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\begin{document}

\title{Animal models in Epilepsy}



\author[1]{Jefry Winner G}%
\author[2]{Anusha Natarajan}%
\affil[1]{JIPMER}%
\affil[2]{Jawaharlal Institute of Postgraduate Medical Education and Research}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Epilepsy, characterized by recurrent seizures, encompasses various
complex syndromes with varied origins. To unravel the intricate biology
of epilepsy and explore novel Antiseizure treatments, researchers have
developed over 100 in vitro and in vivo epilepsy models, each simulating
different seizure types. These experimental models serve as
indispensable tools for investigating the neurochemical,
neurophysiological, cellular, and molecular mechanisms governing
epileptic seizures, offering a comprehensive understanding of this
condition. This article provides a comprehensive overview of diverse
experimental models crucial for studying Antiseizure Medication and
seizures, including Generalized Tonic-Clonic Seizure (GTCS), Temporal
Lobe Epilepsy (TLE), Absence Seizure, Myoclonus, and Status Epilepticus
(SE) Models. Researchers leverage these models to gain critical insights
into epilepsy's underlying causes, available therapies, and potential
therapeutic targets. The study digs into a thorough analysis of the
benefits and drawbacks related to various chemical models used in
epilepsy treatment. This dual approach adds to the continuing discussion
in epilepsy research by clarifying the complicated issues surrounding
therapeutic strategies and improving our understanding of the complexity
of epilepsy. This article includes discusses GTCS, SE, and TLE subtypes
such as WAG/Rij rats, coriaria lactone-induced TLE, pilocarpine-induced
TLE, Tottering 6j mouse, GHB-induced seizure model, PTZ-induced model,
NMDA-induced seizure models, and flurothyl-induced seizure model.
Penicillin-induced TLE, Theiler's virus-induced TLE, and many more.%
\end{abstract}%



\sloppy


\textbf{1. Introduction}

Epilepsy is a neurological condition marked by recurrent seizures. A
seizure is typically described as an abrupt shift in behavior~brought on
by a transient disruption in the electrical activity of the brain. The
brain typically continuously produces minute electrical impulses that
follow a predictable pattern. Epilepsy is world's most prevalent chronic
neurologic disorders, epilepsy is thought to impact nearly 70 million
individuals globally \textbf{{[}1{]}} . Females and males experience the
exact prevalence (46.2 per 100,000 against 50.7 per
100,000)\textbf{{[}2{]}} .~In the US, 1.2\% of the population, including
more than 500,000 women of reproductive age, have an active epilepsy
diagnosis \textbf{{[}3{]}} . One of the most prevalent neurologic
conditions that typically necessitates ongoing therapy is
epilepsy\textbf{{[}4{]}} . EEG abnormalities and clinical abnormalities
are frequently seen in conjunction \textbf{{[}5{]}} . Recurrent seizure
events can damage neurons and necrosis \textbf{{[}6{]}} . Cerebral
dysfunction worsens, and potentially fatal consequences significantly
burden the patients' famil\textbf{ies {[}7{]}} .

Animal models play a crucial part in comprehending the biology of
epilepsy, including developing novel Antiseizure
medications\textbf{{[}8{]}.} Even though several novel Antiseizure
medicines (ASMs) have been developed successfully in recent years,
finding new treatments that are more effective and tolerable is still a
top priority

\textbf{{[}9{]}.}

Preclinical usage of animal models is crucial for discovering and
developing new ASMs to determine their efficacy and safety before
initial human trials \textbf{{[}10{]}} . Animal models have served as
the basis for the discovery of numerous innovative treatments for
epilepsy during the past 80 years \textbf{{[}11{]}.} The importance of
animal models in developing ASMs also shows that animal models react to
ASMs similarly to human seizures, which is a necessary condition for any
medication development program but is frequently disregarded in the
clinical setting. Animal models for other central nervous system (CNS)
illnesses, such as bipolar disorders or migraine, do not have the same
high predictive value \textbf{{[}9{]}.}

Inside animals, the enormous phenotypic variety and known naturally
occurring diseases of any land mammal other than humans are seen in
domestic dogs (Canis lupus familiaris), making an excellent
translational medicine model \textbf{{[}12{]}} . Dogs are also the
principal non-rodent species used in preclinical drug development,
notably for testing drug efficacy, pharmacokinetics, and
safety\textbf{{[}13{]}} . The brains of both dogs and humans are
gyrencephalic, which is significant for translational neuroscience
because mice and rats have lissencephalic brains \textbf{{[}14{]}} . The
most prevalent neurological condition affecting canines is epilepsy
\textbf{{[}15{]}} . At the same time, the mention of employing canines
with innate epilepsy as a viable comparative model of the fundamental
cause and treatment of epilepsy dates back to the 1970s
\textbf{{[}16{]}} . Epilepsy is a group of complex syndromes with many
different etiologies, not a single illness. As a result, more than 100
in vitro and in vivo epilepsy models simulate various seizure types
\textbf{{[}17{]}.} In this study, I briefly present several different
animal epilepsy models, including the Generalised Tonic-Clonic Seizure
(GTCS), Absence Seizure, Myoclonus, and Status Epilepticus models
\emph{Figure 1.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure {[}1{]}:} This diagram shows the classification of many
animal epilepsy models, including Generalised Tonic-Clonic Seizure
(GTCS), Absence Seizure, Myoclonus, and Status Epilepticus models, along
with their subtypes.

