Open access peer-reviewed chapter

Neurotoxicity and Epileptogenesis

Written By

Carmen Rubio, Artemio Rosiles-Abonce, Elisa Taddei and Moisés Rubio-Osornio

Submitted: August 30th, 2021 Reviewed: September 20th, 2021 Published: December 2nd, 2021

DOI: 10.5772/intechopen.103687

Chapter metrics overview

81 Chapter Downloads

View Full Metrics


Many neurotoxic substances produce toxic effects on the nervous system. Given the neurotoxic substances found in the human body, certain people have been regarded as having a propensity to epileptic seizures. In many situations, the neurotransmission processes of these toxins are similar to the physiopathology of epilepsy. Epileptic models have been developed to induce seizures in animals, allowing researchers to study convulsive seizure mechanisms. Pentylenetetrazol, kainic acid, pilocarpine, penicillin, aluminum, bicuculline, picrotoxine, 4-aminopyridine, strictine, domoic acid, and other compounds fall under this category. However, there are some drugs used in clinical practice that can cause neurotoxicity as well. In this chapter, the predominant substances and drugs involved in epileptogenesis through neurotoxicity effects are reviewed. Throughout this chapter, we attempt to describe the mechanisms documented in the literature, in which epileptic seizures cause neurotoxicity in the brain by themselves, as shown with excitotoxicity mediated by glutamate and ions involved.


  • Epilepsy
  • Epileptogenesis
  • Neurotoxic substances
  • Seizures

1. Introduction

The concept of toxicity refers to any substance capable of producing harm on livings organism. Hence, this chapter emphasizes on those compounds that harm the nervous system, particularly those capable of generating seizures. Within the pathophysiology of epilepsy, multiple mechanisms favor epileptogenesis, one of which is neurotoxicity. These excitotoxic mechanisms can exert their action through the glutamate receptors N-methyl-D-aspartate (NMDA); 𝜶-amino-2-3-dihydro-5-methyl-3-oxo-4-isoxazolepropionic acid (AMPA) and kainate, opening ionic channels permeable to calcium (Ca2+), sodium ions (Na+), that participate significantly in the neuronal damage derived from the excitotoxic effects. Though there are spontaneous inducers of epilepsy, different models that replicate seizures have been created to better understand the mechanisms underlying epileptic seizures. These models promote neurotoxicity in the brain and are triggered by certain substances, primarily agonists or antagonists of neurotransmitters involved in epileptic activity. In this review we aim to illustrate the neurotoxic potency of numerous agents administered in the brain with neurotoxic qualities, including medications used in clinical practice that can generate neurotoxicity.

Epileptic seizures, according to the World Health Organization, are defined as a neurological, chronic, recurrent, and repetitive condition of paroxysmal phenomena caused by an excessive abnormal discharge of groups of neurons, which can occur in different parts of the brain [1]. It is the result of synchronous electrical discharge from a group of hyper-excitable neurons, that when repeated consequently leads to neurotoxicity This hyperexcitability is due to an imbalance between the inhibitory processes given mainly by gamma-aminobutyric acid (GABA) and the excitatory ones of glutamate, which consequently modifies the function of ion channels regulated by Ca2+, Na+, and potassium (K+) mainly, which finally play a crucial role between the timing and propagation of abnormal discharges, contributing to the epileptic process [2]. Glutamate release activates NMDA ionotropic receptors, causing a rapid entry of Na+ and a slow entry of Ca2+. In epileptic seizures, with this massive entry of Ca2+, there is an increase of mitochondrial Ca2+ producing, among other effects an excitotoxic effect, in addition to free radicals production, proteases activation, and synthesis of nitric oxide which, by acting as a retrograde messenger, enhances the excitotoxic effect on the cell by also increasing glutamate release from the presynaptic terminals [3]. This glutamate release also activates the AMPA receptors associated with non-voltage-dependent channels, responsible for depolarizing currents, due to the Na+ input. AMPA receptor antagonists are known to have been shown to markedly reduce or decrease epileptic activity [4].

Kainic acid (KA) glutamate agonist acts on glutamatergic receptors with a high affinity for KA which is associated with a Na+ ion channel, this depolarization in turn causes Na+ channels opening, which leads to Ca2+ channels aperture that further increases neuron excitability. Na+ channels’ participation in epileptogenesis and their mutations in many epileptic disorders has been long studied. The Na+channels classified as type Nav 1.1 and Nav 1.6 are over-expressed in mice administered NMDA, which leads to hyperexcitability. However, when these animals are given phenytoin Na+ channel blocker, electrographic excitability decreases. Ion involvement has been described as vital in seizures [5]. The neurotoxic effect of KA appears to exert its action on non-NMDA receptors, located in the postsynaptic region at the dendrites of neurons level or by acting on presynaptic ionotropic glutamate receptors (NMDA, AMPA, and kainate) [6, 7]. Other glutamate receptors are also activated, predominantly found in the membrane of neurons, performing an excitatory response to the cell that presents them. When acting on the cell, there are even injuries to the cytoplasmic membrane, cytoplasmic vacuolization, and edema in the mitochondria, which finally cause cell death [8]. Kainate Glutamate stimulates postsynaptic AMPA receptors. This depolarization is immediately reduced by the GABA receptor recurrent inhibition [9].

Activation of AMPA receptors, particularly NMDA receptors, triggers intracellular Ca2+ cascades. Ca2+ permeability studies indicate that there is also a low permeability of this ion through kainate receptors [10, 11]. Excessive Ca2+ intake, derived from a pathological condition such as epilepsy, contributes to an excitotoxic effect and subsequent neuronal death [12].

In epileptic seizures, glutamate elevation and GABA release are observed from the presynaptic terminals within the synaptic cleft. Astrocytes recapture these abnormally released neurotransmitters during the seizure, protecting neurons from excitotoxicity and eliminating excess glutamate. It is known that, derived from the epileptic processes, there is hypertrophy and significant changes in the ramifications and volume of the astrocyte soma. These changes undoubtedly impact the reuptake of neurotransmitters such as glutamate, allowing an excess of this in the synaptic space [13, 14].

It is worth noting that epilepsy research is so broad that despite not managing to control the neuropathology, some authors have claimed that studying the disease has allowed neuroscience to investigate more than just seizure disorders, but the brain regions not directly implicated in epilepsy, as well. This chapter, however, will concentrate only on epilepsy-related neurotoxicity.


