Subicular Caspase‐1 Contributes to Pharmacoresistance in Temporal Lobe Epilepsy

Xu, Cenglin; Zhang, Shuo; Gong, Yitao; Nao, Jiazhen; Shen, Yujia; Tan, Bei; Xu, Shuheng; Cui, Sunliang; Ruan, Yuanyuan; Wang, Shuang; Wang, Yi; Chen, Zhong

doi:10.1002/ana.26173

Cited by 35 publications

(14 citation statements)

References 53 publications

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“…Using female Wistar rats as in Löscher's initial studies, Xu et al [86] reported that the expression of activated caspase-1 in the subiculum, but not the CA1, was upregulated in phenytoin-resistant amygdala-kindled rats. Genetic ablation of caspase-1 interfered with the genesis of pharmacoresistance in the kindling model.…”

Section: Cellular and Molecular Mechanisms Of Pharmacoresistance In A...mentioning

confidence: 99%

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Löscher

White

2023

Cells

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In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into the market for the treatment of epilepsy using well-established preclinical seizure and epilepsy models. Despite this success, approximately 20–30% of patients with epilepsy have drug-resistant epilepsy (DRE). The current approach to ASM discovery for DRE relies largely on drug testing in various preclinical model systems that display varying degrees of ASM drug resistance. In recent years, attempts have been made to include more etiologically relevant models in the preclinical evaluation of a new investigational drug. Such models have played an important role in advancing a greater understanding of DRE at a mechanistic level and for hypothesis testing as new experimental evidence becomes available. This review provides a critical discussion of the pharmacology of models of adult focal epilepsy that allow for the selection of ASM responders and nonresponders and those models that display a pharmacoresistance per se to two or more ASMs. In addition, the pharmacology of animal models of major genetic epilepsies is discussed. Importantly, in addition to testing chemical compounds, several of the models discussed here can be used to evaluate other potential therapies for epilepsy such as neurostimulation, dietary treatments, gene therapy, or cell transplantation. This review also discusses the challenges associated with identifying novel therapies in the absence of a greater understanding of the mechanisms that contribute to DRE. Finally, this review discusses the lessons learned from the profile of the recently approved highly efficacious and broad-spectrum ASM cenobamate.

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Section: Cellular and Molecular Mechanisms Of Pharmacoresistance In A...mentioning

confidence: 99%

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Löscher

White

2023

Cells

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“…This is consistent with the findings of Galic et al and others ( Vezzani and Granata, 2005 ; Galic et al, 2008 ; D’Ambrosio et al, 2013 ), who found that anti-TNF-α monoclonal antibodies blocked the proepileptic effects of lipopolysaccharide; moreover, Choi et al (2009) demonstrated considerable elevation of pro-inflammatory cytokines such as IL-1β in brain tissue of epileptic patients in addition to TNF-α, but these phenomena did not occur in our experiments, which may be related to the regions of the examined brain tissues. In a recent study, elevated levels of IL-1β has also been considered to probably have brain region specificity in a TLE animal model ( Xu et al, 2021b ). Hence, we will further explore the changes of inflammatory factors in more brain regions in our subsequent experiments.…”

Section: Discussionmentioning

confidence: 99%

Anti-Epileptic Effect of Crocin on Experimental Temporal Lobe Epilepsy in Mice

et al. 2022

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Temporal lobe epilepsy (TLE) is a common kind of refractory epilepsy. More than 30% TLE patients were multi-drug resistant. Some patients may even develop into status epilepticus (SE) because of failing to control seizures. Thus, one of the avid goals for anti-epileptic drug development is to discover novel potential compounds to treat TLE or even SE. Crocin, an effective component of Crocus sativus L., has been applied in several epileptogenic models to test its anti-epileptic effect. However, it is still controversial and its effect on TLE remains unclear. Therefore, we investigated the effects of crocin on epileptogenesis, generalized seizures (GS) in hippocampal rapid electrical kindling model as well as SE and spotaneous recurrent seizure (SRS) in pilocarpine-induced TLE model in ICR mice in this study. The results showed that seizure stages and cumulative afterdischarge duration were significantly depressed by crocin (20 and 50 mg/kg) during hippocampal rapid kindling acquisition. And crocin (100 mg/kg) significantly reduced the incidence of GS and average seizure stages in fully kindled animals. In pilocarpine-induced TLE model, the latency of SE was significantly prolonged and the mortality of SE was significantly decreased by crocin (100 mg/kg), which can also significantly suppress the number of SRS. The underlying mechanism of crocin may be involved in the protection of neurons, the decrease of tumor necrosis factor-α in the hippocampus and the increase of brain derived neurotrophic factor in the cortex. In conclusion, crocin may be a potential and promising anti-epileptic compound for treatment of TLE.

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“…However, one-third of the PWEs cannot achieve desirable outcomes, which is diagnosed as pharmacoresistant epilepsy (Kwan and Brodie, 2000 ). Pharmacoresistant epilepsy usually shares more severe pathological conditions including hyperexcitable circuitry and abnormally activated molecular pathways (Xu et al, 2019 , 2021 ), resulting in the intractability of successful management. With increased clinical findings, it is somehow convincible that epilepsy with ATP1A3 mutation shares a high incidence of being pharmacoresistant.…”

Section: Clinical Evidence About Atp1a3 Alteration...mentioning

confidence: 99%

The role of ATP1A3 gene in epilepsy: We need to know more

Zou

Lan²,

Gong³

et al. 2023

Front. Cell. Neurosci.

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The ATP1A3 gene, which encodes the Na+/K+-ATPase α3 catalytic subunit, plays a crucial role in both physiological and pathological conditions in the brain, and mutations in this gene have been associated with a wide variety of neurological diseases by impacting the whole infant development stages. Cumulative clinical evidence suggests that some severe epileptic syndromes have been linked to mutations in ATP1A3, among which inactivating mutation of ATP1A3 has been intriguingly found to be a candidate pathogenesis for complex partial and generalized seizures, proposing ATP1A3 regulators as putative targets for the rational design of antiepileptic therapies. In this review, we introduced the physiological function of ATP1A3 and summarized the findings about ATP1A3 in epileptic conditions from both clinical and laboratory aspects at first. Then, some possible mechanisms of how ATP1A3 mutations result in epilepsy are provided. We think this review timely introduces the potential contribution of ATP1A3 mutations in both the genesis and progression of epilepsy. Taken that both the detailed mechanisms and therapeutic significance of ATP1A3 for epilepsy are not yet fully illustrated, we think that both in-depth mechanisms investigations and systematic intervention experiments targeting ATP1A3 are needed, and by doing so, perhaps a new light can be shed on treating ATP1A3-associated epilepsy.

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Subicular Caspase‐1 Contributes to Pharmacoresistance in Temporal Lobe Epilepsy

Cited by 35 publications

References 53 publications

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Anti-Epileptic Effect of Crocin on Experimental Temporal Lobe Epilepsy in Mice

The role of ATP1A3 gene in epilepsy: We need to know more

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