Animal models of epilepsy or seizures in the research and development of
ASMs,

\begin{itemize}
\tightlist
\item
  The discovery of new ASMs,
\item
  The characterization of the anticonvulsant activity of new ASMs,
\item
  Specific models for drug-resistant seizures,
\item
  The assessment of whether the efficacy of new ASMs changes during
  chronic treatment,
\item
  The comparison of adverse effects of new ASMs in animals with epilepsy
  versus those without epilepsy and the estimation of effective plasma
  concentrations of new ASMs for initial clinical trials are examples.
\item
  Discovery of disease-modifying or antiepileptogenic drugs discovery of
  disease-modifying or antiepileptogenic therapies \textbf{{[}18{]}.}
\item
  \textbf{In Vitro Model}
\end{itemize}

Studying epilepsy and epileptic convulsions using in vitro preparations
is worthwhile and practical. From practically any species, these
preparations can be obtained \textbf{{[}19{]}} . Mammalian brain slices
are the method that researchers employ the most frequently when looking
at epileptiform activity. These thin brain slices can either be employed
immediately (the acute brain slice preparation) or after being preserved
in culture for several days or weeks in an incubator (the organotypic
brain slice preparation) \textbf{{[}20{]}} .

Brain preparations from various mammalian species, including rabbits,
guinea pigs, rats, mice, and humans after neurosurgical resections, have
induced in vitro epileptiform activity \textbf{{[}21{]}} . The most
often used species has been rats, and several strains have been used.
However, the appeal of using mouse models for experiments has grown due
to the relatively simple process of altering the mouse genome and the
recent widespread usage of transgenic mouse strains. Differing mouse
strains exhibit differing sensitivity to epileptogenic circumstances or
might have developmental flaws or other traits due to their varied
genetic backgrounds. Rats and other rodent species behave
similarly\textbf{{[}22{]}} .

The age of the animal from which brain tissue is obtained significantly
impacts the appearance of epileptiform activity in
vitro\textbf{{[}23{]}} . However, it is unclear how an animal's age
affects how easily they can induce seizure-like episodes in
vitro\textbf{{[}24{]}} . For instance, using the high K+ model,
seizure-like events are not elicited in tissue from animals younger than
postnatal day 5 (P5) in rat hippocampus slices. These are easiest to
evoke at P12 before becoming challenging to create in animal tissue
beyond P21\textbf{{[}23{]}} . Age-related variations in excitability and
seizure propensity are controlled by several different processes, which
leads to such complexity. As one illustration, GABAergic signaling is
hypothesized to depolarize early in development compared to adult tissue
because of high amounts of intracellular chloride \textbf{{[}25{]}} .
Remembering that different species, strains, and sexes have varied
maturational trajectories and alterations in various signaling pathways
is crucial. At P7--P12, Rat and mouse pups are compared to newborn
humans in terms of development. Experimental groups have to be
appropriately randomized for the ages of the animals, and the impact of
age is correctly accounted for in study statistics and reported in
published manuscripts \textbf{{[}26{]}} .

\textbf{In Vivo Models}

To elucidate the neurochemical, neurophysiological, cellular, and
molecular mechanisms that control epileptic seizures, several
experimental models have been created in which epileptic activity is
replicated and various treatments are explored. Studies on these models
have also helped search for pathways similar to those that cause real
epilepsy. The various animal models can be grouped into convulsively
induced chemically, such as penicillin and cobalt, electrically, such as
kindling and electroshock, or genetically, such as audiogenic
seizures\textbf{{[}27{]}} . Scientists and researchers work to
understand the mysteries of life and the intricacies of diseases and to
create novel remedies in the field of biomedical research. In vivo
models, which bridge the gap between in vitro experiments and clinical
trials, are crucial in this endeavor. In vivo models frequently involve
living things and provide unique benefits for examining biological
processes, disease mechanisms, and prospective therapeutic approaches.

Although these models have tried to explain the underlying mechanics of
this condition precisely, the cause of the development of so many
distinct varieties of epilepsy has not yet been identified. Partial
epilepsy, tonic-clonic convulsions, and status epilepticus (SE) were the
three categories Fisher proposed for an epileptogenic classification of
models in 1989. This review comprises the most prevalent in vivo
epileptogenesis models currently understood by this classification.
Fisher's classification of epilepsy models, as modified for this review,
only refers to in vivo models \textbf{{[}28{]}} \emph{. \textbf{See
Figure 1.}}

\textbf{2. Generalized Tonic-Clonic Seizures (GTCS) Models}

A generalized tonic-clonic seizure, or grand mal, is characterized by a
tonic phase and clonic muscle contractions. They are the seizure forms
most feared by patients, relatives, and bystanders. Usually, they are
accompanied by diminished awareness or total loss of consciousness.
Usually, they are accompanied by diminished awareness or total loss of
consciousness\textbf{.}

\textbf{2.1 Chemical Models}

Giving particular chemicals or medications to animals is a popular way
to cause seizures. Rodent seizures can be induced with well-known drugs
like pilocarpine and kainic acid. These simulations closely resemble how
epilepsy manifests in people, from the initial trauma to spontaneous
recurrent episodes. Chemically induced models are used by researchers to
study

\begin{itemize}
\tightlist
\item
  Pentylenetetrazole (PTZ) induced seizure model
\item
  NMDA-induced seizure model
\item
  Flurothyl-induced seizure model
\item
  Iron-induced seizure model
\end{itemize}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 2: Adapted from Jan Van Erum, Debby Van Dam, Peter Paul De Deyn,
PTZ-induced seizures in mice require a revised Racine scale, Epilepsy \&
Behavior, Volume 95, 2019, Pages 51-59

