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Molecular insights into monogenic idiopathic epilepsies have illustrated the central role of channelopathies in their etiology. Among ion channels, both high- and low-voltage-activated calcium channels and their ancillary subunits Cav2.1 (P/Q-type) calcium channels support a number of dynamic processes in neurons at both presynaptic and postsynapti...
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... Dysfunctional calcium channels, implicated in disorders like epilepsy, are promising therapeutic targets. Categorized into families like high-voltageactivated (HVA) and low-voltage-activated (LVA) channels, they comprise subunits including α1, α2δ, β, and γ, influencing function [15,16]. Ca2+ channels consist of α1, α2, β, γ, and δ subunits. ...
Epilepsy is a chronic neurological condition that affects millions of people worldwide and has serious effects on their social, economic, and general well-being. Its complex etiology includes genetic predisposition and acute insults, which cause abnormalities in glutamatergic and GABAergic transmission and result in neuronal hyperexcitability. In addition to seizures, epilepsy is linked to somatic co-morbidities, cognitive impairment, and mental health issues. However, a third of patients continue to show little improvement with current therapies. Using in silico-docking analysis, drug discovery can be done more quickly and affordably. This review explores the role of molecular docking in identifying potential antiepileptic drug candidates by focusing on common targets such as ion channels (sodium, calcium, potassium), GABA system (receptors and GABA transaminase), glutamate system (NMDA and AMPA receptors), carbonic anhydrase, and novel targets like SV2A, cannabinoid receptors, mitochondrial proteins, inflammatory pathways, and endogenous transporters. Molecular docking enables rational drug design, virtual screening, binding affinity prediction, and mode of action elucidation by shedding light on the atomic-level interactions between small compounds and target proteins. To sum up, understanding the intricate molecular pathways behind epilepsy and employing molecular docking to identify innovative medications that target these systems have potential for enhancing therapeutic outcomes. To get these putative therapeutic candidates closer to clinical use, additional experimental validation is needed. These initiatives ultimately seek to improve the quality of life for people with epilepsy by offering more efficient and specialized therapy alternatives.
... Результатом таких нарушений становятся повышенная восприимчивость нейронов к приступам и потенциальное развитие фармакорезистентности [57]. Также мутации в генах, кодирующих различные субъединицы кальциевых каналов, ассоциированы с появлением нейродегенеративных заболеваний, образуя эпилептогенные эффекты без внятного единого механизма, объясняющего их [58]. ...
Currently, the problem of effective therapy for drug-resistant epilepsy remains vastly relevant. The severity of drug-resistant epilepsy, remarkable negative social sequelae and sudden death in epilepsy pose a heavy burden on healthcare system. Although many innovative antiepileptic drugs have been developed in recent decades, surgical approach remains the only effective way to treat drug-resistant epilepsy which is coupled to significant health risks and does not guarantee freedom from seizures. The stumbling block in managing this pathology is the lack of knowledge on pathogenetic mechanisms, leaving a significant proportion of patients without quality medical care. There are different viewpoints on developing drug resistance in epilepsy, which are characterized by multilayered and overlapping molecular disease bases. The review presents the analysis of the existing hypotheses regarding the mechanisms underlying drug resistance development in epilepsy.
... They also modulate cellular excitability by influencing synaptic structure and function. These channels control the release of presynaptic transmitters in dendrites, which is vital for maintaining neuronal excitability and preventing seizure activity [1,2]. The association between VG-CCs and epilepsy is significant, highlighting the critical role of calcium channels in the pathophysiology of epileptic disorders. ...
... binding, circadian rhythm regulation, and endoplasmic reticulum (as highlighted in Table S3), though they exhibited unadjusted p-values greater than 0.05. Only the first pathway has a direct correlation with epilepsy treatment 29,30 , exemplified by calcium ion channel blockers such as thosuximide and topiramate, indicating a novel mechanism of action for Lomitapide distinct from the previously reported target MTTP. The ten novel targets of Lomitapide featured in Table 2 frequently appear in pathways enriched by AEDs. Figure 5b displays only the top three pathways for each GO category-biological process, cellular component, and molecular functionwith Benjamini-Hochberg adjusted p-values. ...
Due to considerable global prevalence and high recurrence rate, the pursuit of effective new medication for epilepsy treatment remains an urgent and significant challenge. Drug repurposing emerges as a cost-effective and efficient strategy to combat this disorder. This study leverages the transformer-based deep learning methods coupled with molecular binding affinity calculation to develop a novel in-silico drug repurposing pipeline for epilepsy. The number of candidate inhibitors against 24 target proteins encoded by gain-of-function genes implicated in epileptogenesis ranged from zero to several hundreds. Our pipeline has repurposed the medications with most anti-epileptic drugs and nearly half psychiatric medications, highlighting the effectiveness of our pipeline. Furthermore, Lomitapide, a cholesterol-lowering drug, first emerged as particularly noteworthy, exhibiting high binding affinity for 10 targets and verified by molecular dynamics simulation and mechanism analysis. These findings provided a novel perspective on therapeutic strategies for other central nervous system disease.
