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Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures

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Neural Regeneration Research 2025年第1期20卷 265-276页

作者： Yao Yuan Lingqi Yu Xudong Zhuang Dongjing Wen Jin He Jingmei Hong Jiayu Xie Shengan Ling Xiaoyue Du Wenfeng Chen Xinrui Wang Institute of Life Sciences College of Biological Science and EngineeringFuzhou UniversityFuzhouFujian ProvinceChina NHC Key Laboratory of Technical Evaluation of Fertility Regulation for Non-human Primate(Fujian Maternity and Child Health Hospital) FuzhouFujian ProvinceChina Medical Research Center Fujian Maternity and Child Health HospitalCollege of Clinical Medicine for Obstetrics&Gynecology and PediatricsFujian Medical UniversityFuzhouFujian ProvinceChina Department of Neurology and Institute of Neurology of The First Affiliated Hospital Institute of Neuroscienceand Fujian Key Laboratory of Molecular NeurologyFujian Medical UniversityFuzhouFujian ProvinceChina

Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

关键词： ATP1A1 Atpα bang-sensitive paralysis Charcot-Marie-Tooth disease type 2 CRISPR/Cas9 homology-directed repair Na^(+)/K^(+)-ATPase point mutation seizures sodium pump

seizures and epilepsy secondary to viral infection in the central nervous system

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Acta Epileptologica 2020年第1期2卷 93-100页

作者： Peng Zhang Yuting Yang Jialin Zou Xinrui Yang Qiankun Liu Yangmei Chen Department of Neurology The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400010China

Viral infection in the central nervous system(CNS)is a common cause of seizures and epilepsy.Acute symptomatic seizures can occur in the context of almost all types of acute CNS viral infection.However,late unprovoked seizures and epilepsy may not be frequent after viral infection of the CNS.The incidence of seizures and epilepsy after CNS viral infection is mainly dependent on the brain region of infection.It remains to be determined whether treatment of CNS viral infection using antiepileptic drugs(AEDs)can prevent seizures and subsequent epilepsy in patients,particularly with regard to the timing,drug choice and dosage,and duration of AEDs.The postoperative outcome of seizures in patients with intractable epilepsy caused by viral encephalitis primarily depends on the epileptogenic zone.In addition,neuroinflammation is known to be widely involved in the generation of seizures during CNS viral infection,and the effects of anti-inflammatory therapies in preventing seizures and epilepsy secondary to CNS viral infection require further studies.In this review,we discuss the incidence,mechanisms,clinical management and prognosis of seizures and epilepsy secondary to CNS viral infection,and summarize common CNS viral infections that cause seizures and epilepsy.

关键词： seizures Epilepsy Viral infection Central nervous system

Reactive glia-to-GABAergic neuron reprogramming:a“golden touch”strategy to alleviate intractable seizures

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Acta Epileptologica 2022年第3期5卷 213-216页

作者： Junzi Chen Zhongxia Li Liying Chen The First School of Clinical Medicine Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang ProvinceCollege of Pharmaceutical ScienceZhejiang Chinese Medical UniversityHangzhou 310053China Department of Pharmacy Sir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou 310020China

This commentary highlights a research article published recently in Cell Stem Cell“Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy”.Generally,Lentini et al.reveal a strategy to fulfill in vivo glia-to-neuron reprogramming,which is a potential disease-modifying strategy for treatment of intractable seizures.Here,we describe exciting research advances in the treatment of intractable seizures based on this research article,summarizing its key findings,emphasizing its importance and providing further discussions.Further,issues worthy of further investigations are also postulated so that clinic translation can be better achieved.

关键词： seizures epilepsy programming

Genetic diagnosis of neonatal-onset seizures

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Genes & Diseases 2019年第4期6卷 441-447页

作者： Xueling Ma Fengzhu Yang Ziyu Hua The Department of Neonatology Children’s Hospital of Chongqing Medical UniversityChongqing400014China Ministry of Education Key Laboratory of Child Development and Disorders Chongqing400014China Chongqing International Science and Technology Cooperation Center for Child Development and Disorders Chongqing400014China Chongqing Key Laboratory of Child Infection and Immunity Chongqing400014China National Demonstration Base of Standardized Training Base for Resident Physicians Chongqing400014China

Many seizures in neonates are due to early-onset epilepsy,which is often difficult to diagnose,especially to explore the causes.Recently,the development of next-generation sequencing(NGS)has led to the discovery of a large number of genes involved in epilepsy.This may improve prompt detection of early-onset epilepsy in neonates.This study aimed at analyzing the genotype-phenotype correlations in neonates with seizures in a bid to improve the understanding of genetic diagnosis of early-onset epilepsy.Clinical features and prognosis of 15 children who underwent genetic testing having had unexplained seizures from February 2016 to May 2018 in Children’s Hospital of Chongqing Medical University were analyzed retrospectively.The salient findings were:poor response to stimulus and abnormal electroencephalogram(EEG)in the initial period were observed in the group with concomitant genetic abnormalities.Despite the recent progress in genetic technology,molecular diagnosis for neonatal-onset epilepsy can be challenging due to genetic and phenotypic heterogeneities.However,some genotypes are associated with specific clinical manifestations and EEG patterns.Therefore,in-depth understanding of genotype-phenotype correlations would be useful to clinicians managing neonates with early-onset seizures.

