NEUROBIOLOGY OF DISEASE
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2024
·
IF 5.1
Lu Deng,Hong Jiang,Jingjing Lin,Di Xu,Ailin Qi,Qing Guo,Ping-Ping Li,Xinshi Wang,Judy S. Liu,Xiaoqin Fu,Peijun Li
Summary Epilepsy is a brain disorder affecting up to 1 in 26 individuals. Despite its clinical importance, the molecular mechanisms of epileptogenesis are still far from clarified. Our previous study showed that disruption of Clock in excitatory neurons alters cortical circuits and leads to generation of focal epilepsy. In this study, a GAD-Cre;Clock flox/flox mouse line with conditional Clock gene knockout in inhibitory neurons was established. We observed that seizure latency was prolonged, the severity and mortality of pilocarpine-induced seizure were significantly reduced, and memory was improved in GAD-Cre;Clock flox/flox mice. We hypothesize that mice with CLOCK knockout in inhibitory neurons have increased threshold for seizure, opposite from mice with CLOCK knockout in excitatory neurons. Further investigation showed Clock knockout in inhibitory neurons upregulated the basal protein level of ARC, a synaptic plasticity-associated immediate-early gene product, likely through the BDNF-ERK pathway. Altered basal levels of ARC may play an important role in epileptogenesis after Clock deletion in inhibitory neurons. Although sEPSCs and intrinsic properties of layer 5 pyramidal neurons in the somatosensory cortex exhibit no changes, the spine density increased in apical dendrite of pyramidal neurons in CLOCK knockout group. Our results suggest an underlying mechanism by which the circadian protein CLOCK in inhibitory neurons participates in neuronal activity and regulates the predisposition to epilepsy.
研究领域:
神经科学
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分子生物学
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昼夜节律
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癫痫学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 8
·1-20
·
IF 5.638
Yang Qin,Zheng Fangshuo,Hu Yida,Yang Yi,Li Yun,Chen Guojun,Wang Wei,He Miaoqing,Zhou Ruijiao,Ma Yuanlin,Xu Demei,Tian Xin,Gao Xiaoya,Wang Qing,Wang Xuefeng
Epilepsy is one of the most prevalent and drug-refractory neurological disorders. Zinc finger DHHC-type containing 8 (ZDHHC8) is a putative palmitoyltransferase that is highly expressed in the brain. However, the impact of ZDHHC8 on seizures remains unclear. We aimed to explore the association of ZDHHC8 with epilepsy and investigate its in epileptogenesis in in vivo and in vitro models through behavioral, electrophysiological, and pathological studies. We used kainic acid- and pilocarpine-induced C57BL/6 mice and magnesium-free-induced pyramidal neurons as experimental epileptic models in this study. We first found increased ZDHHC8 expression in the brains of temporal lobe epilepsy (TLE) patients, similar to that observed in chronic epileptic mice, strongly suggesting that ZDHHC8 is correlated with human epilepsy. In the in vitro seizure models, knocking down ZDHHC8 using recombinant adeno-associated virus (rAAV) delayed seizure precipitation and decreased chronic spontaneous recurrent seizures (SRSs) and epileptiform-like discharges, while ZDHHC8 overexpression had the opposite effect. ZDHHC8 levels were consistent with seizure susceptibility in induced mice with SRSs. In an in vitro magnesium-free model, neuronal hyperexcitability and hypersynchrony were reduced in ZDHHC8-knockdown neurons but were increased in ZDHHC8-overexpressing neurons. To further explore the potential mechanisms, we observed that ZDHHC8 had a significant modulatory effect on 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor-related excitatory, but not inhibitory, glutamatergic synaptic neurotransmission, further affecting the inward rectification of AMPA currents in acute hippocampal slices in whole-cell recordings. ZDHHC8 facilitated GluA1 trafficking to the neuronal surface in the hippocampus, as shown by immunoprecipitation and Western blotting. These results suggest that ZDHHC8 may promote the generation and propagation of seizures in humans and that knocking down ZDHHC8 might produce anti-epileptogenic effects in drug-resistant epilepsy. Our study provides evidence that may facilitate the development of an alternative approach for the treatment of epilepsy by modulating AMPA/GluA1-mediated neurotransmission.
