronal excitability to suppress abnormal hyperexcitability and hypersynchrony in brain circuits, thereby controlling epileptic seizures. In the past century, the discovery of ASMs has progressed from early serendipitous ndings to
the application of animal model screening and, currently, to rational development
[201]. Most of the medications currently used to treat epilepsy control symptoms
(seizures), but they have no known effect on the disease processes of patients at
38
Q. Wang et al.
risk of developing epilepsy or patients with epilepsy. Therefore, in recent years, we
have used the term “antiseizure medications” (ASMs) to replace antiepileptic
drugs [202, 203]. To date, there are more than 30 different antiseizure medications
available for clinical selection [204]. With the increasing number of antiepileptic
drugs, it is essential to understand their mechanisms of action and pharmacokinetics and how they interact with one another for precise individualized drug treatment of epilepsy. This section summarizes the mechanisms of antiseizure
medications that have been applied in clinical practice and briey discusses the
interactions between various drugs. Finally, we will briey outline the future
development directions of antiepileptic drugs. Epileptic activity manifests as intermittent and excessive excitation of cortical networks, limbic system networks or
more diffuse networks. Existing antiseizure medications have been clearly classied into four major mechanisms: 1) regulation of voltage-gated ion channels, 2)
attenuation of glutamate-mediated excitatory neurotransmission, 3) modulation of
neurotransmitter release by presynaptic action, and 4) enhancement of
γ-aminobutyric acid (GABA)-mediated inhibitory neuronal function. In this chapter, we will discuss the antiseizure medications that have been used clinically,
based on the above mechanisms.
1.5.1 Voltage-Gated Ion Channel Modulation Mechanism
1.5.1.1 Blocking Voltage-Gated Sodium Channels
Voltage-gated sodium channels (VGSCs) are transmembrane proteins that can be activated to form ion channels when the nearby membrane potential changes. They are
essential for generation and conduction of action potential and expressed throughout
the entire neuronal membrane, including that of dendrites and axons [205]. VGSCs
exist in one of three basic conformational states: (1) at hyperpolarized potentials, the
channel is usually in a resting, closed state; (2) when depolarized, the channel transitions to an open state, allowing sodium ions to permeate; and (3) after depolarization,
the channel enters a closed, nonconductive inactivated state [206]. In a single round of
depolarization, the channel cycles through these states—from rest to open, from open
to inactivated, and from inactivated to rest. When the neuron is at rest or inactivated,
sodium ions cannot pass through the channel. Sodium ion channels can be subdivided
into fast inactivation channels and slow inactivation channels [207].
Some antiseizure medications are sodium channel inhibitors. They bind to an
inactivated voltage-gated channel after neuronal depolarization and change its permeability to sodium ions, thereby reducing the inward ow of sodium ions. This
leads to an increase in the inactivation (or refractory) period of frequently ring
neurons [208]. The main mechanism of action for drugs such as phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate, zonisamide, phenobarbital, and
lacosamide involves controlling the fast inactivation of voltage-gated sodium channels. In contrast, drugs such as lacozamide and eslicarbazepine acetate act by
1 Overview
39
controlling the slow inactivation of sodium channels to reduce neuronal hyperexcitability and, consequently, control seizures [209]. Recent research indicates that
cenobamate also has an inhibitory effect on sodium ion channels [210].
Research has shown that a common characteristic of anti-seizure medications
that act as sodium channel blockers is their preferential afnity for the channel
when it is in an inactivated state [211]. Once bound to the channel, these medications block the process of channel reactivation, thereby limiting the repetitive ring
of neurons. This action has little effect on the generation of single action potentials
or low-frequency (less than 1Hz) ring [212]. Runamide is a prototypical agent
that induces the slow inactivation of sodium ion channels. As epileptic seizure discharges occur on a timescale of seconds, the slow action of runamide may confer
greater selectivity for epileptogenic action potential discharges than for nonepileptogenic discharges, potentially enhancing efcacy and reducing side effects, thus
increasing patient tolerance [213].
1.5.1.2 Blocking Voltage-Gated Calcium Channels
Voltage-gated calcium channels (VGCCs) mediate the inux of calcium ions, leading to membrane depolarization and regulating intracellular processes in many different cell types. The activity of calcium channels is crucial for the coupling of
surface electrical signals with intracellular physiological events. Calcium channels
are widely expressed in brain tissues, participate in neuronal burst ring, and are
responsible for controlling the release of neurotransmitters from presynaptic nerve
terminals and neuronal structural plasticity [214, 215]. There are four main types of
voltage-gated calcium channels in the human brain. L-type, P/Q-type, and N-type
calcium channels are high-voltage-activated calcium channels (high-voltageactivated HVA) that respond to strong depolarization. L-type channels are composed of the α1 subunit of the CaV1 family, while P/Q-type and N-type channels are
composed of CaV2.1 and CaV2.2 subunits [216]. Low-voltage-activated T-type calcium channels (low-voltage-activated LVA) include the α1 subunit of the CaV3
family, which opens at the resting membrane potential or undergoes moderate depolarization and then rapidly inactivates, generating transient (hence T-type) currents
involved in intrinsic oscillatory activity [217]. Numerous studies have shown that
T-type calcium channels play a key role in the generation of thalamocortical hypersynchronous oscillatory activity, which is the basis for epileptic seizures, especially
absence seizures [218–220]. Voltage-gated calcium channels are therapeutic targets
for several clinical antiepileptic drugs. Zonisamide and ethosuximide block T-type
calcium channels in a voltage-dependent manner, have greater afnity for channels
in the inactivated state and block voltage-gated sodium channels, thereby increasing
the threshold for the generation of action potentials [221]. Zonisamide-mediated
blockade of T-type calcium channels is considered one of its mechanisms of action
against epileptic seizures. Gabapentin and pregabalin bind with high afnity to the
2–1 subunit of voltage-gated calcium channels, which is considered one of the
mechanisms of these drugs against epileptic seizures [221]. Research has shown