\textbf{2.1.1 Pentylenetetrazole (PTZ) induced seizure model}

A typical chemically induced seizure model uses pentylenetetrazole
(PTZ), a Gamma-aminobutyric acid~(GABA)~receptor
antagonist\textbf{.}Pentylenetetrazole-induced seizures are classified
as a model of generalized seizure among all animal models of seizure and
epilepsy (as opposed to partial or focal seizure) \textbf{{[}29{]}} . It
causes a myoclonic seizure that mimics absence seizures (petit
mal)\textbf{.} Its characteristics as a generalized seizure model set it
apart from the MES Seizure model\textbf{,} another generalized seizure
model. Another study conducted by sheds light on the impact of repeated
PTZ (pentylenetetrazole) injections on seizure exacerbation and its
subsequent effects on brain structure and behavior in mice. The
observations from this research can be summarized as follows:

Repeated administration of PTZ injections (100 mg/kg) in rats led to a
progressive increase in seizure severity. This observation contrasted
with the control group, which received saline injections and did not
exhibit seizures or abnormal behaviors. The study revealed that
recurrent seizures, induced by PTZ injections, stimulated the
development of abnormal axonal branches referred to as ``mossy fiber
sprouting'' within the granule cell layer of the hippocampal region.
Additionally, improper granule cell migration was observed in the hilus
region of the PTZ-treated brain slices.

\textbf{Advantages:} Pentylenetetrazol-induced seizures can be generated
in rats within 30 seconds after treatment. This applicable Model of
human absence epilepsy and generalized tonic-clonic epilepsy allows for
collecting continuous, high-resolution, multislice pictures at subsecond
intervals\textbf{.} Especially when using PTZ, pharmacological seizure
induction is a quick and easy way to cause severe seizures. The
intensity of seizures is correlated with changes in injection dose. By
varying the PTZ dose and observing the ensuing behavior over several
trials, it is, therefore, straightforward to determine the proper dose.

\textbf{Disadvantages:} After a seizure is induced, the histological
changes brought on by epilepsy take time to manifest.

\textbf{NMDA-induced seizure model}

NMDA receptors are critical players in the control of physiology and
behavior\textbf{.} Intense research is being done to find NMDA receptor
antagonists that could potentially safely modulate neurological
illnesses, including epilepsy and stroke, because of their functional
control in these conditions. Male Sprague-Dawley rats (200-250 g) were
implanted with an i.c.v. Cannula targeted the right lateral ventricle
under surgical anesthesia (70 mg/kg ketamine and 6 mg/kg xylazine,
i.m.). NMDA convulsions were then elicited in these rats\textbf{.} The
animals were separated into groups (n=6 for each group) for three to
five days following surgery for testing. Just as previously
explained\textbf{.} Witkin JM et al. focused on investigating a series
of N-substituted-3-alkoxy-substituted dextromethorphan analogs to
determine whether they exert their effects in vivo by blocking NMDA
receptors \textbf{{[}30{]}.} The interest in developing such compounds
arises from the need for minimal side-effect NMDA receptor antagonists
for treating neurological and psychiatric disorders, with esketamine as
a recent example.

Here are the key observations and findings from the study:

Witkin JM et al. evaluated the effect of Esketamine because of its
propensity to bind to NMDA receptors. To evaluate the in vivo effects of
these compounds, the study employed a rat model of NMDA-induced
seizures. The analogs were administered intracerebroventricularly to
mitigate issues related to systemic drug metabolism. The potency of the
dextromethorphan analogs in blocking convulsions was positively
correlated with their affinities for binding to the NMDA receptor ion
channel, as evidenced by {[}3H{]}-TCP binding. This observation suggests
that NMDA receptor antagonism likely mediates their effects in
preventing seizures \textbf{{[}31{]}.}

\begin{itemize}
\tightlist
\item
  \textbf{Advantages:} NMDA-induced seizure model with receptor
  antagonists can be used to screen for various neurological and
  psychiatric disorders.
\item
  \textbf{Disadvantages:} Seizures induced by NMDA receptor activation
  may not fully replicate the natural mechanisms that lead to seizures
  in clinical conditions. This Model bypasses many complex factors
  contributing to seizures in patients, potentially limiting its
  relevance to understanding human epilepsy. Significant differences
  between the rodent and human brain can make it challenging to
  accurately extrapolate findings to human conditions.
\item
  \textbf{Flurothyl-induced seizure model}
\end{itemize}

Flurothyl (10\%) is a volatile chemoconvulsant that works as a GABA
antagonist. It has traditionally been widely used to cause seizures in
people who are very depressed as a substitute for electroconvulsive
shock therapy\textbf{.} The ability to easily manage seizures by
exposing the animals to room air \textbf{{[}32{]}} also contributes to
the brief duration of flurothyl-induced seizures (usually 15--60
seconds, depending on the type expressed). The recurrent flurothyl
seizure model can examine the mechanical intersection of the forebrain
or brainstem seizure network that may result in more complex seizure
types and how seizures evolve and grow more complicated over
time\textbf{.} In this study, the seizure latency was measured in
seconds from administering flurothyl inhalation to the first signs of
convulsion.