... It seems important to focus on the role of the electrolyte profile in the diagnostic approach of seizures in children, even in the context of febrile seizures. Fever can reveal underlying phosphocalcic abnormality associated with increasing needs for calcium [7]. ...
Pediatric hypoparathyroidism is an uncommon endocrine disease that can be either isolated or syndromic. It occurs when the secretion of parathormone is insufficient to maintain normal levels of ionized calcium. Patients with hypoparathyroidism can exhibit cerebral calcifications and metabolic disorders, and the severity of such features is inversely correlated with hypocalcemia.
We report a case of a 13-year-old patient who was initially diagnosed with epilepsy by another medical team two years before her admission to our hospital and who was subjected to oral valproate therapy. The anti-epileptic therapy proved to be unsuccessful even with increasing doses. The diagnosis was corrected when we performed adequate biological investigations. This case is underlying the importance of the electrolytes profile, especially the serum phosphocalcic test, in the management of patients with new onset or recurrent epileptic seizures.
... Since absence seizures and episodic ataxia have been confirmed in patients and animals with presynaptic voltage-gated P/Q-type (Ca v 2.1) calcium channel-related gene mutations [3,4], the essential role of these channels in brain functioning and neurotransmitter release have been investigated over the last decade [5,6]. Evidence showed that alterations in the expression of these channels may have a role in the pathogenesis of epilepsy [7,8]. Therefore, it has been thought that specific blockers of Ca v 2.1 channels can normalize abnormal electrical discharges in the brain and alleviate seizure activity [9]. ...
... Even though P/Q-type calcium channels (Ca v 2.1) can be localized in different brain regions, expressions of these channels have been found mainly in the hippocampus and cerebellum [33]. Evidence showed that alterations in the expression of these channels may have a role in the pathogenesis of epilepsy [7,8], myasthenia gravis, Lambert-Eaton myasthenic syndrome [34], and migraine [31]. ...
High-voltage-gated calcium channels have pivot role in the cellular and molecular mechanisms of various neurological disorders, including epilepsy. Similar to other calcium channels, P/Q-type calcium channels (Cav2.1) are also responsible for vesicle release at synaptic terminals. Up to date, there are very limited reports showing the mechanisms of Cav2.1 in epileptogenesis. In the present study, we investigated the anticonvulsive and neuroprotective effects of ω-agatoxin IVA, a specific Cav2.1 blocker, in a chemical kindling model of epileptogenesis. Righting reflex and inclined plane tests were used to assess motor coordination. Electroencephalography was recorded for electrophysiological monitoring of seizure activity in freely moving rats. Immunohistochemical analyses were performed for brain-derived neurotrophic factor (BDNF) and cleaved caspase-3 expressions in the prefrontal cortex, striatum, hippocampus, and thalamic nucleus. ω-Agatoxin IVA injected into the right lateral ventricle significantly prolonged the onset of seizures in a dose-dependent manner. In addition, repeated intraperitoneal administrations of ω-agatoxin IVA significantly suppressed the development of kindling and epileptic discharges without altering motor coordination. In addition, ω-agatoxin IVA significantly increased BDNF expressions, and decreased cleaved caspase-3 expressions in the brain when compared to PTZ + saline group. Our current study emphasizes the significance of the inhibition of P/Q type calcium channels by ω-agatoxin IVA, which suppresses the development of epileptogenesis and provides a new potential pathway for epilepsy treatment.
... 18 VGCC is a key component in controlling neuronal excitability and is thus of importance in the pathogenesis of different types of epilepsies, including absence epilepsies, which account for 10% of epileptic seizures. 18,19 T-type calcium channels initially respond to small depolarization, and their effect further depolarizes the cell, where HVA and sodium channels activate, allowing excess calcium entry and action potential generation. 20 VGCC is an important target for most of the AEDs. ...
Background
Epilepsy is a chronic neurological disorder that affects approximately 50–70 million people worldwide. Epilepsy has a significant economic and social burden on patients as well as on the country. The recurrent, spontaneous seizure activity caused by abnormal neuronal firing in the brain is a hallmark of epilepsy. The current antiepileptic drugs provide symptomatic relief by restoring the balance of excitatory and inhibitory neurotransmitters. Besides, about 30% of epileptic patients do not achieve seizure control. The prevalence of adverse drug reactions, including aggression, agitation, irritability, and associated comorbidities, is also prevalent. Therefore, researchers should focus on developing more effective, safe, and disease-modifying agents based on new molecular targets and signaling cascades.
Summary
This review overviews several clinical trials that help identify promising new targets like lactate dehydrogenase inhibitors, c-jun n-terminal kinases, high mobility group box-1 antibodies, astrocyte reactivity inhibitors, cholesterol 24-hydroxylase inhibitors, glycogen synthase kinase-3 beta inhibitors, and glycolytic inhibitors to develop a new antiepileptic drug.
