2.1.1 Pentylenetetrazole (PTZ) induced seizure model
A typical chemically induced seizure model uses pentylenetetrazole
(PTZ), a Gamma-aminobutyric acid (GABA) receptor antagonist.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) [29] . It causes a
myoclonic seizure that mimics absence seizures (petit mal). Its
characteristics as a generalized seizure model set it apart from the MES
Seizure model, 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.
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. 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.
Disadvantages: After a seizure is induced, the histological
changes brought on by epilepsy take time to manifest.
NMDA-induced seizure model
NMDA receptors are critical players in the control of physiology and
behavior. 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. The
animals were separated into groups (n=6 for each group) for three to
five days following surgery for testing. Just as previously
explained. 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 [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 [31].
- Advantages: NMDA-induced seizure model with receptor
antagonists can be used to screen for various neurological and
psychiatric disorders.
- 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.
- Flurothyl-induced seizure model
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. The ability to easily manage seizures by
exposing the animals to room air [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. In this study, the seizure latency was measured in
seconds from administering flurothyl inhalation to the first signs of
convulsion.
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.
Disadvantages: Flurothyl-induced seizures are uncommon, and
persons with epilepsy rarely experience spontaneous seizures.