\textbf{Advantages:} Chemo-convulsant flurothyl offers three key
advantages. First, the rats are not under much stress because flurothyl
is so volatile. Since the flurothyl is injected into a chamber and then
inhaled by the animal, there is no need for needles. Second, without
being metabolized, flurothyl is promptly evacuated through the lungs,
negating any potential adverse effects from any convulsant that may
still be in the body.

\textbf{Disadvantages:} Flurothyl-induced seizures are uncommon, and
persons with epilepsy rarely experience spontaneous seizures.

\textbf{2.1.4 Iron Induced Seizure Model}

FeCl2 or FeCl3 iron injections induce chronic epileptogenic foci in the
rat cerebral cortex that discharges independently\textbf{.} This
experimental epileptogenic focus has been extensively studied to
understand the mechanism of clinical post-traumatic epilepsy and
GTCS\textbf{.} In their study by Sharma Varsha et al., 60 male Wistar
rats weighing 250--300 g were five mcL/ 100 mM \textbf{{[}33{]}.} Sharma
Varsha et al. focused on the iron-induced Model of post-traumatic
chronic focal epilepsy in rats. It aimed to investigate the
characteristics of epileptic events detected through electrocorticogram
(ECoG) recordings and their associated behavioral manifestations.
Epileptiform activity was observed chronically in the cortical and depth
recordings during wake behavior, starting around day eight post-iron
injection. Between day three and day 8, minimal epileptiform seizure
activity was detected in the EEG records. By day eight post-iron
injection, frequent electrical outbreaks, characterized by spike-wave
complexes, were evident. In later time points, such as day 18 and day
28, the recordings showed longer-duration electrical paroxysms,
including spike-wave complexes and poly spiking, both in cortical and
depth recordings.

\begin{itemize}
\tightlist
\item
  \textbf{Advantages:} A valuable framework for researching and
  comprehending the mechanisms underlying epilepsy is provided by using
  an iron-induced model of post-traumatic chronic focal epilepsy in
  rats. This Model allows researchers to study the onset and progression
  of human epilepsy by simulating some elements.
\item
  \textbf{Disadvantages:} Most of the drugs are ineffective in reducing
  iron-induced epilepsy, and only ethosuximide has been studied
\item
  \textbf{Mechanical/Electrical Models}
\end{itemize}

\begin{itemize}
\tightlist
\item
  Maximal electroshock model
\item
  Audiogenic seizure model
\item
  Impact acceleration model
\item
  Optogenetics
\end{itemize}

\textbf{2.2.1} \textbf{Maximal electroshock model}

Maximal electroshock seizure (MES) is used to cause acute epileptic
behaviors\textbf{.} Adult mice or rats (those older than six weeks) are
often given an electrical stimulus. Mice and rats were given stimuli 50
mA and 150 mA, respectively. The pulse frequency is 50-60 Hz, pulse
width is 0.6 ms, and the stimulus duration is 0.2 ms. In the MES model,
roughly 3--10 times greater than the animal's electrical seizure
threshold is administered \textbf{{[}33{]}} . The everyday MES actions
include Foaming at the mouth and urinary incontinence, followed by
hindlimb extension, falling, and back rigidity\textbf{.} Experimental
research on novel ASMs has primarily been conducted on healthy mice and
rats in which seizures were generated using chemicals or electricity for
practical reasons. The maximal electroshock seizure (MES) model has
persisted over time as one of the benchmarks for initial testing.

MES seizure score:

\begin{enumerate}
\tightlist
\item
  No seizure
\item
  Forelimb extension without hindlimb extension
\item
  Complete forelimb extension and partial hindlimb extension
\item
  Total Hindlimb extension
\item
  Post ictal depression
\end{enumerate}

\begin{itemize}
\tightlist
\item
  \textbf{Advantages:} The MES model predicts generalized tonic-clonic
  seizures in animals because it causes highly repeatable seizures. This
  predictability is necessary for determining whether a proposed ASM is
  successful.
\item
  \textbf{Disadvantages:} Different seizure types, like focal and
  absence seizures, cannot be evaluated.
\item
  \textbf{Audiogenic Seizure Model}Audiogenic seizures (AGS), brought on
  by sound stimulation (\textgreater{}30 dB), cause SUDEP in animal
  models\textbf{{[}34{]}} . The mouse exhibits a stereotyped behaviour
  right after the sound is presented, including wild running, a clonic
  seizure, a tonic-clonic seizure in which the mouse falls on its
  flanks, and a tonic seizure with an extension of the limbs towards the
  tail, which may or may not be followed by death\textbf{.} AGS in
  129/SvTer mice is a valuable model for SUDEP because both SUDEP and
  AGS share a respiratory mechanism of death since death can occur
  during a seizure.
\end{itemize}

\textbf{Advantages:} SUDEP can be very well studied by this model, and
the mechanism almost mimics humans.

\textbf{Disadvantages:} Audiogenic seizure models are poorly repeatable.

\textbf{2.2.3 Optogenetics}

Optogenetics is a method for activating or inhibiting neurons using
light-sensitive ion channels. Three separate in vivo mouse models of
epilepsy have recently used this technology to demonstrate its
effectiveness. Principal neurons were transfected with a lentiviral
vector containing halo rhodopsin in the rat tetanus toxin injection
model. Epileptiform EEG activity was reduced when 561 nm light was shone
on the transfected cells. Reduced high-frequency power and event
frequency were also seen, related to bursts of activity in human
epilepsy \textbf{{[}35{]}} . \emph{Table 1}

\textbf{Advantages:} This molecular therapy strategy uses the ability of
these opsins to control how neurons react to light, providing a
biologically relevant approach for investigation and future therapeutic
interventions.