2. Calcium channels and epilepsy

When Ca2+ enters, it produces hyperexcitability in the excitable neuron through voltage-dependent Ca2+ channels (VDCCs). Intracellular processes are initiated when Ca2+ enters the cell, such as membrane excitability regulation, which permits neurotransmitters to be released. The biophysical and pharmacological properties of six types of Ca2+ channels (T, L, N, P, Q, and R) have been characterized. Low-threshold channels have been classed as T-type channels, while the rest have been classified as high-threshold channels. The number of depolarizations required for their activation has led to this classification. All channels have four subunits referred to as I through IV, each of which is made up of six transmembrane segments referred to as S1, S2, S3, S4, S5, and S6. The N, P and Q type channels are particularly crucial in controlling the release of neurotransmitters like glutamate and GABA, which, as previously stated, play a key role in epilepsy. The fact that a decrease in extracellular Ca2+ concentration can cause hyperexcitability in neurons is evidence that VDCCs play a major role in the epileptic activity [15]. In epilepsy, this correlates with paroxysmal depolarizations. Which correlates with paroxysmal depolarizations in epilepsy. This phenomenon has been observed in the hippocampus’s neurons and dendrites, particularly in the CA1 and CA3 neuroanatomical, critical regions in epileptic seizures. Ca2+ currents have been demonstrated to promote the development of epileptic seizures; this is thought to be due to an increase in postsynaptic responses triggered by excessive excitement, which then initiates an epileptic seizure. However, this type of activity also leads to neuronal death.

Epileptic activity can also be triggered by the input of extracellular Ca2+ into the neuron, which promotes neuronal membrane depolarization and action potential production, resulting in abnormal discharges and seizures. The rise in intracellular Ca2+ in the postsynaptic neuron has been linked to various factors that produce epileptogenesis, including persistent depolarization, inducing neurotoxicity. Animal models in mice (tottering, du-du, or stargazer) in which genes coding for Ca2+ channel subunits formation have been altered and made it possible to illustrate the role of Ca2+ in epileptogenesis, implying that channelopathies may be part of the substrate for abnormal activity. Because Ca2+ plays such a role in abnormal epileptic activity, drugs like ethosuximide have been developed to block T-type Ca2+ channels by reducing Ca2+ entry. Hence, neurotransmitter release is implicated in neuronal excitability [16, 17, 18, 19].


3. Molecular signaling pathways for epileptogenesis

This chapter proposes several molecular signaling pathways that are involved in epileptogenesis. We described the most representative pathways in the epileptogenesis study. Until now, the complicated epileptogenesis pathophysiology and molecular processes that lead to seizures have remained a mystery. However, various anatomical pathways mechanisms, pathological pathways, and molecular interactions are known and have been explored based on the research available. Inhibitory and excitatory neurotransmission abnormalities have a big impact on neuron stability. Neuroinflammation and oxidative stress, for example, encourage the emergence of epileptic seizures and can potentially intensify them [20].

It has been claimed that the inflammatory state, and the elevation of its mediators, including IL-1ß, IL-6, high mobility group box TNF-α8, and cyclooxygenase-2. TNF-α produces endocytosis of GABA receptors through AMPA. Therefore, hyperexcitability in the hippocampus is boosted, resulting in seizures. Several studies have linked neuroinflammation to oxidative stress at the same time. The involvement of oxidative stress as a seizure generator is owing to an imbalance in the generation of reactive oxygen and nitrogen species, resulting in a deficiency in antioxidant mechanisms. The mitochondria are the body’s principal generator of oxygen radicals [21]. Other free radicals, including nicotinamide adenine dinucleotide phosphate oxidase and xanthine oxidase, have been shown to act through glutamate receptors. The activation of the NMDA receptor is linked to epileptic activity [22].

Another pathway described in the study of epileptogenesis is the Wnt/ β-Catenin pathway. Wnt/β-catenin is implicated in temporal lobe epilepsy. This pathway modulates, among other events, neuronal circuit formation and synaptic assemblages. Brain areas involved in epileptogenesis also play a key role in neuronal excitability modulation and neurotransmitter secretion. Wntproteins dock with membrane receptors to initiate one of two major signal pathways: the canonical β-catenin pathway or the non-canonical pathway. β-catenin pathway manages transcriptional activity regulation and gene activation through the T-cell factor/lymphoid enhancing factor pathway (TCF / LEF), that dictates cell determination, proliferation, and differentiation. Wnt1, Wnt3a, Wnt7a, and Wnt8 are most commonly found in β-catenin-dependent signaling. When one of these proteins binds to lipoprotein-related protein receptors, they lead to selective activation of the canonical pathway. Therefore, β-catenin dissociates from the degradation complex composed of axin, adenomatous polyposis coli protein (APC), casein kinase 1 (CK1), and glycogen synthase kinase 3 β (GSK3β). This promotes the accumulation of β-catenin in the cytosol, which is then translocated to the nucleus and associated with transcription factors of the TCF/LEF family to regulate Wnt-dependent gene expression. In the absence of the Fzd receptor by Wnt, the Axin and APC proteins boost phosphorylation of β-catenin through the kinases CK1 and GSK3-β. These proteins promote the ubiquitination and subsequent degradation of β-catenin by the proteasome [23].

Notoginsenoside R1 (NGR1, was recently discovered to upregulate mRNA levels of the proteins β-catenin, Dvl, and Fzd, as well as promote the proliferation of cultured cortical neurons. NGR1 has also been discovered to reduce persistent K+ currents in hippocampus neurons, resulting in a reduced peak threshold. Treatment with a Wnt3a ligand, which activates the FZD receptor, caused K+ channel internalization and enhanced β-catenin expression, according to a recent study. GSK-3β inhibition caused by Wnt/β-catenin activation resulted in a lack of phosphorylation of GSK on the surface of K+ channels, resulting in internalization. This action lowers the current density of K+ channels, preventing them from acting as hyperexcitability regulators. The non-canonical route refers to pathways that do not rely on β-catenin-TCF/LEF and instead rely on alternative downstream effectors to produce a transcription response. The Wnt/PCP (planar cell polarity) pathway, via Wnt-cGMP/Ca2+, via Wnt/Via Ror, via Wnt-RYK, and via Wnt-mTOR are some of these pathways. Epileptogenesis has been linked to the mTOR signaling pathway. Wnt7a, a Wnt family ligand, is expressed in cerebellar granule cells and operates as a particular canonical signaling activator. Wnt7a is expressed in the developing hippocampus as well, particularly in the dentate gyrus and CA1 regions, as indicated by an increase in active β-catenin immunofluorescence after recombinant Wnt7a was applied. Other studies have shown that Wnt7a has a role in synapse formation, with an increase in the number of vesicular glutamate transporters puncta per dendritic area after hippocampal neurons were treated with recombinant Wnt7a, resulting in an increase in excitatory neurotransmitter. Wnt8a is also involved in synaptic terminal excitability modulation. Additionally, it is also involved in the regulation of synaptic terminal excitability. These findings show that Wntimpacts synaptic regions important in excitatory neurotransmitter release control and regulation and ligand-gated ion channels in the postsynaptic membrane via canonical activation. These physiological changes on the synaptic terminal of hippocampus neurons may play a role in the temporal lobe epilepsy pathophysiological pathway. The aforementioned is attributed to synaptic transmission imbalances between inhibitory and excitatory synapses [24].

