Identification of novel gene and pathway targets for human epilepsy treatment

Jin, Ying; Zhao, Chunsong; Chen, Lihui; Liu, Xiangyu; Pan, Shuxiao; Ju, Dongsheng; Ma, Jing; Li, Jinying; Wei, Bo

doi:10.1186/s40659-015-0060-5

Cited by 11 publications

(5 citation statements)

References 32 publications

(33 reference statements)

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“…Basically, dysfunction of ion channels, abnormal expression of epilepsy genes, and imbalance release of neuronal transmitters are responsible for the epileptic activity. 5 – 7 γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter and decrease of GABA will lead to oversynchronization, subsequent to epilepsy. 8 – 10 Therefore, GABA receptors were considered as one of the therapeutic targets for epilepsy.…”

Section: Introductionmentioning

confidence: 99%

Involvement of upregulation of miR-210 in a rat epilepsy model

Chen¹,

Zheng²,

Zhang³

2016

NDT

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Epilepsy is a common type of neurological disorder with complex etiology. The mechanisms are still not clear. MicroRNAs are endogenous noncoding RNAs with many physiological activities. Multiple microRNAs were abnormally expressed in status epilepticus, including miR-210. In this study, we applied lithium chloride and pilocarpine to induce epileptic activity and aimed to disclose the potential mechanisms. Our data showed that miR-210 was significantly upregulated in hippocampus one day after modeling (P<0.05 vs control) and the high expression of miR-210 lasted for at least 30 days. By contrast, γ-aminobutyric acid (GABA) level significantly decreased concurrently after modeling (P<0.05 vs control). To question whether miR-210 could be a potential therapeutic target for epilepsy, miR-210 inhibitor was administrated through intrahippocampal injection after epilepsy modeling. Our data showed that morphological changes of hippocampal neurons and apoptosis triggered by epilepsy were mitigated by miR-210 inhibition. More importantly, the expressions of GABA-related proteins, including GABAA receptor α1, glutamate decarboxylase, and GABA transporter 1, were significantly elevated after epilepsy modeling in both mRNA and protein levels 3 days postmodeling (P<0.05 vs control), which were mitigated by miR-210 inhibitor treatment (P<0.05 vs model). In addition, epilepsy-induced upregulation of GABA transaminase was alleviated by miR-210 inhibitor. Taken together, these data implicated potential roles of miR-210 in lithium chloride–pilocarpine-induced epilepsy model and miR-210 could serve as a potential therapeutic target in status epilepticus.

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Section: Introductionmentioning

confidence: 99%

Involvement of upregulation of miR-210 in a rat epilepsy model

Chen¹,

Zheng²,

Zhang³

2016

NDT

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“…We also found that shared biological and cellular processes driven from PLS1 and risk gene lists were related to ‘chemical synaptic transmission’, ‘neurotransmitter transport’, ‘regulation of cell projection organization’, ‘modulation of chemical synaptic transmission’ and ‘synapse organisation’. These processes, particularly change the function of many ion channels, regulating synaptic function and neurotransmitter receptors and have previously been reported to contribute to epileptogenesis [68, 69]. Disturbances in synaptic transmission, in particular to the balance between excitatory and inhibitory synapses, play a role in the pathogenesis of seizures and epilepsy, and the processes of synaptic transmission are also targets for therapies for epilepsy [70].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, MSN-related transcriptomic data in endothelial cells may be associated with inflammatory and immune responses for GGE [88]. The mechanism related to pro-inflammatory expression may involve the regulation of the innate immune reaction in response to seizures [50,69,89]. Taken together, excitatory neurons and inhibitory neurons may contribute to the generation of epileptic seizures and immune responses in epilepsy pathogenesis.…”

Section: Chromosome- Cell Type-and Disease-specific Gene-set Enrichmentsmentioning

confidence: 99%

Cortical morphometric vulnerability to generalised epilepsy reflects chromosome‐ and cell type‐specific transcriptomic signatures