关键词： Genetic Genotype-phenotype Molecular diagnosis Neonate seizures

Oxcarbazepine oral suspension in young pediatric patients with partial seizures and/or generalized tonic-clonic seizures in routine clinical practice in China: a prospective observational study

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World Journal of Pediatrics 2018年第3期14卷 280-289页

作者： Jiong Qin Yi Wang Xin-Fang Huang Yu-Qin Zhang Fang Fang Yin-Bo Chen Zhong-Dong Lin Yan-Chun Deng Fei Yin Li Jiang Ye Wu Xiang-Shu Hu Department of Pediatrics Peking University People’s HospitalNo.11 Xi Zhi Men Nan Da JieXicheng DistrictBeijing 100044China Department ofP ediatrics Peking University First HospitalBeijingChina Department ofN eurology Children’s HospitalFudan UniversityShanghaiChina Department ofP ediatrics Quanzhou Women’s andChildren’s HospitalQuanzhouChina Department of N eurology Tianjin Children’s HospitalTianjinChina Department of N eurology Beijing Children’s HospitalBeijingChina Department of Pediatric Neurology The First Bethune HospitalJilin UniversityChangchunChina Department of Pediatric Neurology The 2nd Affi liated HospitalWenzhou Medical UniversityWenzhouChina Department of N eurology Xijing HospitalXi’anChina Department of P ediatrics Xiangya HospitalCentral South UniversityChangshaChina Department of N eurology Children’s HospitalChongqing Medical UniversityChongqingChina The third Department ofN eurology Guangdong 999 Brain HospitalGuangzhouChina

Background This study aimed to assess efficacy and safety of oxcarbazepine (OXC) oral suspension in pediatric patients aged 2-5 years with partial seizures (PS) and/or generalized tonic-clonic seizures (GTCS) in real-world clinical practice in China. Methods This 26-week, prospective, single-arm, multicenter, observational study recruited pediatric patients aged 2-5 years with PS or GTCS suitable for OXC oral suspension treatment based on physicians' judgments from 11 medical centers in China. Enrolled subjects started OXC oral suspension treatment as monotherapy or in combination with other antiepileptic drugs. Primary efficacy outcome was the percentage of pediatric subjects achieving ≥ 50% seizure frequency reduction at the end of the 26-week treatment. Secondary efficacy-related parameters and safety parameters such as adverse events (AEs) and serious AEs (SAEs) were also monitored during the 26-week treatment period. Results Six hundred and six pediatric patients were enrolled and 531 (87.6%) completed the study. After 26 weeks of treat-ment, 93.3% subjects achieved ≥ 50% seizure frequency reduction, and 81.8% achieved 100% seizure frequency reduction compared to baseline. Among diff erent seizure types, OXC was eff ective in all subjects with simple PS and in > 90% of subject with other type of seizure present in the study. AEs were observed in 49 (8.1%) subjects. Only three subjects expe-rienced SAE. Rash (n = 18, 2.97%) was the most common AE. Only 17 subjects discontinued due to AEs. Conclusion This study, reporting the real-world data, further confi rms the efficacy and good safety profi le of OXC oral suspension in Chinese pediatric patients aged 2-5 years with PS and/or GTCS.

关键词： Antiepileptic drugs Generalized tonic-clonic seizures Oxcarbazepine oral suspension Partial seizures Pediatric patients

Threshold for maximal electroshock seizures(MEST) at three developmental stages in young mice

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Zoological Research 2019年第3期40卷 231-235页

作者： Cheng Xiang Zhi-Na Li Tian-Zhuang Huang Jing-Hui Li Lei Yang Jing-Kuan Wei Faculty of Life Science and Technology Kunming University of Science and Technology First Affiliated Hospital of Kunming Medical University Department of Neurosurgery Kunming Children's Hospital

Early brain development after birth is extremely dynamic,suggest!ng that potential functional changes occur during this period.In this study,the maximal electroshock seizure threshold(MEST)was used to explore the electrophysiological variation among three developmental stages in young mice(no more than 5 weeks old).The induced electroshock seizure(ES)behavior of early post natal mice(1-2-weeks old)differed from that during weaning(3 weeks old)and early puberty(4-5-weeks old).Thus,we further explored their respective characteristic responses to the ES parameters.When the stimulation current(SC)was limited to 4.0 mA,only the 1-2-week-old mice were induced to exhibit ES behavior at voltages of 30 V and 40 V,indicating they were more sensitive to maximal electroshock seizure(MES)(response to lower voltage).