In a previous study, a significant increase in β-catenin signaling in the cerebellar cortex of rats after kindling-induced generalized seizures was observed. β-catenin activation induces apoptosis through the expression of cMyc upregulation, a protein that negatively regulates anti-apoptotic proteins such as Bcl-2. This leads to a loss of mitochondria, membrane potential, releasing cytochrome-c and promoting activation of caspases 3 and 9, leading to neuronal death. The Wnt/β-catenin pathway participates not only in neuronal synchrony regulation. But also in NMDA receptor modulation, which, as previously described, plays an important role not only in epilepsy but also in epileptogenesis [25, 26].


4. Toxic substances that cause seizures

Exposure to toxins can trigger seizures due to their damaging effect on the nervous system through different mechanisms (Table 1). The ability of organophosphate insecticides to induce epileptic seizures is known through the inhibition of acetylcholinesterase due to its chemical structure that contain the groups carbamoyl and thiocarbamoyl, due to its capacity to phosphorylate and inactivate acetylcholinesterase and in addition to stimulating cholinergic receptors, these pesticides include parathion, chlorpyrifos, aldicarb, and carbaryl. Certain toxins present a dual mechanism for epileptic seizures production through the facilitation of the activation and the inhibition of voltage-gated Na+channels, how is the case for chemical and biological warfare agents like sarin and soman, as well as toxins such as scorpion venom and ciguatoxin that can lead to seizures by modulating ion flow through Na+channels. In other instance, anatoxin is a potent agent that causes seizures by the nicotinic receptor activation. The imbalance in inhibitory and excitatory neurotransmission is one of the mechanisms by which seizures occur. Par excellence GABA is the inhibitory neurotransmitter and glutamate is the excitatory neurotransmitter in the CNS, seizures are triggered by the activation of glutamate receptors by kainic acid and domoic acid, cyanide and azide both display the same process after cellular damage. Interference with the inhibition produced by GABA can trigger epileptic events, GABA receptor inhibition is caused by lindane, picrotoxin, strychnine, and tetramethylenedisulfotetramine [27, 28, 29].

Toxic substanceMechanism
Parathion, chlorpyrifos, aldicarb, and carbarylInhibiting acetylcholinesterase and hyperstimulation of cholinergic receptors
Sarin, soman, scorpion venom and ciguatoxinModulating ion flow through voltage-gated sodium channels
AnatoxinNicotinic receptor activation
Kainic acid and domoic acidActivation of glutamate receptors
Lindane, picrotoxin and strychnineGABA receptor inhibition

Table 1.

Toxic substances that can trigger seizures and their exerting mechanism.


5. Drugs associated with seizures

The administration of different drugs used therapeutically can predispose to epileptic seizures presence either by lowering the epileptogenic threshold, intoxication, or overdose of these. The main groups of antimicrobials that can cause seizures are beta-lactams, anti-tuberculous, and antimalarials. The pro epileptogenic effect of beta-lactams is related to high doses or their toxicity. Seizures related to drugs used to treat tuberculosis are mainly due to vitamin B6 deficiency. Mefloquine and chloroquine are reported antimalarial drugs that can lead to seizures. The proconvulsive effect of methylxanthines is thought to be due to A1 adenosine receptor inhibition. Paradoxically, it is known that carbamazepine can worsen generalized-onset seizures. As well as the withdrawal effect of benzodiazepines, which in some cases can lower the seizure threshold [30, 31, 32, 33, 34]. Table 2 summarizes the main drugs associated with seizures. The following part reviews some of the toxic effects of the main antiepileptic drugs used in clinical practice.

CategoryDrugs associated with seizures
SympathomimeticsPhenylephrine, pseudoephedrine, and anorexiants
Anticancer drugsInterferon alfa, methotrexate, mitoxantrone, nelarabine, platinum-based, cisplatin, vinblastine, vincristine, busulfan, chlorambucil, cytarabine, doxorubicin, etoposide, and fluorouracil
AntimicrobialsCarbapenems, cephalosporins, fluoroquinolones, isoniazid, and penicillin
HypoglycemicsAny antidiabetic that causes hypoglycemia
ImmunosuppressantsCyclosporine, mycophenolate, tacrolimus, and azathioprine
PsychopharmaceuticalsMonoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin modulators, tricyclic antidepressants, antipsychotics, atomoxetine, bupropion, buspirone, and lithium
StimulantsAmphetamines and methylphenidate
XanthineAminophylline and theophylline
AntiepilepticsCarbamazepine and benzodiazepines

Table 2.

Main drugs associated with drugs.

5.1 Valproic acid

Since 1978, valproic acid or Na+ valproate has been characterized as an antiepileptic drug that suppresses the neuronal excitation of different types of epilepsy, such as partial seizures and generalized seizures [35]. It appears that valproic acid exerts its inhibition by blocking the reuptake of the neurotransmitter GABA, the main inhibitory neurotransmitter. It also lowers glutamate levels and modifies K+ conductance [36], exerting an inhibition through the voltage-dependent Na+ channels. In this way, it reduces the excitement caused by epileptic seizures [37]. Once this drug reaches the central nervous system (CNS), it binds to plasma proteins and is distributed throughout the extracellular space [38]. It is metabolized in the liver and discharged through the urine. Although it is also eliminated with expirations in the form of CO2 [39]. However, this drug is known to have frequent toxic effects derived from the therapeutic dose in patients with toxic plasma levels greater than 120 μg/ml [40]. After an overdose, the patient may be lethargic and coma, most likely due to inhibition produced in the CNS [41]. Another adverse situation that derives from the consumption of this antiepileptic drug is cerebral edema, probably caused by the overstimulation of the stimulation of NMDA receptors [42]. Cardiovascular alterations such as hypotension with tachycardia, gastric alterations such as pancreatitis, and hepatotoxicity have manifested with elevated transaminases, jaundice, and abdominal pain with inflammation, among others, may also occur [43].