研究领域:
神经科学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF NEUROSCIENCE RESEARCH
·
2025
·Vol. 103
·期 7
·e70064
·
IF 3.4
Sun Hong,Liu GuoYan,Wu JiaWen,Yu Xin,Zhan ShuQin,Reng HongWei,Chen MengYing,Cheng YuXuan
Chronic epilepsy is mainly characterized by spontaneous recurrent seizures (SRS). The peroxisome proliferator activated receptor gamma/phosphatase and tensin homolog/protein kinase B (PPARγ/PTEN/Akt) pathway is involved in the pathogenesis of SRS and neuronal loss. Curcumin is a natural compound, and previous studies have shown it provides neuroprotection via anti-inflammation and anti-oxidant effects in many central nervous system (CNS) diseases. In the present study, we show that curcumin regulates the abnormal expression of PTEN and Akt in the SRS phase, improves the neuronal loss in the hippocampus, and suppresses SRS development and seizure spike activity in epileptic rats. More importantly, these effects are reversed by the PPARγ antagonist, T0070907, suggesting that curcumin exerts neuroprotective and anti-epileptic effects through the PPARγ/PTEN/Akt signaling pathway. Other studies have shown that curcumin can cross the BBB and has a safety profiles and pleiotropic pharmacological effects. Thus, our data support the proposition that curcumin might be a potential neuroprotective and anti-epileptic agent for chronic epilepsy.
研究领域:
神经病学
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分子生物学
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药理学
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转化医学
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中枢神经系统疾病
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产品关联
DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND FUNCTION
·
2024
·Vol. 42
·期 3
·e4003
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IF 2.8
Mengnan Xing,Xinlei Yang,Sinan Jin,Xiangping Xu
Neuronal pentraxin 2 (Nptx2), a member of the synaptic protein family linked to excitatory synaptic formation, is found to be upregulated in epileptic mice, yet its role in epilepsy has been unclear. In vivo, we constructed a mouse model of epilepsy by using kainic acid induction. In vitro experiments, a Mg 2+ -free medium was used to induce epileptiform discharges in neurons. The results showed that the Nptx2 was upregulated in epileptic mice. Moreover, Nptx2 knockdown reduced the number of seizures and seizure duration. Knocking down Nptx2 not only reduced the number and duration of seizures but also showed a decrease in electroencephalogram amplitude. Behavioral tests indicated improvements in learning and memory abilities after Nptx2 knockdown. The Nissl staining and Timms staining revealed that Nptx2 silencing mitigated epilepsy-induced brain damage. The immunofluorescence staining revealed that Nptx2 absence resulted in a reduction of apoptosis. Nptx2 knockdown reduced Bax, cleaved caspase3, and cleaved caspase9 expression, while increased Bcl-2 expression. Notably, Nptx2 knockdown inhibited GluA1 phosphorylation at the S831 site and reduced the GluA1 membrane expression. The PSD95 expression declined in the epilepsy model, while the Nptx2 knockdown reversed it. Collectively, our study indicated that Nptx2 silencing not only alleviated brain damage and neuron apoptosis but also improved learning and memory ability in epileptic mice, suggesting Nptx2 as a promising target for epilepsy treatment. Significant statement Nptx2 is associated with excitatory synaptic formation, while the role of Nptx2 in epilepsy remains unclear. Our finding indicated an upregulation of Nptx2 in epileptic mice, and knockdown of Nptx2 leading to a reduction in seizure frequency and duration, alongside improvements in learning and memory. Nptx2 knockdown alleviated neuron apoptosis. More importantly, GluA1 phosphorylation in the S831 site was increased in KA mice, while knockdown of Nptx2 reversed it. Nptx2 knockdown decreased the GluA1 membrane expression. Overall, our study suggested that Nptx2 silencing alleviated brain damage and inhibited neuron apoptosis. This study offers novel insights into epilepsy treatment.