Keller

Seidlitz

et al. 2022

Neuropathology Appl Neurobio

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Aims: Generalised epilepsy is thought to involve distributed brain networks. However, the molecular and cellular factors that render different brain regions more vulnerable to epileptogenesis remain largely unknown. We aimed to investigate epilepsy-related morphometric similarity network (MSN) abnormalities at the macroscale level and their relationships with microscale gene expressions at the microscale level.Methods: We compared the MSN of genetic generalised epilepsy with generalised tonic-clonic seizure patients (GGE-GTCS, n = 101) to demographically matched healthy controls (HC, n = 150). Cortical MSNs were estimated by combining seven morphometric features derived from structural magnetic resonance imaging for each individual.Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen Human Brain Atlas.Results: GGE-GTCS patients exhibited decreased regional MSNs in primary motor, prefrontal and temporal regions and increases in occipital, insular and posterior cingulate cortices, when compared with the HC. These case-control neuroimaging differences were validated using split-half analyses and were not affected by medication or drug response effects. When assessing associations with gene expression, genes associated

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“…In a five-generational Chinese epileptic family with generalized seizure, SCN3B gene was not associated with seizure susceptibility (Lu et al, 2010). Inconsistent, the dysregulation of SCN3B gene might play an important role in the progression of epilepsy and a potential target for epilepsy treatment (Jin et al, 2016). Furthermore, the current study found no significant associations in the SCN3B gene of Nav channel with epilepsy susceptibility and AEDs treatment response and in Jordanian population.…”

Section: Discussionmentioning

confidence: 99%

Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility

AL-Eitan

Al-Dalalah

Aljamal

2019

Saudi Pharmaceutical Journal

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BackgroundPharmacotherapy of epilepsy including antiepileptic drugs (AEDs) is one of the main treatment approaches. As a biological target, sodium channels (Nav channels) and glutamate receptor genes are playing a major role in the etiology and treatment of epilepsy.ObjectiveThis study aims to investigate the genetic associations of certain genetic polymorphisms with increased risk of epilepsy susceptibility and variability in response to AEDs treatment in a Jordanian Arab population.MethodA pharmacogenetics and case-control study on 296 unrelated epileptic Jordanian patients recruited from the pediatric neurology clinic at the Queen Rania Al-Abdullah Hospital (QRAH) in Amman, Jordan and 299 healthy individuals was conducted. Children up to 15 years old which receiving AEDs for at least three months were scanned for genetic association of 7 single nucleotide polymorphisms (SNPs) within three candidate genes (SCN2A, SCN3B and GRM4) with epilepsy susceptibility.ResultsSCN2A rs2304016 (P = 0.04) and GRM4 rs2499697 (P = 0.031) were statistically significant with generalized epilepsy. Haplotype of CAACG GRM4 was genetically associated with epilepsy and partial epilepsy (P = 0.036; P = 0.024, respectively). This study also found that TGTAA genetic haplotype formed within GRM4 gene was associated with generalized epilepsy susceptibility (P = 0.006). While, no significant linkage of SCN3B rs3851100 to either disease susceptibility or drug responsiveness was found.ConclusionThis study identified no significant associations of allelic or genotypic SNPs with the susceptibility of epilepsy and medication response with an exception of rs2304016 and rs2499697 SNPs that were associated with the generalized type of epilepsy among Jordanian population. Further studies are required in different populations to confirm our results and identify genetic factors that involved in susceptibility and treatment response.

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Identification of novel gene and pathway targets for human epilepsy treatment

Cited by 11 publications

References 32 publications

Involvement of upregulation of miR-210 in a rat epilepsy model

Involvement of upregulation of miR-210 in a rat epilepsy model

Cortical morphometric vulnerability to generalised epilepsy reflects chromosome‐ and cell type‐specific transcriptomic signatures

Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility

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