5.2 Phenobarbital

Phenobarbital belongs to the family of barbiturates. These are characterized by providing the central nervous system with a depressant effect depending on the administered dose [44]. Its anticonvulsant mechanism is based on increasing the inhibitory activity of GABA, binding to the GABA receptor, and facilitating even more inhibitory neurotransmission. This inhibition reduces ATP levels, which causes the opening of Ca2+ channels associated with the NMDA receptor, coupled with the fact that a prolonged opening of these Ca2+ would lead to excitotoxic neuronal death [45]. The anticonvulsant dose ranges between 10 and 40 μg/ml. The administration of these doses and higher ones generates toxicity that is generally due to the increase in Ca2+ entry into the neuron [46]. Mitochondria are an intracellular target of barbiturates since they depolarize the mitochondrial membrane by inhibiting complex one of the electron transports chains and, furthermore, they could have an uncoupling effect on oxidative phosphorylation [47]. Its absorption of phenobarbital is gastric, which generates a decrease in peristaltic tone. Although it is metabolized in the liver and discharged through the kidneys and urine, it has a great fat solubility that crosses cell membranes, producing several alterations [48].

5.3 Carbamazepine

Carbamazepine is a mainly antiepileptic psychotropic drug whose mechanism of action is based on reducing glutamate release, reducing the permeability of neuronal membranes to Na+ and K+ ions, stabilizing neuronal membranes, and depressing dopamine and norepinephrine turnover, though an inhibitory effect on muscarinic and nicotinic receptors is also known [49]. When its therapeutic plasma concentrations are higher than 10 μg/ml, it produces toxic effects initially characterized by tachycardia, hypotension and hypertension, lethargy, ataxia, dysarthria, and nystagmus can occur, there are also gastric alterations such as vomiting and nausea. When intoxication is severe, it could even cause a coma [50]. Carbamazepine absorption is digestive, metabolized in the liver where it can cause liver dysfunction and, as its elimination is via the kidneys, adverse effects can also occur in this way [51].

5.4 Phenytoin

Phenytoin has been the most commonly used antiepileptic drug for patients with focal and generalized epilepsies since 1938 [52]. Its mechanism of action is exerted by inactivating voltage-gated Na+ channels. It also acts by inhibiting the flow of Ca2+ through neuronal membranes, such as it is to be expected at the cardiac level, it also inhibits Na+ channels, which is why it has toxic effects on the myocardium [53]. Phenytoin is bound to plasma proteins, such as albumin, which is metabolized in the liver, so it can cause liver diseases. Toxic effects are present even if the patient has adequate therapeutic levels, like at concentrations lower than 20 mg/Kg [54, 55]. Among the clinical toxic effects, patients may present nystagmus, ataxia, and numbness [56]. With more severe intoxications, in addition to the above: dysarthria, ataxia, the patient might not be able to walk, and may present hyperreflexia, besides consciousness usually being inhibited [57]. With higher doses, patients may even display a coma [58].

5.5 Lamotrigine

Lamotrigine is an antiepileptic drug principally used for generalized and partial seizures; it is also used in the adjunctive treatment of refractory crises [59]. Its action mechanism at the cellular level is based on blocking excitatory neurotransmitters, especially glutamate, through its NMDA receptors, as well as inhibiting voltage-dependent Na+ currents [60]. The toxic effects on patients who take this drug above 600 mg are characterized primarily at the CNS level by difficulty in concentration, showing dysarthria, nystagmus, and blurred or double vision. Patients may even present a loss of balance or coordination [61]. Its absorption is intestinal, its elimination in the urine, metabolized in the liver. Thus, there is idiosyncratic hepatotoxicity that commonly requires liver transplantation [62].

5.6 Oxcarbazepine

Oxcarbazepine is a derivative of carbamazepine, approved as an antiepileptic drug in America in 2000 [63]. This drug is used in the treatment of any type of epileptic seizure. The cellular mechanism by which it exerts its antiepileptic effects is based on the fact that it blocks voltage-gated Na+ channels, modulates the activity of Ca2+ channels, and increases K+ conductance, which consequently produces a stabilization of hyperexcited neuronal membranes for epileptic seizures [64]. Oxcarbazepine is a drug that is metabolized like other antiepileptic drugs by the liver and excreted by the kidney [65]. Toxic effects when daily doses are above 30 mg/kg are basically characterized by gastric alterations: mainly nausea and vomiting. The alterations in the CNS are identified by headache, fatigue, drowsiness, and ataxia. It has also been reported that some patients may have vertigo and hyponatremia [66].

5.7 Ethosuximide

Ethosuximide is an anticonvulsant used to reduce the frequency of absence-type seizures. It exerts its mechanism by reducing Ca2+ currents antagonized by the T-type Ca2+ channels. Furthermore, linked to this drug, modulation of the function of voltage-activated Na+ channels and Na+/K+ dendritic hyperpolarization-activated cyclic nucleotide-gated channel 1 channels has been suggested. It also reduces neuronal excitability by inhibiting the Na+/K+ pump [67]. However, ethosuximide is almost entirely absorbed in the digestive tract and metabolized in the liver, which can cause liver disease. The toxic effects of patients who consume above 25 mg/kg comprise gastric issues, nausea, vomiting, constipation, a state of sedation, headache, decreased alertness, drowsiness, and even comas have been reported at the CNS level [68]. Other adverse effects may include weight loss, as well as leukopenia [69].

5.8 Gabapentin

Gabapentin acts mainly by inhibiting partial and generalized seizures. Its mechanism of action is based on enhancing the inhibitory action of GABA [70]. A dose above 1,500 mg of gabapentin can cause hepatotoxicity, additionally, coupling various toxic effects like headaches, diplopia, nystagmus, diplopia, even involuntary movements have been described at the CNS level [71].

5.9 Topiramate

Topiramate is a drug used as an antiepileptic drug that acts by inhibiting partial and generalized seizures. Its action mechanism is exerted by blocking Na+ channels. As an AMPA receptor antagonist, it reduces excitatory neurotransmission, in addition to enhancing the inhibitory action of GABA [72]. Topiramate taken at a dose above 50 mg produces toxic effects, including dizziness. At the CNS level, patients have headaches, drowsiness, decreased concentration, and even confusion. Nevertheless, other anomalies have also been reported [73].


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, 79, 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, 84, 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, 91, 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, 94, 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+/K+ ATPase and NMDA receptors [100, 101, 102, 103].