研究领域:
神经科学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2017
·
IF 5.012
Zhenzhou Lin,Hua Huang,Yong Gu,Kaibin Huang,Yafang Hu,Zhong Ji,Yongming Wu,Shengnan Wang,Tingting Yang,Suyue Pan
Glibenclamide (GBC), a sulfonylurea receptor 1 blocker, emerges recently as a promising neuron protectant in various neurological disorders . This study aimed to determine whether GBC improves survival and neurological outcome of status epilepticus (SE). Male Sprague-Dawley rats successfully undergoing SE for 2.5 h (n = 134) were randomly assigned to GBC or vehicle group. Rats in the GBC group received a loading dose of 10 μg/kg of GBC, followed by 1.2 μg/6 h for 3 days, while same dose of vehicle was used as control. The 28-day survival rate in the GBC group (11/23) was significantly higher than that in the vehicle group (8/36). In addition, the frequency and duration of spontaneous recurrent seizures in SE rats were profoundly reduced by GBC but not by vehicle treatment. Moreover, cognitive impairment was observed in the SE rats at day 28, which was reversed by GBC treatment. Meanwhile, cerebral edema , as well as neuronal loss, was decreased in several brain areas in the GBC group. Additionally, on the molecular basis, the subunits of sulfonylurea receptor 1/transient receptor potential M4 (SUR1-TRPM4) heterodimer were both strongly upregulated after SE but partly suppressed by GBC treatment. Furthermore, gene knockdown of Trpm4 in SE rats reduced BBB disruption and neuronal loss, similar to the inhibitory effects with GBC treatment. Taken together, GBC treatment markedly improved survival and neurologic outcomes after SE. The salutary effects of GBC were correlated to the alleviation of cerebral edema and reduction in neurological injury via down-regulation of SUR1-TRPM4 channel.
研究领域:
神经病学
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药理学
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神经科学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Xiong Zhonghua,Deng Jiahui,Xie Pandeng,Tang Chongyang,Wang Jing,Deng Qinqin,Yang Yujiao,Zhang Jing,Guo Mengyi,Wang Xiongfei,Guan Yuguang,Luan Guoming,Zhou Jian,Li Tianfu
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus is an efficacious treatment option for patients with refractory epilepsy. Our previous study demonstrates that adenosine is a potential target of DBS for the treatment of epilepsy. Equilibrative nucleoside transporters-1 (ENT1) and ectonucleotidases (CD39, CD73) function as regulators of extracellular adenosine in the brain. It is unclear whether ENT1, CD39, and CD73 are involved in the mechanism of DBS for epilepsy. A total of 48 SD male rats were divided into four groups: control (naïve rats), Pilo (pilocarpine induced rats with epilepsy), DBS (rats with epilepsy treated with DBS for 8 weeks), and sham. In the present study, video electroencephalogram monitoring, Morris water maze assays, in vivo measurements of adenosine using fiber photometry, histochemistry, and western blot were performed on the hippocampus. DBS markedly attenuated spontaneous recurrent seizures (SRSs) and enhanced spatial learning in rats with epilepsy, assessed through video-EEG and water maze assays. Fibred photometry measurements of an adenosine sensor revealed dynamic increase in extracellular adenosine during DBS. The expressions of ENT1, CD39, and CD73 in Pilo group and sham group increased compared with the control group, while the expressions of ENT1, CD39, and CD73 in DBS group decreased compared to that of Pilo group and sham group. The findings indicate that DBS reduces the number of SRSs and improves spatial memory in rats with epilepsy with concomitant decrease of ENT1, CD39, and CD73 expressions. Adenosine-modulating enzymes might be the potential targets of DBS for the treatment of epilepsy.