\textbf{Disadvantages:} Opsins, which are light-sensitive ion channels
or pumps, are essential to Optogenetics. Opsin-deficient cells are
insensitive to optogenetic control. Expensive to test in small set-ups.

Chemical Model of GTCS\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
S. No. & \textbf{Model Name} & \textbf{Animal}\tabularnewline
1. & PTZ-induced seizure models & Mice\tabularnewline
2. & NMDA-induced seizure models & Male Sprague-Dawley
Rats\tabularnewline
3. & Flurothyl-induced seizure model & Mice\tabularnewline
4. & Iron-induced seizure model & Wister Rat\tabularnewline
Mechanical/Electrical Model of GTCS & Mechanical/Electrical Model of
GTCS & Mechanical/Electrical Model of GTCS\tabularnewline
S. No. & \textbf{Model Name} & \textbf{Animal}\tabularnewline
1. & Maximal electroshock model & Adult Mice older than six
weeks\tabularnewline
2. & Audiogenic seizure model & Mice 129/SvTer Mouse\tabularnewline
3. & Optogenetics & Mouse\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table {[}1{]}:} Generalised Tonic-Clonic Seizures (GTCS) Models
Overview.

\textbf{3. Absence Seizure Model}

An Absence seizure is characterized by a blank stare into space and may
or may not be associated with loss of consciousness. In the absence
seizure, there is no convulsive activity like a generalized tonic-clonic
seizure. Since, only EEG changes will be evident Modified Racine Scale
is used {[}Figure 2{]}

\textbf{3.1 Chemical Models}

GHB-induced seizure model

PTZ-induced seizure model

\textbf{3.1.1 GHB-induced seizure model}

In rhesus monkeys, Low doses of GHB (100--200 mg/kg) caused a
low-voltage slowing of the EEG and tiredness. An ongoing activity with
2-3 Hz high-voltage slow waves was visible in the EEG at a dose of 400
mg/kg \textbf{{[}36{]}} . Rats have by far the finest documentation of
any animal for GHB effects. In Wistar rats, systemic treatment of GHB
(25--100 mg/kg) increased slow-wave sleep, which continued for up to 4
hours. Instead, higher doses (200 mg/kg) were reported to elicit two
distinct forms of activity in Wistar rats, which were distinguished from
one another both behaviorally and EEG \textbf{{[}37{]}} . Initially, the
EEG showed occasional bursts or brief (5-8 seconds) episodes of
hypersynchronous 5- 6 Hz ``spikes and waves.''

\textbf{Advantages:} Humans, nonhuman primates like rhesus monkeys, and
rodents like rats and mice have all been used in scientific studies.
Cross-species comparisons can highlight similarities in pathophysiology

\textbf{Disadvantages:} Seizures brought on by GHB might not entirely
reflect the complexity and features of seizures experienced by people
with epilepsy.

\textbf{3.1.2: PTZ-induced seizure model:} Wistar rats weighing around
200 -- 250 g are taken for the seizure model. They were injected with 20
mg/kg of PTZ intraperitoneally. SWD characterizes the absence of seizure
activity in rats as in humans \textbf{{[}29{]}} .

\textbf{3.2 Genotypic Models}

\begin{itemize}
\tightlist
\item
  GAERS rats
\item
  WAG/Rij rats
\item
  Tottering 6j mouse
\end{itemize}

\textbf{3.2.1 GAERS Rats}

GARES stands for the ``Genetic Absence Epilepsy Rat from Strasbourg.''
GAERS is a strain descended from Wistar that simulates elements of AE,
such as spontaneous bilateral, synchronous spike-wave discharges, SWDs,
and behavioral changes \textbf{{[}38{]}.} Gain of function mutations in
the CaV3.2 T-type Ca2+ channel, lacking in Non-Epileptic Controls, is
associated with seizure genesis\textbf{.}

\textbf{Advantages:} An absence epilepsy modeling rat strain called
GAERS has essential features like SWDs.

\textbf{Disadvantages:} Although the GAERS model benefits from
gain-of-function mutations in the CaV3.2 T-type Ca2+ channel,
understanding the specific genetic foundation and how it interacts with
other genes and pathways can be difficult.

\textbf{3.2.2 WAG/Rij rats}

Created as an animal model for epilepsy in humans, WAG/Rij rats exhibit
EEG and behavioral traits similar to absence epilepsy, including the
exact mechanisms of action as different Antiseizure medications. They
show properties similar to gain-of-function in calcium and sodium
channels \textbf{{[}39{]}.}

\begin{itemize}
\tightlist
\item
  \textbf{Advantages:} In a single animal model, WAG/Rij rats present a
  rare chance to research the absence of epilepsy and depressive-like
  behaviors.
\item
  \textbf{Disadvantages:} Even because WAG/Rij rats display
  depressed-like traits, they could not accurately reflect the range of
  depressive illnesses in humans
\item
  \textbf{Tottering 6j mouse}
\end{itemize}

The study by KIM YT et al. aimed to investigate whether tottering-6j
mice exhibited absence-like seizures. EEG and behavioral data were
collected, revealing that tottering-6j mice displayed 5-8 Hz
spike-and-wave discharges (SWDs) in the bilateral cortex, accompanied by
sudden immobility and staring. The study further explored the effects of
Antiseizure Medication on these absence-like seizures in tottering-6j
mice. Episodic sodium channel modulator (ESM) by Valproic acid (VPA)
significantly inhibited SWD development at 20-40 minutes and 60-80
minutes after administration \textbf{{[}40{]}}

\textbf{Advantages:} Tottering-6j mice, a recognized and widely used
absence seizure model. The study examines how absence-like seizures are
affected by Antiseizure medications (ESM, VPA, and PHT).