Key messages
Approximately 30% of epileptic patients do not achieve seizure control. The current anti-seizure drugs are not disease modifying, cure or prevent epilepsy. Lactate dehydrogenase inhibitor, cholesterol 24-hydroxylase inhibitor, glycogen synthase kinase-3 beta inhibitors, and mTOR inhibitors have a promising antiepileptogenic effect.
... The pharmacological properties of N-type VOCCs are characteristic of a calcium entry pathway leading to neurotransmitter release in sympathetic neurons, nerve (motor) endings, and synaptosomes [84][85][86]. Two other VOCCs were reported in neurons, P-(Purkinje) and Q-types [84,87]. The single channel conductance of both types of channels is 10-20 pS (Table 1) (for review, please see ref. [88]). ...
Calcium is a highly positively charged ionic species. It regulates all cell types’ functions and is an important second messenger that controls and triggers several mechanisms, including membrane stabilization, permeability, contraction, secretion, mitosis, intercellular communications, and in the activation of kinases and gene expression. Therefore, controlling calcium transport and its intracellular homeostasis in physiology leads to the healthy functioning of the biological system. However, abnormal extracellular and intracellular calcium homeostasis leads to cardiovascular, skeletal, immune, secretory diseases, and cancer. Therefore, the pharmacological control of calcium influx directly via calcium channels and exchangers and its outflow via calcium pumps and uptake by the ER/SR are crucial in treating calcium transport remodeling in pathology. Here, we mainly focused on selective calcium transporters and blockers in the cardiovascular system.
... At these synapses, Ca 2+ influx through Ca V 2.1 supports action potential-triggered neurotransmitter release [5,[7][8][9]. Missense point mutations in CACNA1A cause a wide range of clinical symptoms including Familial Hemiplegic Migraine type 1 (FHM1) [9][10][11][12][13][14][15][16], Episodic Ataxia type 2 (EA2) [17][18][19] and epilepsy [20][21][22], as described in detail the Online Mendelian Inheritance in Man website (OMIM 601011). These point mutations, which typically result in a single amino acid substitution in Ca V 2.1, can alter channel gating, ion selectivity and expression and are typically categorized as either Gain-of-Function (GOF) or Loss-of-Function (LOF) [23][24][25][26][27][28][29][30]. ...
P/Q-type Ca2+ flux into nerve terminals via CaV2.1 channels is essential for neurotransmitter release at neuromuscular junctions and nearly all central synapses. Mutations in CACNA1A, the gene encoding CaV2.1, cause a spectrum of pediatric neurological disorders. We have identified a patient harboring an autosomal-dominant de novo frameshift-causing nucleotide duplication in CACNA1A (c.5018dupG). The duplicated guanine precipitated 43 residues of altered amino acid sequence beginning with a glutamine to serine substitution in CaV2.1 at position 1674 ending with a premature stop codon (CaV2.1 p.Gln1674Serfs*43). The patient presented with episodic downbeat vertical nystagmus, hypotonia, ataxia, developmental delay and febrile seizures. In patch-clamp experiments, no Ba2+ current was observed in tsA-201 cells expressing CaV2.1 p.Gln1674Serfs*43 with β4 and α2δ-1 auxiliary subunits. The ablation of divalent flux in response to depolarization was likely attributable to the inability of CaV2.1 p.Gln1674Serfs*43 to form a complete channel pore. Our results suggest that the pathology resulting from this frameshift-inducing nucleotide duplication is a consequence of an effective haploinsufficiency.
... This review will help future studies on the mechanisms of ID/ GDD to develop novel treatment strategies for this condition. Although previous narrative reviews summarised the relationship between calcium channelopathies and epilepsy as well as autism spectrum disorder [17,[35][36][37] to the best of our knowledge, this is the first systematic review to explore the relationship between calcium channelopathies and ID/GDD. ...
... Previous narrative reviews summarised the relationship between calcium channelopathies and epilepsy as well as autism spectrum disorder [17,[35][36][37]. To the best of our knowledge, this is the first systematic review to explore the relationship between calcium channelopathies and ID/GDD. ...
... CACNA1E, CACNA1G, CAC-NA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. In another review, both gain-and loss-of-function variants in CACNA1A, gain-of-function variants in CACNA1H, and variants in CACNA1G were linked to epilepsy [35,36,214]. Calcium overload resulting to mitochondrial dysfunction, oxidative stress, and cell damage was concluded as a possible pathomechanism important for the development of acquired epilepsies [36]. ...
Background
Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel.
Main body
A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C , CACNA1I, CACNA1H, CACNA1D , CACNA2D1 , CACNA2D2 , CACNA1E , CACNA1F , and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E , CACNA1G , CACNA1F , CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C , CACNA1A , and CACNA1E . Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro.
Conclusion
Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.