研究领域:
神经科学
·
药理学
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癫痫学
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神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY
·
2025
·
IF 3.1
Lingling Zhang,Yi Liu,Xinyi Du,Di Zhu,Zhe Shi,Mang Lin,Biao Jin
Chlorinated organic compounds (COCs) are industrially produced for different applications. These chemicals occur as common organic contaminants in soil and groundwater. Compound specific isotope analysis (CSIA) has been widely applied to delineate underlying transformation processes of organic contaminants. However, it remains unclear how volatilization processes would influence observed CSIA signals of different COCs, which is of special interest for remediation techniques such as soil vapor extraction and soil bioventing that rely on volatilization. To fill this data gap, our study developed an experimental setup and applied our optical CSIA approach to resolve carbon isotope fractionation of 12 different COCs during volatilization. Inverse carbon isotope fractionation was observed for all the target compounds, where positive carbon isotope enrichment factors (ε) were obtained. The extent of carbon isotope fractionation was correlated with the elemental compositions of the target compounds, indicating that chlorine substitutions lead to more pronounced inverse carbon isotope effects. Our study widened applications of the optical carbon CSIA method, and provided valuable data to evaluate volatilization-induced carbon isotope fractionation of different COCs.
研究领域:
环境科学
·
地球化学
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产品关联
DOI
高影响因子
HIPPOCAMPUS
·
2023
·
IF 3.5
Shicheng Jiang,Bei Liu,Kaiwen Lin,Lianjun Li,Rongrong Li,Shuo Tan,Xinyu Zhang,Lei Jiang,Hong Ni,Yuanyuan Wang,Haihu Ding,Jing Hu,Hao Qian,Rongjing Ge
Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.
研究领域:
神经科学
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药理学
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分子生物学
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遗传学
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DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2025
·Vol. 31
·期 2
·e70238
·
IF 5
Shihao Chen,Linqian Zhao,Xing Jin,Qichang Liu,Yuqing Xiao,Huiqin Xu
The AST activates the Nrf2/GPX4 signaling pathway to regulate glutathione metabolism and inhibit ferroptosis to preventing epileptic seizures.
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EBioMedicine
·
2019
·
IF 6.68
Qin Yang,Zifeng Huang,Yangfu Luo,Fangshuo Zheng,Yida Hu,Hui Liu,Shuzhen Zhu,Miaoqing He,Demei Xu,Yun Li,Min Yang,Yi Yang,Xiaobo Wei,Xiaoya Gao,Wei Wang,Junhong Ma,Yuanlin Ma,Xuefeng Wang,Qing Wang
Background NACHT and WD repeat domain-containing protein 1 (Nwd1) is a member of the innate immune protein subfamily. Nwd1 contributes to the androgen receptor signaling pathway and is involved in axonal growth. However, the mechanisms that underlie pathophysiological dysfunction in seizures remain unclear. Methods Biochemical methods were used to assess Nwd1 expression and localization in a mouse model of kainic acid (KA)-induced acute seizures and temporal lobe epilepsy (TLE) patients. Electrophysiological recordings were used to measure the role of Nwd1 in regulating synaptic transmission and neuronal hyperexcitability in a model of magnesium-free-induced seizure in vitro . Behavioral experiments were performed, and seizure-induced pathological changes were evaluated in a KA-induced seizure model in vivo . GluN2B expression was measured and its correlation with Tyr1472-GluN2B phosphorylation was analyzed in primary hippocampal neurons. Findings We demonstrated high protein levels of Nwd1 in brain tissues obtained from mice with acute seizures and TLE patients. Silencing Nwd1 in mice using an adeno-associated virus (AAV) profoundly suppressed neuronal hyperexcitability and the occurrence of acute seizures, which may have been caused by reducing GluN2B-containing NMDA receptor-dependent glutamatergic synaptic transmission. Moreover, the decreased activation of Nwd1 reduced GluN2B expression and the phosphorylation of the GluN2B subunit at Tyr1472. Interpretation Here, we report a previously unrecognized but important role of Nwd1 in seizure models in vitro and in vivo , i.e. , modulating the phosphorylation of the GluN2B subunit at Tyr1472 and regulating neuronal hyperexcitability. Meanwhile, our findings may provide a therapeutic strategy for the treatment of epilepsy or other hyperexcitability-related neurological disorders. Fund The funders have not participated in the study design, data collection, data analysis, interpretation, or writing of the report.