\textbf{Disadvantages:} The study needs to detail the underlying
mechanisms of how the Cav2.1a1 subunit contributes to absence-like
seizures, which is lacking.

Chemical Models of Absence Seizure\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
S. No. & \textbf{Model Name} & \textbf{Animal}\tabularnewline
1. & GHB-induced seizure model & Nonhuman primates like rhesus
monkeys\textbf{,} Rats and Mice\tabularnewline
2. & PTZ-induced seizure model & Mice\tabularnewline
Genotypic Models of Absence Seizure & Genotypic Models of Absence
Seizure & Genotypic Models of Absence Seizure\tabularnewline
S. No. & \textbf{Model Name} & \textbf{Animal}\tabularnewline
1. & GAERS rats & Rat\tabularnewline
2. & WAG/Rij rats & Rat\tabularnewline
3. & Tottering 6j mouse & Mouse\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table {[}2{]}:} Absence Seizure Models Overview

\textbf{4. Myoclonous Models}

Myoclonus is a rapid, brief, electric shock-like muscular contraction
known as myoclonus, often restricted to a single limb or muscle group.
However, they might occasionally affect the entire body

\textbf{4.1 Chemical model}

PTZ-induced myoclonus

\textbf{4.1.1 PTZ-induced myoclonus}

The acute pentylenetetrazole (PTZ)-induced myoclonus model is the most
popular Model for evaluating the anticonvulsant effect of potential
ASMs. 0.5 ml IV at a dose of 45 mg/kg is administered and the animal
exhibits typical myoclonic behaviour \textbf{{[}29{]}} .

\textbf{4.2 Mechanical/Electrical Model}

Electric corneal stimulation model

\textbf{4.2.1 Electrical Corneal Simulation Model}

A new version of this Model was found to assess potential alternatives
for treating drug-resistant seizures \textbf{{[}41{]}} . When CD-1 mice
were treated with 6-Hz corneal stimulation for 4 sessions with an
amplitude of 32 mA with an interval of 72 h between each sessions. A
group of was given ketogenic diet which showed reduced seizure severity
as assessed by modified racine scale. \textbf{{[}42, 43{]}.} \emph{Table
3.}

\textbf{Advantages:} The ketogenic diet can stop seizures brought on by
6-Hz corneal stimulation, highlighting the Model's applicability to
clinical practice.

\textbf{Disadvantages:} The concept primarily concentrates on a single
mechanism for causing seizures (corneal stimulation), which may not
account for the multifactorial character of epilepsy.

Chemical Models of Myoclonous Models\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
S. No.\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Model Name}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Animal}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
PTZ-induced seizure model\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Rodent\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Mechanical/Electrical Model of Myoclonous Models\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Mechanical/Electrical Model of Myoclonous Models\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Mechanical/Electrical Model of Myoclonous Models\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
S. No.\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Model Name}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Animal}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Electric corneal stimulation model\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
CD-1 Mice\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table {[}3{]}:} Myoclonus Seizure Models Overview

\textbf{5. Status Epilepticus Models}

A life-threatening emergency known as status epilepticus (SE) is
characterized by extended convulsions that never end\textbf{.}Continuous
seizure activity or several seizures without regaining consciousness for
more than 5 minutes are considered SE\textbf{.} Human SE is a medical
emergency that, if left untreated, can cause death and brain
damage\textbf{.}

\textbf{5.1 Chemical Models}

Pilocarpine induced model

PTZ induced model

\textbf{5.1.1 Pilocarpine Induced Model}

Pilocarpine-induced status epilepticus (SE) is a frequently used mouse
seizure model. The study by Phelan KD et al. sheds essential light on
the intricate link between seizure behaviours and EEG activity at
various stages of pilocarpine-induced epileptic seizures. Pilocarpine is
injected at a dose of 100-400 mg/kg Intraperitoneally, and the animals
exhibit prolonged seizure activity without regaining consciousness in
between. To understand seizure dynamics thoroughly, it uses modified
Racine scale {[}Figure 2{]} in determining seizure strength during the
SE stage. It also emphasizes the necessity of adding EEG
data\textbf{{[}44{]}} . \emph{Table 4.}

\textbf{Advantages:} The relationship between EEG and seizure activity
can be very well correlated by this model.

\textbf{Disadvantages:} Although fast Fourier transformation (FFT) is
helpful for EEG research, it may also be challenging and complicated for
interpretation.

