Metabotropic glutamate receptors as drug targets for the treatment of absence epilepsy

Ngomba, Richard Teke; Luijtelaar, Gilles van

doi:10.1016/j.coph.2018.01.012

Cited by 17 publications

(11 citation statements)

References 62 publications

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“…STX1B plays an important role in the regulation of synaptic vesicle exocytosis, including release of glutamatergic and GABAergic synaptic transmission (Mishima et al, 2014). Furthermore, some important neurotransmitters, such as glutamate and GABA have been found to be involved in epilepsy and drug treatment (Teichgräber et al, 2009;Ngomba and van Luijtelaar, 2018;Chun et al, 2019;Alcoreza et al, 2021). Therefore, STX1B may be involved in epilepsy and drug responsiveness by regulating synaptic vesicle exocytosis.…”

Section: Discussionmentioning

confidence: 99%

The Association Between STX1B Polymorphisms and Treatment Response in Patients With Epilepsy

Wang

Zhou

et al. 2021

Front. Pharmacol.

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Background: Epilepsy is a debilitating brain disease with complex inheritance and frequent treatment resistance. However, the role of STX1B single nucleotide polymorphisms (SNPs) in epilepsy treatment remains unknown.Objective: This study aimed to explore the genetic association of STX1B SNPs with treatment response in patients with epilepsy in a Han Chinese population.Methods: We first examined the associations between STX1B SNPs and epilepsy in 1000 Han Chinese and the associations between STX1B SNPs and drug-resistant epilepsy in 450 subjects. Expression quantitative trait loci analysis was then conducted using 16 drug-resistant epileptic brain tissue samples and results from the BrainCloud database (http://eqtl.brainseq.org).Results: The allelic frequencies of rs140820592 were different between the epilepsy and control groups (p = 0.002) after Bonferroni correction. The rs140820592 was associated with significantly lower epilepsy risk among 1,000 subjects in the dominant model after adjusting for gender and age and Bonferroni correction (OR = 0.542, 95%CI = 0.358–0.819, p = 0.004). The rs140820592 also conferred significantly lower risk of drug-resistant epilepsy among 450 subjects using the same dominant model after adjusting for gender and age and Bonferroni correction (OR = 0.260, 95%CI = 0.103–0.653, p = 0.004). Expression quantitative trait loci analysis revealed that rs140820592 was associated with STX1B expression level in drug-resistant epileptic brain tissues (p = 0.012), and this result was further verified in the BrainCloud database (http://eqtl.brainseq.org) (p = 2.3214 × 10–5).Conclusion: The STX1B rs140820592 may influence the risks of epilepsy and drug-resistant epilepsy by regulating STX1B expression in brain tissues.

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Section: Discussionmentioning

confidence: 99%

The Association Between STX1B Polymorphisms and Treatment Response in Patients With Epilepsy

Wang

Zhou

et al. 2021

Front. Pharmacol.

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“…6 mGluR is expressed in key regions of the cortex and the thalamus and are known to regulate spike and wave discharges. 32 Up-regulation of mGluR1 mRNA and protein occurs in the hippocampus of different animal models of epilepsy, suggesting that it may be involved in the neuronal hyperexcitability, loss, and subsequent epileptogenesis at acute stages after status epilepticus or kindling. 23 Stimulation of group I mGluRs elicits epileptogenesis, while group I mGluR antagonist 2-methyl-6-(phenylethynyl)-pyridine prevents status epilepticus and subsequent neuronal loss and epileptogenesis.…”

Section: Discussionmentioning

confidence: 99%

<p>microRNA-182 Negatively Influences the Neuroprotective Effect of Apelin Against Neuronal Injury in Epilepsy</p>