研究领域:
神经科学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
NEUROSCIENCE
·
2025
·
IF 2.8
Viveka Chinnasamy,Carl E. Stafstrom,Li-Rong Shao
Seizures are a common comorbidity in children with Down syndrome (DS) yet seizure genesis in the DS brain is poorly understood. The two most common types of seizures in DS patients are infantile spasms (IS) and generalized tonic-clonic seizures. Using a novel humanized DS model (TcMAC21), we revealed an increased propensity to IS associated with a heightened neocortical excitation-inhibition ratio. Here, we examined the susceptibility of TcMAC21 mice to flurothyl-induced tonic-clonic type seizures and their propensity to epileptiform activity in neocortical-hippocampal slices. At postnatal day (P) 9–11, TcMAC21 mice exhibited significantly shorter latencies to flurothyl seizures but similar seizure durations compared with euploid controls. At P17-18, TcMAC21 mice showed both shorter seizure latencies and longer seizure durations than euploid mice. In neocortical-hippocampal slices, the frequency and duration of spontaneous epileptiform bursts (induced by 0 Mg 2+ and 4-aminopyridine) in hippocampal CA3 and neocortical layers II/III and V were not significantly different between the euploid and TcMAC21 mice. In addition, we assessed evoked responses in layer II/III by electrical stimulation at the junction of layer VI and white matter, in the presence of a GABA A receptor blocker, gabazine (1 uM). At P9-P13, evoked responses in layer II/III were similar between TcMAC21 and euploid mice; however, at P17-P20, the responses were significantly greater in TcMAC21 than euploid controls. Together, these data show that TcMAC21 mice exhibit heightened susceptibility to tonic-clonic seizures and an age-dependent increased neocortical excitability compared to euploid mice. These results provide new insights into the pathophysiology of seizures in DS.
研究领域:
神经科学
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发育生物学
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癫痫研究
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染色体疾病
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脑电生理学
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转化神经病学
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分子神经病理学
✓ 已验证
DOI
PubMed
高影响因子
NEUROENDOCRINOLOGY
·
2024
·
IF 3.2
Zhang Jiaxian,Lai Wanlin,Tang Yusha,Gao Jing,Zhou Xiangyang,Chen Lei
Introduction:
In women of childbearing age with epilepsy, 40% experience the comorbidity of polycystic ovary syndrome (PCOS), which is marked by a higher prevalence of hyperandrogenism. Our recent clinical observations indicate the potential contribution of hyperandrogenism-induced PCOS to epilepsy susceptibility, and this study aimed to unravel the underlying factors that increase the susceptibility of females to epilepsy. Methods:
A letrozole-induced PCOS rat model was employed to simulate endogenous hyperandrogenism. Susceptibility was assessed through seizure kindling rates using pentetrazol and electroencephalogram recordings. Additionally, the role of androgens in epilepsy was verified through interventions using Diane-35. Results:
This study revealed that letrozole induced elevated testosterone levels and PCOS-related changes in female rats. PCOS rats, through pentetrazol-kindling, exhibited a reduced seizure threshold compared with controls. Elevated testosterone levels were observed in both the hippocampal and frontal brain tissues, accompanied by changes in circulation. Two weeks of Diane-35 intervention showed a tendency to alleviate these changes, modifying testosterone levels in both the plasma and brain tissue. Western blotting and immunohistochemistry revealed increased expression of GABA-A receptor in the hippocampus and decreased AMPA receptor expression in the frontal cortex, correlating with anti-epileptic status in PCOS rats. Conclusion:
This study delves into the impact of elevated androgen levels on seizure threshold, providing crucial insights into the underpinnings of the comorbidity between PCOS and epilepsy. These findings significantly contribute to the evolving field of epilepsy research, emphasizing the imperative consideration of hormonal influences for the development of targeted therapeutic interventions in individuals with epilepsy and PCOS
研究领域:
神经科学
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内分泌学
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癫痫研究
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生殖医学
✓ 已验证
DOI
PubMed
高影响因子
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