How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

Yu, Nian; Lin, Xingjian; Qin, Di

doi:10.2174/1570159x18666200128124338

Cited by 4 publications

(4 citation statements)

References 144 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, various individual targets for antiepileptogenic drugs have been identified 10 ; however, different forms of brain injuries and pathophysiological phenotypes, alone or in combination, drive the occurrence of epilepsy. Therefore, the targeting of one pathway would not be antiepileptogenic for all patients.…”

mentioning

confidence: 99%

MicroRNAs and target genes in epileptogenesis

et al. 2020

View full text Add to dashboard Cite

Epilepsy is a chronic brain dysfunction. Current antiepileptic medicines cannot prevent epileptogenesis. Increasing data have shown that microRNAs (miRNAs) are selectively altered within the epileptic hippocampi of experimental models and human tissues, and these alterations affect the genes that control epileptogenesis. Furthermore, manipulation of miRNAs in animal models can modify epileptogenesis. As a result, miRNAs have been proposed as promising targets for treating epilepsy. We searched PubMed using the terms "microRNAs/miRNAs AND epilepsy", "microRNAs/miRNAs AND epileptogenesis", and "microRNAs/miRNAs AND seizure". We selected the articles in which the relationship between miRNAs and target gene(s) was validated and manipulation of miRNAs in in vivo epilepsy models modified epileptogenesis during the chronic phase via gene regulation. A total of 13 miRNAs were found in the present review. Based on the current analysis of miRNAs and their target gene(s), each miRNA has limitations as a potential epilepsy target. Importantly, miR-211 or miR-128 transgenic mice displayed seizures. These findings highlight new developments for epileptogenesis prevention. Developing novel strategies to modify epileptogenesis will be effective in curing epilepsy patients. This article provides an overview of the clinical application of miRNAs as novel targets for epilepsy.

show abstract

mentioning

confidence: 99%

MicroRNAs and target genes in epileptogenesis

et al. 2020

View full text Add to dashboard Cite

show abstract

“…2,3 The traditional ASMs mainly target remodeling the balance of excitation and inhibition, including regulating ligand-gated glutamate receptors, enhancing γ-aminobutyric acid (GABA) function, etc. 4 However, epilepsy is a chronic progressive disease with cell damage, triggering the inflammation response and recapitulation of development. 5 In 2002, Löscher et al 6 proposed that the development of diseasemodifying therapies (DMTs) is one of the important future goals for epilepsy treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Although the first‐line treatments for epilepsy are anti‐seizure medications (ASMs), about 30% of patients with epilepsy fail to benefit from seizure control 2,3 . The traditional ASMs mainly target remodeling the balance of excitation and inhibition, including regulating ligand‐gated glutamate receptors, enhancing γ‐aminobutyric acid (GABA) function, etc 4 . However, epilepsy is a chronic progressive disease with cell damage, triggering the inflammation response and recapitulation of development 5 .…”

Section: Introductionmentioning

confidence: 99%

Inhibiting acid‐sensing ion channel exerts neuroprotective effects in experimental epilepsy via suppressing ferroptosis