Han¹,

Dong²,

Zhang³

et al. 2020

NDT

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Purpose: To explore the neuroprotective effects and mechanisms of Apelin (APLN), and to study the regulation of APLN expression by microRNA (miRNA) in epilepsy. Materials and Methods: In vitro and in vivo epileptic models were established with hippocampal neurons and Wistar rats. Apoptosis of neurons was identified by flow cytometry. Western blotting was used to detect the expression of proteins, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to analyze the expression of miRNA and messenger RNA (mRNA). Bioinformatics software was used to predict target genes of miRNA, which were confirmed by dual-luciferase reporter gene system and functional experiments. Results: Our study demonstrated protective effects of APLN against neuronal death in epilepsy both in vitro and in vivo. The underlying mechanisms involved are inhibiting the expression of metabotropic glutamate receptor 1 (mGluR1), Bax, and caspase-3; promoting the expression of Bcl-2; and increasing phosphorylated-AKT (p-AKT) levels in neurons. For the first time, we found that miR-182 could negatively regulate both transcriptional and translational levels of APLN, and that the up-regulation of miR-182 inhibited the expression of APLN and Bcl-2, and promoted the expression of Bax and caspase-3. Conclusion: APLN could protect the neurons from injury in epilepsy by regulating the expression of apoptosis-associated proteins and mGluR1 and increasing p-AKT levels, which were attenuated by miR-182. Hence, miR-182/APLN may be potential targets for epilepsy control and treatment.

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“…This contrasts with metabotropic glutamate (mGlu) receptors, which, once binding extracellular glutamate, activate specific intracellular biochemical pathways through an intramembrane G protein. The role of mGlu receptors in the pathophysiology of convulsive and absence epilepsy has been extensively discussed in a number of review articles [ 12 , 15 , 17 - 24 ].…”

Section: Ionotropic Glutamate Receptors As Target In Epilepsymentioning

confidence: 99%

Targeting Ionotropic Glutamate Receptors in the Treatment of Epilepsy

Celli

Fornai

2021

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Background: A dysfunction in glutamate neurotransmission is critical for seizure. Glutamate is the major excitatory drive in the cerebral cortex, where seizures occur. Glutamate acts via (i) ionotropic (iGlu) receptors, which are ligand-gated ion channels mediating fast excitatory synaptic transmission; and (ii) G proteins coupled metabotropic (mGlu) receptors. Objective: To overview the evidence on the role of iGlu receptors in the onset, duration, and severity of convulsive and nonconvulsive seizures to lay the groundwork for novel strategies for drug-resistant epilepsy. Methods: We used PubMed crossed-search for “glutamate receptor and epilepsy” (sorting 3,170 reports), searched for “ionotropic glutamate receptors”, “AMPA receptors”, “NMDA receptors”, “kainate receptors”, “convulsive seizures”, “absence epilepsy”, and selected those papers focusing this Review’s scope. Results: iGlu receptors antagonists inhibit, whereas agonists worsen experimental seizures in various animal species. Clinical development of iGlu receptor antagonists has been limited by the occurrence of adverse effects caused by inhibition of fast excitatory synaptic transmission. To date, only one drug (perampanel) selectively targeting iGlu receptors is marketed for the treatment of focal epilepsy. However, other drugs, such as topiramate and felbamate, inhibit iGlu receptors in addition to other mechanisms. Conclusion: This review is expected to help dissecting those steps induced by iGlu receptors activation, which may be altered to provide antiepileptic efficacy without altering key physiological brain functions, thus improving safety and tolerability of iGlu-receptor directed antiepileptic agents. This effort mostly applies to drug resistant seizures, which impact the quality of life and often lead to status epilepticus, which is a medical urgency.

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Metabotropic glutamate receptors as drug targets for the treatment of absence epilepsy

Cited by 17 publications

References 62 publications

The Association Between STX1B Polymorphisms and Treatment Response in Patients With Epilepsy

The Association Between STX1B Polymorphisms and Treatment Response in Patients With Epilepsy

<p>microRNA-182 Negatively Influences the Neuroprotective Effect of Apelin Against Neuronal Injury in Epilepsy</p>

Targeting Ionotropic Glutamate Receptors in the Treatment of Epilepsy

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