关键词： maximal electroshock seizures young mice

Oxcarbazepine oral suspension in pediatric patients with partial seizures and/or generalized tonic-clonic seizures: a multi-center, single arm, observational study in China

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World Journal of Pediatrics 2017年第6期13卷 551-559页

作者： Yi Wang Yin-Bo Chen Yu-Qin Zhang Rong Luo Hua Wang Jun-Lan Lv Dong Wang Sui-Qiang Zhu Zhong-Dong Lin Jiong Qin Department of Neurology Children's Hospital of Fudan UniversityShanghaiChina Department of Pediatric Neurology The First Bethune Hospital of Jilin UniversityChangchunChina Department of Neurology Tianjin Children's HospitalTianjinChina Department of Pediatric Neurology West China Second University Hospital of Sichuan UniversityChengduChina Department of Pediatric Neurology Shengjing Hospital of China Medical UniversityShenyangChina Department of Neurology Beijing Children's HospitalCapital Medical UniversityBeijingChina Department of Neurology Xi'an Children's HospitalXi'anChina Department of Neurology Tongji HospitalTongji Medical College of Huazhong University of Science&TechnologyWuhanChina Department of Pediatric Neurology The 2nd Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina Department of Pediatrics Peking University People's HospitalBeijingChina

Background:To assess efficacy and safety of oxcarbazepine (OXC) oral suspension in pediatric patients aged 2-16 years with partial seizures (PS) and/or generalized tonic-clonic seizures (GTCS) in real-world clinical practice in China.Methods:This 26-week,single arm,multicenter and observational study recruited patients aged 2-16 years with PS or GTCS suitable for OXC oral suspension treatment.Enrolled patients received OXC oral suspension treatment for 26 weeks.Primary endpoints included mean seizure frequency at the end of the treatment and mean seizure frequency reduction at the end of the treatment vs.baseline.Secondary efficacy-related endpoints and safety parameters were also assessed.Results:Nine hundred and eighty-seven pediatric patients were enrolled and 912 (92.4%) completed the study.The mean seizure frequencies at baseline and the end of week 26 were 13.40±64.92 and 1.62±19.47 times/month,respectively.The mean seizure frequency reduction was 10.03±63.67 times/month and the mean seizure frequency reduction percentage was 90.02%±5127.0% (P<0.0001).After 26 weeks of treatment,82.36%,7.24% and 3.86% of the patients became controlled,significantly improved and improved,respectively.Adverse events (AEs) were reported in 74 (7.65%) patients.Rash was the most common AE.The efficacy of OXC was not affected by seizure types,age or gender.Conclusion:This study confirms the efficacy and good safety profile of OXC oral suspension in Chinese pediatric patients aged 2-16 years with PS and/or GTCS.

关键词： children efficacy generalized tonic-clonic seizures oxcarbazepine oral suspension partial seizures

Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits

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Signal Transduction and Targeted Therapy 2023年第7期8卷 3427-3442页

作者： Liying Chen Yingwei Xu Heming Cheng Zhongxia Li Nanxi Lai Menghan Li Yeping Ruan Yang Zheng Fan Fei Cenglin Xu Jiao Ma Shuang Wang Yan Gu Feng Han Zhong Chen Yi Wang Institute of Pharmacology&Toxicology College of Pharmaceutical SciencesSchool of MedicineZhejiang UniversityHangzhouChina Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhouChina Zhejiang Rehabilitation Medical Center Department The Third Affiliated HospitalZhejiang Chinese Medical UniversityHangzhouChina Key Laboratory of Cardiovascular&Cerebrovascular Medicine Drug Target and Drug Discovery CenterSchool of PharmacyNanjing Medical UniversityNanjingChina

Temporal lobe epilepsy(TLE),one common type of medically refractory epilepsy,is accompanied with altered adult-born dentate granule cells(abDGCs).However,the causal role of abDGCs in recurrent seizures of TLE is not fully understood.Here,taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner.

关键词： epilepsy seizures maintain

The toxic natural product tutin causes epileptic seizures in mice by activating calcineurin

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1916-1925页

作者： Qing-Tong Han Wan-Qi Yang Caixia Zang Linchao Zhou Chong-Jing Zhang Xiuqi Bao Jie Cai Fangfei Li Qinyan Shi Xiao-Liang Wang Jing Qu Dan Zhang Shi-Shan Yu State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China

Tutin,an established toxic natural product that causes epilepsy in rodents,is often used as a tool to develop animal model of acute epileptic seizures.However,the molecular target and toxic mechanism of tutin were unclear.In this study,for the first time,we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome profiling.Our studies showed that calcineurin(CN)was a target of tutin,and that tutin activated CN,leading to seizures.Binding site studies further established that tutin bound within the active site of CN catalytic *** inhibitor and calcineurin A(CNA)knockdown experiments in vivo proved that tutin induced epilepsy by activating CN,and produced obvious nerve damage.Together,these findings revealed that tutin caused epileptic seizures by activating CN.Moreover,further mechanism studies found that N-methyl-D-aspartate(NMDA)receptors,gammaaminobutyric acid(GABA)receptors and voltage-and Ca2+-activated K+(BK)channels might be involved in related signaling pathways.Our study fully explains the convulsive mechanism of tutin,which provides new ideas for epilepsy treatment and drug development.

关键词： epilepsy seizures epileptic