7. Conclusion

The described above has enabled us to identify the excitotoxic effect induced by epileptic seizures, whether clinical or experimental. Likewise, it illustrated some of the toxic effects of antiepileptic drugs. From what has been illustrated, it is necessary to conduct research that allows offering other therapeutic alternatives to reduce the toxic effects of seizures and pharmacological therapy. The proposal of alternative treatments to treat seizures is essential to boost anti-toxic defense mechanisms. It can be suggested to propose therapies that minimize neuronal death or treatments with substances that activate antiepileptic protein activity, such as the extrinsic and intrinsic Wntpathway stimulation, or molecules that interact with the proteins involved in inflammatory and oxidative processes. The above mentioned could overall help reduce the interactions between the epileptic and pharmacological processes that ulteriorly lead to toxic effects on epileptic patients.Advertisement

Appendices and nomenclature


Glutamate receptors N-methyl-D-aspartate


𝜶-amino-2-3-dihydro-5-methyl-3-oxo-4-isoxazolepropionic acid


Gamma-aminobutyric acid




Sodium ions




Central nervous system


T-cell factor / lymphoid enhancing factor pathway


Adenomatous polyposis coli protein


Casein kinase 1


Glycogen synthase kinase 3 β


Notoginsenoside R1


Notoginsenoside R1


  1. 1. Epilepsy [Internet]. [cited 2021 Aug 21]. Available from:
  2. 2. An Introduction to Epilepsy [Internet] - PubMed [Internet]. [cited 2021 Aug 21]. Available from:
  3. 3. Blanke ML, VanDongen AMJ. Activation Mechanisms of the NMDA Receptor. Biol NMDA Recept [Internet]. 2009 Jan 1 [cited 2021 Aug 21];283-312. Available from:
  4. 4. Boison D. New insights into the mechanisms of the ketogenic diet. Curr Opin Neurol [Internet]. 2017 Apr 1 [cited 2021 Aug 21];30(2):187. Available from: /pmc/articles/PMC5409832/
  5. 5. J L, JM M. Kainate receptors in health and disease. Neuron [Internet]. 2013 Oct 16 [cited 2021 Aug 21];80(2):292-311. Available from:
  6. 6. Garthwaite J, Garthwaite G. The mechanism of kainic acid neurotoxicity. Nat 1983 3055930 [Internet]. 1983 [cited 2021 Aug 21];305(5930):138-40. Available from:
  7. 7. Y Y, J B, AJ B, ML M, AY L. Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics. Structure [Internet]. 2013 Oct 8 [cited 2021 Aug 21];21(10):1788-99. Available from:
  8. 8. SS W, S K. Glutamate, glutamate receptors, and downstream signaling pathways. Int J Biol Sci [Internet]. 2013 Sep 22 [cited 2021 Aug 21];9(9):948-59. Available from:
  9. 9. MY M, DA R, DM K. Activation of AMPA, kainate, and metabotropic receptors at hippocampal mossy fiber synapses: role of glutamate diffusion. Neuron [Internet]. 1998 [cited 2021 Aug 21];21(3):561-70. Available from:
  10. 10. Egebjerg J, Heinemann SF. Ca2+ permeability of unedited and edited versions of the kainate selective glutamate receptor GluR6. Proc Natl Acad Sci U S A [Internet]. 1993 Jan 15 [cited 2021 Aug 21];90(2):755. Available from: /pmc/articles/PMC45744/?report=abstract
  11. 11. L VDB, W V, H K, E VH, W R. Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons. J Neurol Sci [Internet]. 2000 Nov 1 [cited 2021 Aug 21];180(1-2):29-34. Available from:
  12. 12. Rajakulendran S, Hanna MG. The Role of Calcium Channels in Epilepsy. Cold Spring Harb Perspect Med [Internet]. 2016 Jan 1 [cited 2021 Aug 21];6(1). Available from: /pmc/articles/PMC4691803/
  13. 13. HF B. Glutamate, GABA and epilepsy. Prog Neurobiol [Internet]. 1995 [cited 2021 Aug 21];47(6):477-511. Available from:
  14. 14. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, et al. Glutamate Receptor Ion Channels: Structure, Regulation, and Function. Pharmacol Rev [Internet]. 2010 Sep [cited 2021 Aug 21];62(3):405. Available from: /pmc/articles/PMC2964903/
  15. 15. Catterall WA. Voltage-Gated Calcium Channels. Cold Spring Harb Perspect Biol [Internet]. 2011 [cited 2021 Sep 19];3(8):1-23. Available from: /pmc/articles/PMC3140680/
  16. 16. Van Loo KMJ, Schaub C, Pitsch J, Kulbida R, Opitz T, Ekstein D, et al. Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1. Nat Commun [Internet]. 2015 Oct 26 [cited 2021 Jun 12];6. Available from:
  17. 17. Dezsi G, Ozturk E, Stanic D, Powell KL, Blumenfeld H, O’Brien TJ, et al. Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia [Internet]. 2013 Apr [cited 2021 Jun 12];54(4):635-43. Available from:
  18. 18. Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. Vol. 588, Journal of Physiology. 2010. p. 1849-59.
  19. 19. Bondy SC. Intracellular calcium and neurotoxic events. Neurotoxicol Teratol. 1989 Nov 1;11(6):527-531.
  20. 20. Rowley S, Patel M. Mitochondrial involvement and oxidative stress in temporal lobe epilepsy [Internet]. Vol. 62, Free Radical Biology and Medicine. Elsevier Inc.; 2013 [cited 2020 May 12]. p. 121-31. Available from:
  21. 21. Waldbaum S, Patel M. Mitochondria, oxidative stress, and temporal lobe epilepsy. Vol. 88, Epilepsy Research. 2010. p. 23-45.
  22. 22. Zhu LJ, Chen Z, Zhang LS, Xu SJ, Xu AJ, Luo JH. Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures. Neurosci Lett [Internet]. 2004 Feb 6 [cited 2021 Jun 6];356(1):53-6. Available from:
  23. 23. Rosiles A, Rubio C, Trejo C, Gutierrez J, Hernández L, Paz C. Commentary: Participation of Sox-1 Expression and Signaling of β-Catenin in the Pathophysiology of Generalized Seizures in Cerebellum of Rat. CNS Neurol Disord - Drug Targets. 2016;15(1):3-6.
  24. 24. XT L, W M, XB W, Z L, JW Y, Y H, et al. Notoginsenoside R1 Promotes the Growth of Neonatal Rat Cortical Neurons via the Wnt/β-catenin Signaling Pathway. CNS Neurol Disord Drug Targets [Internet]. 2018 Jul 11 [cited 2021 Sep 19];17(7):547-56. Available from:
  25. 25. Rubio C, Rosiles-Abonce A, Trejo-Solís C, Rubio-Osornio M, Mendoza C, Custodio V, et al. Increase signaling of Wnt/β-catenin pathway and presence of apoptosis in cerebellum of kindled rats. CNS Neurol Disord - Drug Targets. 2017;16(7).
  26. 26. Rubio C, Luna R, Rosiles A, Rubio-Osornio M. Caloric Restriction and Ketogenic Diet Therapy for Epilepsy: A Molecular Approach Involving Wnt Pathway and KATP Channels. Front Neurol. 2020;11(November):1-17.
  27. 27. Jett DA. Chemical toxins that cause seizures. Neurotoxicology [Internet]. 2012 Dec [cited 2021 Jun 12];33(6):1473-5. Available from:
  28. 28. Jett DA. Neurotoxic Pesticides and Neurologic Effects [Internet]. Vol. 29, Neurologic Clinics. Neurol Clin; 2011 [cited 2021 Jun 12]. p. 667-77. Available from:
  29. 29. Assessment UENC for E. Handbook of neurotoxicology. 2009 Mar 15;
  30. 30. Sutter R, Rüegg S, Tschudin-Sutter S. Seizures as adverse events of antibiotic drugs : A systematic review [Internet]. Vol. 85, Neurology. Lippincott Williams and Wilkins; 2015 [cited 2021 Jun 12]. p. 1332-41. Available from:
  31. 31. Hitchings AW. Drugs that lower the seizure threshold. Adverse Drug React Bull. 2016 Jun 1;298(1):1151-1154.
  32. 32. Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: A review of the evidence [Internet]. Vol. 61, Epilepsy and Behavior. Academic Press Inc.; 2016 [cited 2021 Jun 12]. p. 282-6. Available from:
  33. 33. Johannessen Landmark C, Henning O, Johannessen SI. Proconvulsant effects of antidepressants — What is the current evidence? [Internet]. Vol. 61, Epilepsy and Behavior. Academic Press Inc.; 2016 [cited 2021 Jun 12]. p. 287-91. Available from:
  34. 34. Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: Management considerations. Br J Clin Pharmacol [Internet]. 2011 Sep [cited 2021 Jun 12];72(3):381-93. Available from:
  35. 35. N K, K G, A A, PS C, M T. Valproic acid as an antiepileptic drug: Is there a clinical relevance for the epilepsy surgeon? Epilepsy Res [Internet]. 2016 Nov 1 [cited 2021 Aug 21];127:191-4. Available from:
  36. 36. Bourin M. Mechanism of Action of Valproic Acid and Its Derivatives. 2020 [cited 2021 Aug 21]; Available
  37. 37. M R, P M, R D, S S, VE R, A V, et al. Valproic Acid and Epilepsy: From Molecular Mechanisms to Clinical Evidences. Curr Neuropharmacol [Internet]. 2019 Dec 28 [cited 2021 Aug 21];17(10):926-46. Available from:
  38. 38. MM Z, HL L, LH S, XP C, J L, ZL Z. The pharmacogenomics of valproic acid. J Hum Genet [Internet]. 2017 Dec 1 [cited 2021 Aug 21];62(12):1009-14. Available from:
  39. 39. Y G-P, CF T, JK L, JS L, W S, AK B, et al. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics [Internet]. 2013 [cited 2021 Aug 21];23(4):236-41. Available from:
  40. 40. Diederich M, Chateauvieux S, Morceau F, Dicato M. Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010;2010.
  41. 41. RM N, MG N. Adverse drug reactions induced by valproic acid. Clin Biochem [Internet]. 2013 Oct [cited 2021 Aug 21];46(15):1323-38. Available from:
  42. 42. MD S. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol [Internet]. 2002 [cited 2021 Aug 21];40(6):789-801. Available from:
  43. 43. V G, AK M, M K, B S, P G, M K. Valproic acid induced acute liver injury resulting in hepatic encephalopathy- a case report and literature review. J community Hosp Intern Med Perspect [Internet]. 2018 Sep 3 [cited 2021 Aug 21];8(5):311-4. Available from:
  44. 44. GM P. Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics. Curr Pediatr Rev [Internet]. 2016 Feb 1 [cited 2021 Aug 21];12(1):48-54. Available from:
  45. 45. N A-M, A S-R, S V, PA F. Neonatal phenobarbital exposure disrupts GABAergic synaptic maturation in rat CA1 neurons. Epilepsia [Internet]. 2018 Feb 1 [cited 2021 Aug 21];59(2):333-44. Available from:
  46. 46. Cherian, Thomas S V. Status epilepticus. Ann Indian Acad Neurol [Internet]. 2009 Jul 1 [cited 2021 Aug 21];12(3):140. Available from:;year=2009;volume=12;issue=3;spage=140;epage=153;aulast=Cherian
  47. 47. Phenobarbital: biopharmacology - PubMed [Internet]. [cited 2021 Aug 21]. Available from:
  48. 48. S K, RB S, JT D. Drug absorption. V. Influence of food on oral absorption of phenobarbital in rats. J Pharm Sci [Internet]. 1971 [cited 2021 Aug 21];60(11):1639-41. Available from:
  49. 49. J G, M G, SR B. Carbamazepine-related antiepileptic drugs for the treatment of epilepsy - a comparative review. Expert Opin Pharmacother [Internet]. 2016 May 2 [cited 2021 Aug 21];17(7):885-8. Available from:
  50. 50. Carbamazepine Toxicity - PubMed [Internet]. [cited 2021 Aug 21]. Available from:
  51. 51. L B. Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet [Internet]. 1978 [cited 2021 Aug 21];3(2):128-43. Available from:
  52. 52. Gupta M, Tripp J. Phenytoin. Encycl Toxicol Third Ed [Internet]. 2021 Jul 25 [cited 2021 Aug 21];895-7. Available from:
  53. 53. Y Y, ME S, JH P. Phenytoin: mechanisms of its anticonvulsant action. Ann Neurol [Internet]. 1986 [cited 2021 Aug 21];20(2):171-84. Available from:
  54. 54. Bochner F, Hooper WD, Tyrer JH, Eadie MJ. Effect of dosage increments on blood phenytoin concentrations. J Neurol Neurosurg Psychiatry [Internet]. 1972 [cited 2021 Aug 21];35(6):873. Available from: /pmc/articles/PMC494195/?report=abstract
  55. 55. J P, Q W, E N, K K. Phenytoin - An anti-seizure drug: Overview of its chemistry, pharmacology and toxicology. Food Chem Toxicol [Internet]. 2020 Aug 1 [cited 2021 Aug 21];142. Available from:
  56. 56. A I, BZ H. Phenytoin Toxicity. 2021 [cited 2021 Aug 21]; Available from:
  57. 57. JM M, R M, O D. Phenytoin intoxication. South Med J [Internet]. 1991 [cited 2021 Aug 21];84(10):1199-204. Available from:
  58. 58. Soderstrom J, Murray L, Little M, Daly FFS. Toxicology case of the month: carbamazepine overdose. Emerg Med J [Internet]. 2006 Nov [cited 2021 Aug 21];23(11):869. Available from: /pmc/articles/PMC2464388/
  59. 59. Lamotrigine. An update of its pharmacology and therapeutic use in epilepsy - PubMed [Internet]. [cited 2021 Aug 21]. Available from:
  60. 60. Betchel NT, Fariba K, Saadabadi A. Lamotrigine. Essence Analg Analg [Internet]. 2021 Aug 6 [cited 2021 Aug 21];306-9. Available from:
  61. 61. G P. Risks associated with lamotrigine prescription: a review and personal observations. Australas Psychiatry [Internet]. 2018 Dec 1 [cited 2021 Aug 21];26(6):640-2. Available from:
  62. 62. Lamotrigine | CAS#84057-84-1 | Anticonvulsant | MedKoo [Internet]. [cited 2021 Aug 21]. Available from:
  63. 63. MM K, NA H. Oxcarbazepine, an antiepileptic agent. Clin Ther [Internet]. 2001 [cited 2021 Aug 21];23(5):680-700. Available from:
  64. 64. S S. Oxcarbazepine: a review. Seizure [Internet]. 2000 [cited 2021 Aug 21];9(2):75-9. Available from:
  65. 65. EJ P, C S, M W-C, DJ M, HM D, W C, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther [Internet]. 2018 Apr 1 [cited 2021 Aug 21];103(4):574-81. Available from:
  66. 66. Hu X, Fu X, Jiang A, Yang X, Fang X, Gong G, et al. Multiomic analysis of mice epilepsy models suggest that MIR-21a expression modulates mRNA and protein levels related to seizure deterioration. Genet Res (Camb). 2015 Dec 22;97.
  67. 67. JJ A. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol [Internet]. 2014 [cited 2021 Aug 21];119:417-32. Available from:
  68. 68. H S, M G, J O. Ethosuximide induced macroglossia and oropharyngeal edema. Int J Pediatr Otorhinolaryngol [Internet]. 2021 Jan 1 [cited 2021 Aug 21];140. Available from:
  69. 69. T W, P C, J C. Ethosuximide-induced drug reaction with eosinophilia and systemic symptoms with mediastinal lymphadenopathy. Pediatr Dermatol [Internet]. 2019 Jul 1 [cited 2021 Aug 21];36(4):e99-101. Available from:
  70. 70. S M, CC L, M U, S E. Pregabalin and gabapentin for pain. BMJ [Internet]. 2020 Apr 28 [cited 2021 Aug 21];369. Available from:
  71. 71. KE E, JR C, AM P, L O, KE H. Reports of gabapentin and pregabalin abuse, misuse, dependence, or overdose: An analysis of the Food And Drug Administration Adverse Events Reporting System (FAERS). Res Social Adm Pharm [Internet]. 2019 Aug 1 [cited 2021 Aug 21];15(8):953-8. Available from:
  72. 72. Bonifacio SL, VanMeurs K. Neuroprotective Therapies in Infants. Infect Dis Pharmacol. 2019 Jan 1;227-241.
  73. 73. JP R, ALF C. Topiramate-Associated Movement Disorder: Case Series and Literature Review. Clin Neuropharmacol [Internet]. 2020 Jul 1 [cited 2021 Aug 21];43(4):116-20. Available from:
  74. 74. Rubio C, Rubio-Osornio M, Retana-Marquez S, Lopez M, Custodio V, Paz C. In Vivo Experimental Models of Epilepsy. Cent Nerv Syst Agents Med Chem [Internet]. 2010 Dec 1 [cited 2020 May 12];10(4):298-309. Available from:
  75. 75. Jasper HH. E |An. O. Basic Mechanisms of the Epilepsies. Little, Brown and Company, 34 Beacon Street, Boston, Massachusetts 02106; 1969.
  76. 76. Ribak CE, Harris AB, Vaughn JE, Roberts E. Inhibitory, GABAergic nerve terminals decrease at sites of focal epilepsy. Science (80- ) [Internet]. 1979 [cited 2021 Jun 6];205(4402):211-4. Available from:
  77. 77. JS L, V U, LL D, JA F, BJ H. Efficacy of standard anticonvulsants in monkey model with spontaneous motor seizures. Epilepsia [Internet]. 1975 [cited 2021 Aug 21];16(2):301-17. Available from:
  78. 78. Borbély S, Dobó E, Czégé D, Molnár E, Bakos M, Szucs B, et al. Modification of ionotropic glutamate receptor-mediated processes in the rat hippocampus following repeated, brief seizures. Neuroscience [Internet]. 2009 Mar 3 [cited 2021 Jun 6];159(1):358-68. Available from:
  79. 79. Craig CR, Colasanti BK. GABA receptors, lipids, and gangliosides in cobalt epileptic focus. [Internet]. Vol. 44, Advances in neurology. 1986 [cited 2021 Jun 6]. p. 379-91. Available from:
  80. 80. Tsuda T, Sugaya A, Ohguchi H, Kishida N, Sugaya E. Protective effects of peony root extract and its components on neuron damage in the hippocampus induced by the cobalt focus epilepsy model. Exp Neurol [Internet]. 1997 [cited 2021 Jun 6];146(2):518-25. Available from:
  81. 81. Kapur J, Macdonald RL. Rapid Seizure-Induced Reduction of Benzodiazepine and Zn 2 Sensitivity of Hippocampal Dentate Granule Cell GABA A Receptors. 1997.