\textbf{5.1.2 PTZ-Induced Model}

Pentylenetetrazole (PTZ) was injected intraperitoneally into the test
animals to cause status epilepticus at 70 mg/kg. Only the animals in
status epilepticus, or generalized tonic-clonic seizures lasting at
least 45 minutes, were chosen for the experiment. \textbf{{[}45{]}}

A. Mechanical/Electrical Model of Status Epilepticus Models\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Chemical Model of Status Epilepticus Models\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Chemical Model of Status Epilepticus Models\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Chemical Model of Status Epilepticus Models\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
S. No.\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Model Name}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Animal}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Pilocarpine induced model\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Mice\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
PTZ-induced seizure model\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Rat\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table {[}4{]}:} Status Epilepticus Models Overview

\textbf{6. Temporal Lobe Epilepsy Models}

Temporal Lobe epilepsy is the most common form of secondary epilepsy.
The characteristic feature of TLE is mesial temporal sclerosis or
hippocampal sclerosis, which can result in seizures. Some people with
TLE become refractory and require surgical intervention.

\textbf{6.1 Chemical Models}

\begin{itemize}
\tightlist
\item
  KA-induced TLE
\item
  Pilocarpine Induced TLE
\item
  Coriaria lactone induced TLE
\item
  Penicillin-induced TLE
\item
  Tetanus toxin-induced TLE
\end{itemize}

\textbf{6.1.1 KA-Induced TLE}

KA is an ionotropic KA receptor agonist and a cyclic analog of
L-glutamate. Acute seizures are characterized by symptoms comparable to
those seen after intrahippocampal injections following intra-amygdaloid
injections of KA (0.4-2 g) in rats \textbf{{[}46{]}} . In monkeys,
however, intracerebral administration of KA (0.5-10 \selectlanguage{greek}μ\selectlanguage{english}g/\selectlanguage{greek}μ\selectlanguage{english}l of saline) in
the hippocampus or the amygdala does not produce generalized seizures
but is linked to focal seizures.

\textbf{Advantages:} The main benefit of administering KA systemically
instead of intracerebrally is that more animals can be injected
simultaneously with fewer complications.

\textbf{Disadvantages:} The way different species react to KA treatment
can differ. This calls into doubt the Model's applicability to epilepsy
in humans.

\textbf{6.1.2 Pilocarpine Induced TLE}

This Model has been used to evaluate the long-term effectiveness of new
treatments for reducing SRS and enhancing the cognitive and
neuropathological changes brought on by severe mTLE. Many of the
neuropathological characteristics of mTLE, such as severe seizures, the
loss of GABAergic interneurons in the dentate gyrus, Ammon's Horn
sclerosis, and cognitive deficits, are recapitulated in this mouse model
of TLE \textbf{{[}47{]}} .

\textbf{6.1.3 Coriaria Lactone Induced TLE}

An experimental paradigm for studying epilepsy is coriaria
lactone-induced temporal lobe epilepsy (TLE). Animal subjects, primarily
rodents, are given Coriaria lactone, a substance produced from the
Coriaria plant, to cause TLE-like seizures \textbf{{[}48{]}} . Repeated
intramuscular/intraperitoneal injections (median 48) of Coriaria lactone
(0.75-2 mg/kg) serve as a kindling TLE model in Rhesus monkeys,
indicating a primate animal model of epileptogenesis. Resemblance of
TLE's behavioral, electrographic, and anatomical traits were produced
using this Model.

\textbf{Advantages:} This Model is used by researchers to examine how
epilepsy alters neuronal excitability, neurotransmitter activity, and
neuroinflammation in primates.

\textbf{Disadvantages:} Animal seizures brought on by coriaria lactone
may resemble TLE in specific ways, but they might not completely capture
the complexity and diversity of human epilepsy.

\textbf{6.1.4 Penicillin-Induced TLE}

Sherdil A. et al. conducted a study where the hippocampus was injected
with penicillin in each experiment, and the animals were watched for
five hours straight. A mean cumulative dose of \textgreater{}16000 IU of
penicillin was administered over 98 to 276 days, and injections were
repeated at least once weekly \textbf{{[}49{]}.} The seizure severity
was assessed with the help of Modified Racine scale {[}Figure 2{]}

\textbf{Advantages:} This Model can change from a chronic model with
spontaneous seizures following accumulative penicillin injections to an
on-demand model with on-demand seizures.

\textbf{Disadvantages:} Repeated penicillin injections and stereotaxic
insertion of deep recording electrodes are intrusive, difficult
procedures.

\textbf{6.1.5 Tetanus toxin-induced TLE}

A chronic model of temporal lobe epilepsy (TLE) marked by intermittent
spontaneous seizures beginning after a latent period of around seven
days is provided by intrahippocampal TeNT \textbf{{[}50{]}.} The TeNT
model is distinct from other spontaneously seizing Rat TLE models,
lacking early status epilepticus (prolonged epileptic seizures). It
causes little to no neuronal death in 70--90\% of instances while
producing highly localized lesions in the remaining cases.

\textbf{Advantages:} The teNT model can be utilized to develop a chronic
TLE model with sporadic spontaneous seizures. This Model shows how TLE
develops and progresses.

\textbf{Disadvantages:} Tetanus toxin affects the brain by destroying
inhibitory synapses. Even though it sheds light on the pathophysiology
of epilepsy, this complicated system may not adequately encompass the
various mechanisms causing various forms of epilepsies.

\textbf{6.2 Mechanical/Electrical Models}

Controlled cortical impact TLE model

Theiler's virus-induced TLE

\textbf{6.2.1 Controlled cortical impact TLE model}

The purpose of developing the testing platform for the controlled
cortical impact (CCI), a mechanical model of traumatic brain injury
(TBI). CCI is made with the help of an electromagnetic piston with set
parameters. Tip diameter -- 6 to 8 mm, Velocity -- 4 m/s, Dwell time --
50 to 250 ms, Depth -- 1 to 2 mm. In addition, significant long-term
pathological effects have been seen, including delayed hippocampal
lesions and mossy fiber sprouting, considered hallmark TLE symptoms. CCI
models are as certified as possible TLE models \textbf{{[}51{]}} . The
CCI model has a short latent period, spontaneous seizures, and is
repeatable.

