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].
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.