  82. 82. Sørensen J, Slomianka L, Christensen J, Zimmer J. Zinc-containing telencephalic connections to the rat striatum: a combined Fluoro-Gold tracing and histochemical study. Exp Brain Res [Internet]. 1990 Feb 1 [cited 2021 Jun 6];105(3):370-82. Available from:
  83. 83. Furtinger S, Bettler B, Sperk G. Altered expression of GABAB receptors in the hippocampus after kainic-acid-induced seizures in rats. Mol Brain Res [Internet]. 2003 May 12 [cited 2021 Jun 6];113(1-2):107-15. Available from:
  84. 84. Vezzani A, Sperk G, Colmers WF. Neuropeptide Y: Emerging evidence for a functional role in seizure modulation [Internet]. Vol. 22, Trends in Neurosciences. Elsevier Ltd; 1999 [cited 2021 Jun 6]. p. 25-30. Available from:
  85. 85. Sperk G. Kainic acid seizures in the rat [Internet]. Vol. 42, Progress in Neurobiology. Prog Neurobiol; 1994 [cited 2021 Jun 6]. p. 1-32. Available from:
  86. 86. Tian FF, Zeng C, Guo TH, Chen Y, Chen JM, Ma YF, et al. Mossy fiber sprouting, hippocampal damage and spontaneous recurrent seizures in pentylenetetrazole kindling rat model. Acta Neurol Belg [Internet]. 2009 Dec 1 [cited 2021 Jun 6];109(4):298-304. Available from:
  87. 87. Li X, Kuang H, Jiang N, Hu Y. Involvement of Scn1b and Kcna1 ion channels in audiogenic seizures and PTZ-induced epilepsy. Epilepsy Res [Internet]. 2005 [cited 2021 Jun 6];66(1-3):155-63. Available from:
  88. 88. Clark CR. Comparative Anticonvulsant Activity and Neurotoxicity of 4-Amino-N-(2,6-dimethylphenyl) benzamide and Prototype Antiepileptic Drugs in Mice and Rats. Epilepsia [Internet]. 1988 Apr 1 [cited 2021 Aug 21];29(2):198-203. Available from:
  89. 89. RA U, AY C, EA S. Effects of gamma-aminobutyric acid (GABA) receptor agonists on the neurotoxicity and anticonvulsant activity of barbiturates in mice. J Pharmacol Exp Ther [Internet]. 1986 [cited 2021 Aug 21];237(2):468-72. Available from:
  90. 90. Bertram EH, Lothman EW, Lenn NJ. The hippocampus in experimental chronic epilepsy: A morphometric analysis. Ann Neurol [Internet]. 1990 [cited 2021 Jun 6];27(1):43-8. Available from:
  91. 91. Nevander G, Ingvar M, Auer R, Siesjö BK. Status epilepticus in well–oxygenated rats causes neuronal necrosis. Ann Neurol [Internet]. 1985 [cited 2021 Jun 6];18(3):281-90. Available from:
  92. 92. Szot P, Weinshenker D, White SS, Robbins CA, Rust NC, Schwartzkroin PA, et al. Norepinephrine-deficient mice have increased susceptibility to seizure- inducing stimuli. J Neurosci [Internet]. 1999 Dec 15 [cited 2021 Jun 6];19(24):10985-92. Available from:
  93. 93. Avoli M. Feline generalized penicillin epilepsy. Ital J Neurol Sci [Internet]. 1995 Mar [cited 2021 Jun 6];16(1-2):79-82. Available from:
  94. 94. Akdogan I, Adiguzel E, Yilmaz I, Ozdemir MB, Sahiner M, Tufan AC. Penicillin-induced epilepsy model in rats: Dose-dependant effect on hippocampal volume and neuron number. Brain Res Bull [Internet]. 2008 Oct 22 [cited 2021 Jun 6];77(4):172-7. Available from:
  95. 95. Ni H, Jiang Y wu, Tao L yuang, Cen J nong, Wu X ru. Effects of penicillin-induced developmental epilepticus on hippocampal regenerative sprouting, related gene expression and cognitive deficits in rats. Toxicol Lett [Internet]. 2009 Jul 24 [cited 2021 Jun 6];188(2):161-6. Available from:
  96. 96. Söderfeldt B, Kalimo H, Olsson Y, Siesjö B. Pathogenesis of brain lesions caused by experimental epilepsy - Light- and electron-microscopic changes in the rat cerebral cortex following bicuculline-induced status epilepticus. Acta Neuropathol [Internet]. 1981 Sep 1 [cited 2021 Jun 6];54(3):219-31. Available from:
  97. 97. Seutin V, Johnson SW. Recent advances in the pharmacology of quaternary salts of bicuculline [Internet]. Vol. 20, Trends in Pharmacological Sciences. Elsevier Ltd; 1999 [cited 2021 Jun 6]. p. 268-70. Available from:
  98. 98. Mitchell J, Gatherer M, Sundstrom LE. Aberrant Timm-stained fibres in the dentate gyrus following tetanus toxin-induced seizures in the rat. Neuropathol Appl Neurobiol [Internet]. 1996 Apr 1 [cited 2021 Jun 6];22(2):129-35. Available from:
  99. 99. Jordan SJ, Jefferys JGR. Sustained and selective block of IPSPs in brain slices from rats made epileptic by intrahippocampal tetanus toxin. Epilepsy Res. 1992 Apr 1;11(2):119-129.
  100. 100. Cavalheiro EA, Leite JP, Bortolotto ZA, Turski WA, Ikonomidou C, Turski L. Long-Term Effects of Pilocarpine in Rats: Structural Damage of the Brain Triggers Kindling and Spontaneous I Recurrent Seizures. Epilepsia [Internet]. 1991 [cited 2021 Jun 6];32(6):778-82. Available from:
  101. 101. Gibbs JW, Shumate MD, Coulter DA. Differential epilepsy-associated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons. J Neurophysiol [Internet]. 1997 [cited 2021 Jun 6];77(4):1924-38. Available from:
  102. 102. Fernandes MJS, Naffah-Mazzacoratti MG, Cavalheiro EA. Na+K+ ATPase activity in the rat hippocampus: A study in the pilocarpine model of epilepsy. Neurochem Int [Internet]. 1996 [cited 2021 Jun 6];28(5-6):497-500. Available from:
  103. 103. Scorza CA, Garrido YDC, Arida RM, Amado D, Cavalheiro EA, Naffah-Mazzacoratti MDG. Levels of the synaptic protein X11 alpha/mint1 are increased in hippocampus of rats with epilepsy. Epilepsy Res [Internet]. 2003 [cited 2021 Jun 6];57(1):49-57. Available from:

Written By

Carmen Rubio, Artemio Rosiles-Abonce, Elisa Taddei and Moisés Rubio-Osornio

Submitted: August 30th, 2021 Reviewed: September 20th, 2021 Published: December 2nd, 2021