\textbf{Advantages:} The temporal lobe epilepsy (TLE) symptoms of
delayed hippocampal lesions and mossy fiber sprouting have been
demonstrated in the Model as significant long-term pathological effects.
This increases its usefulness for researching TLE.

\textbf{Disadvantages:} The relatively short period of the CCI model may
restrict its potential to reflect the complete range of TBI outcomes,
particularly those that evolve or deteriorate over time. It's
complicated and requires a specialized instrument.

\textbf{6.2.2 Theiler's virus-induced TLE}

After intracortical injections of TMEV or PBS, C57Bl/6 mice were
monitored for acute seizures. Between days 3 and 7 after infection
(dpi), mice infected with TMEV exhibited behavioural seizures. Most
seizures were stage 4 or 5 on the modified Racine scale {[}Figure 2{]}
at six days post-induction as the severity of the seizures grew over
time. The biochemical tests were performed on mice that had experienced
at least one seizure throughout the observation period. At 3-, 4-, and
14-days post-inoculation GSH levels in TMEV-infected mice were
dramatically decreased and concurrently GSSH levels rose and the redox
status was compromised. This study is the first to show that the TMEV
model of infection-induced TLE experiences oxidative stress

\textbf{{[}52{]}.}

\textbf{Advantages:} Since infections have been linked to human
epilepsy, the TMEV model of infection-induced temporal lobe epilepsy
(TLE) offers an appropriate setting for evaluating oxidative stress, and
understanding how oxidative stress functions in this model can shed
light on comparable mechanisms in human TLE.

\textbf{Disadvantages:} In this approach, it can be challenging to
establish a causal link between oxidative stress and seizure incidence.
Correlations may be found in the study, but more research is needed to
determine causation.

Chemical Models of Temporal Lobe Epilepsy\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
S. No. & \textbf{Model Name} & \textbf{Animal}\tabularnewline
1. & KA-induced TLE & Rat, Monkey\tabularnewline
2. & Pilocarpine Induced TLE & Mouse\tabularnewline
3. & Coriaria lactone induced TLE & rhesus monkeys\tabularnewline
4. & Penicillin Induced TLE & Macaques\tabularnewline
5. & Tetanus toxin-Induced TLE & Rat\tabularnewline
Mechanical/Electrical Models of Temporal Lobe Epilepsy &
Mechanical/Electrical Models of Temporal Lobe Epilepsy &
Mechanical/Electrical Models of Temporal Lobe Epilepsy\tabularnewline
S. No. & \textbf{Model Name} & \textbf{Animal}\tabularnewline
1. & Controlled cortical impact TLE model & Rat, Mice\tabularnewline
2. & Theiler's virus-induced TLE & C57Bl/6 mice\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table {[}5{]}:} Temporal lobe Epilepsy model's overview.

\textbf{Conclusion}

Neurochemical agents, electrical stimulation protocols, thermal or
hypoxic insults, traumatic traumas, optogenetics, and rodent strains
with idiopathic or audiogenic-induced seizures are only a few of the
techniques used in animal models of epilepsy. Figure 1 summarises the
key characteristics, applications, and limitations of the models
examined here. In the last 20 years, many experimental compounds have
been tested in animal models to find novel, third-generation ASMs. This
has surely increased the therapeutic possibilities, especially for
patients requiring a change in treatment. But the effectiveness of these
new ASMs for treating newly diagnosed epilepsy is, at best, comparable
to that of older ASMs.

In biomedical research, the search for appropriate animal models is a
critical aspect of various clinical conditions, such as the pursuit of
novel treatments for seizures that are resistant to current medications.
Unlike a one-size-fits-all approach, the principle of
``fit-for-purpose'' guides the selection of animal models, acknowledging
that there is no single ideal model for every aspect of a complex
condition like autism spectrum disorder (ASD) or pharmacoresistant
seizures. An essential prerequisite for advancing drug development is
the availability of animal models that accurately predict therapeutic
responses to drugs.

Animal models, when thoughtfully chosen, designed, and executed,
constitute crucial components of translational drug development
strategies. These models gain even more translational value when
combined with other tools such as quantitative systems pharmacology,
biomarkers, or experimental clinical trials. It is important to
recognize that animal models are simplified representations of complex
systems, and their purpose is not to replicate the entire complexity of
a human disease but to model specific facets of the disease, such as
drug-resistant partial seizures.

When employing animal models, it is imperative to have a well-defined
research question and ensure that the chosen model aligns with that
question. The Development of new therapies for epilepsy necessitates a
close alignment between the animal model and the clinical syndrome. This
alignment requires ongoing and effective collaboration between skilled
clinicians and basic scientists. Besides relying on animal models, the
insights and ingenuity of experienced scientists are crucial for
discovering novel targets and correctly interpreting unexpected
findings, potentially leading to the development of truly impactful
drugs.

In this context, emerging pharmacological and gene discovery strategies
offer the potential to target specific subpopulations of patients with
drug-resistant epilepsy rather than searching for a universal remedy
effective for all forms of intractable epilepsies.

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