Shi,

Liu,

Wang

et al. 2024

CNS Neurosci Ther

View full text Add to dashboard Cite

BackgroundEpilepsy is a chronic neurological disease characterized by repeated and unprovoked epileptic seizures. Developing disease‐modifying therapies (DMTs) has become important in epilepsy studies. Notably, focusing on iron metabolism and ferroptosis might be a strategy of DMTs for epilepsy. Blocking the acid‐sensing ion channel 1a (ASIC1a) has been reported to protect the brain from ischemic injury by reducing the toxicity of [Ca2+]i. However, whether inhibiting ASIC1a could exert neuroprotective effects and become a novel target for DMTs, such as rescuing the ferroptosis following epilepsy, remains unknown.MethodsIn our study, we explored the changes in ferroptosis‐related indices, including glutathione peroxidase (GPx) enzyme activity and levels of glutathione (GSH), iron accumulation, lipid degradation products‐malonaldehyde (MDA) and 4‐hydroxynonenal (4‐HNE) by collecting peripheral blood samples from adult patients with epilepsy. Meanwhile, we observed alterations in ASIC1a protein expression and mitochondrial microstructure in the epileptogenic foci of patients with drug‐resistant epilepsy. Next, we accessed the expression and function changes of ASIC1a and measured the ferroptosis‐related indices in the in vitro 0‐Mg2+ model of epilepsy with primary cultured neurons. Subsequently, we examined whether blocking ASIC1a could play a neuroprotective role by inhibiting ferroptosis in epileptic neurons.ResultsOur study first reported significant changes in ferroptosis‐related indices, including reduced GPx enzyme activity, decreased levels of GSH, iron accumulation, elevated MDA and 4‐HNE, and representative mitochondrial crinkling in adult patients with epilepsy, especially in epileptogenic foci. Furthermore, we found that inhibiting ASIC1a could produce an inhibitory effect similar to ferroptosis inhibitor Fer‐1, alleviate oxidative stress response, and decrease [Ca2+]i overload by inhibiting the overexpressed ASIC1a in the in vitro epilepsy model induced by 0‐Mg2+.ConclusionInhibiting ASIC1a has potent neuroprotective effects via alleviating [Ca2+]i overload and regulating ferroptosis on the models of epilepsy and may act as a promising intervention in DMTs.

show abstract

“…However, available therapies are only symptomatic and often ineffective, which could not thoroughly inhibit the development of epilepsy. One third of the patients treated with antiepileptic drugs continue to experience seizures (Pfisterer et al., 2020; Yu et al., 2020). Thus, studying the molecular mechanism underlying epileptogenesis is critical for exploring novel therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of SLITRK5 in patients with epilepsy and in a rat model

Liu

Zhang

et al. 2023

Synapse

View full text Add to dashboard Cite

SLIT and NTRK‐like protein‐5 (SLITRK5) is one of the six members of SLITRK protein family, which is widely expressed in central nervous system (CNS). In brain, SLITRK5 plays important roles in neurite outgrowth, dendritic branching, neuron differentiation, synaptogenesis, and signal transmission of neurons. Epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. The pathophysiological mechanism of epilepsy remains unclear. Neuronal apoptosis, abnormal nerve excitatory transmission, and synaptic remodeling are thought to be involved in the development of epilepsy. To explore whether there is a potential relationship between SLITRK5 and epilepsy, we investigated the expression and distribution of SLITRK5 in patients with temporal lobe epilepsy (TLE) and a rat model of epilepsy. We collected cerebral cortex samples from patients with drug‐refractory temporal lobe epilepsy, and a rat model of epilepsy induced by lithium chloride/pilocarpine was established. The ways of immunohistochemistry, double‐immunofluorescence labeling and western blot have been used in our study to research the expression and distribution of SLITRK5 in the temporal lobe epilepsy patients and epilepsy animal model. All of the results have shown that SLITRK5 is mainly localized in the cell cytoplasm of neurons both in patients with TLE and in epilepsy model. In addition, compared with nonepileptic controls, the expression of SLITRK5 was upregulated in the temporal neocortex of TLE patients. And both in the temporal neocortex and hippocampus of pilocarpine‐induced epilepsy rats, the expression of SLITRK5 was increased at 24 h after status epilepticus (SE), with a relatively high level within 30 days, and reached the peak on the 7th day after SE. Our preliminary results revealed that SLITRK5 may have a potential relationship with epilepsy, which may be a foundation for the further study of the underlying mechanism between SLITRK5 and epilepsy and the therapeutic targets of antiepileptic drugs.

show abstract

How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

Cited by 4 publications

References 144 publications

MicroRNAs and target genes in epileptogenesis

MicroRNAs and target genes in epileptogenesis

Inhibiting acid‐sensing ion channel exerts neuroprotective effects in experimental epilepsy via suppressing ferroptosis

Upregulation of SLITRK5 in patients with epilepsy and in a rat model

Contact Info

Product

Resources

About