Neurotoxicity and Epileptogenesis

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

## **Abstract**

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.

**Keywords:** 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); -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<sup>+</sup> ion channel, this depolarization in turn causes Na+ channels opening, which leads to Ca2+ channels aperture that further increases neuron excitability. Na<sup>+</sup> channels' participation in epileptogenesis and their mutations in many epileptic disorders has been long studied. The Na<sup>+</sup> 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<sup>+</sup> 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.
