**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 [16–19].

### **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. *Wnt* proteins 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*, *Wnt*3a, *Wnt*7a, and *Wn*t8 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 *Wn*t-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 *Wn*t-mTOR are some of these pathways. Epileptogenesis has been linked to the mTOR signaling pathway. *Wnt*7a, a *Wn*t family ligand, is expressed in cerebellar granule cells and operates as a particular canonical signaling activator. *Wnt*7a 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 *Wnt*7a was applied. Other studies have shown that *Wnt*7a 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 *Wn*t7a, resulting in an increase in excitatory neurotransmitter. *Wnt*8a is also involved in synaptic terminal excitability modulation. Additionally, it is also involved in the regulation of synaptic terminal excitability. These findings show that *Wnt* impacts synaptic regions important in excitatory neurotransmitter release control and regulation and

#### *Neurotoxicity and Epileptogenesis DOI: http://dx.doi.org/10.5772/intechopen.103687*

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].
