**6. Experimental models of epilepsy and neurotoxicity**

As noted, before the development of epilepsy, experimental models have been crucial in the further research of a neurological disorder affecting approximately 1% of the worldwide population. Some drugs cause structural and metabolic alterations in the nervous system as demonstrated by experimental epileptic models, culminating in seizure generation [74]. Antiepileptic drugs that are conventionally used in clinical practice have been successfully tested in many of these models, even though certain models have neurotoxic consequences, as we will discuss below.

With the aluminum model, focal seizures are studied by directly applying the substance to the cerebral cortex of the animal under study, where it has been observed that this substance generates dendritic loss, gliosis, loss of GABAergic neurons, and a decrease in glutamate decarboxylase [75, 76]. This model has been used to study antiepileptic drugs including diphenylhydantoin and pentobarbital, both of which have shown positive outcomes in reducing epileptic seizures frequency [77].

Focal seizures have been researched using cobalt powder, which has been applied to the research animal's cortex or thalamus for epileptogenesis as part of the model development. This has reported GABA and glutamate decarboxylase enzyme production decreased, whereas neuronal death has been observed in the hippocampus. This cobalt model has also been suggested to interfere with Ca2+ signaling at NMDA glutamate receptors [78–80].

Similarly, using Zinc as an epilepsy model has been associated to neuronal death in the hippocampus, interference with GABAA receptors, and changes in the synapses of mossy fibers when there is a high concentration of this metal. It has also been observed to interfere with the responses of various receptors, including GABA, NMDA, and AMPA [81, 82]. While kainic acid, as an epileptic model, functions similarly to glutamate. The hippocampus is the most sensitive structure to this agent, with the highest number of receptors reported in the CA3 layer. This epilepsy model is used to examine focal seizures, with the hippocampus being the most sensitive structure to this substance. Changes in neuropeptide Y levels, hippocampus mossy fiber formation and a decrease in GABAB receptors are reported [83–85].

Pentylenetetrazol is used as an epileptic model to research generalized seizures. Shifts in the CA3 layer of the hippocampus, increased voltage in voltage-responsive K+ receptors, and interactions with GABAA and NMDA receptors have all been documented [86, 87]. The model has been shown to be suppressed by phenytoin and pentobarbital [88, 89]. Flurothyl gas, on the other hand, can cause status epilepticus in laboratory animals. Although this gas has long been utilized to investigate generalized seizures, the exact mechanism through which it causes seizures is yet uncertain. However, alterations in the lipidic membranes of hippocampus, amygdala, and cerebral cortex cells have been reported. A decrease in GABA synthesis and activation of the c-Fos gene have also been reported [90–92].

On the other hand, penicillin, like cobalt, has been utilized as a model for focal seizures in epilepsy research, causing myoclonic seizures. The loss of GABAergic neurons, neuronal death, and an increase in mossy fibers in the hippocampus are the key abnormalities seen in this model [93–95]. While bicuculline is classified as a GABA antagonist, it causes generalized seizures when used. Edema has been found in the astrocytes of the cerebral cortex, where it interacts with Ca2+ and K+ channels [96, 97]. Tetanus toxin has also been employed as a model of epilepsy because of its effect on seizure induction. There are interactions with inhibitory neurotransmission, synapse formation, exocytosis blocking, and a decrease in GABAergic signaling threshold with this substance [98, 99].

Additionally, pilocarpine affects the muscarinic acetylcholine receptors. The increase in activation of these receptors in the hippocampus characterizes its epileptogenic effect. In experimental animals, it can even cause status epilepticus. Significant damage to nervous system structures has been observed, particularly the entorhinal and piriform cortex, olfactory bulb, amygdala, hippocampus, and thalamus, as well as abnormalities in the function of Na<sup>+</sup> /K+ ATPase and NMDA receptors [100–103].
