Applied Materials Today
·
2020
·
IF 8.352
Xiaoqin Zhu,Yan He,Zhongrui Liu,Ziting Zhu,Yuehua He,Jiewen Qiu,Danqiong Liu,Mingshu Mo,Peng Wang,Xiumei Tian,Pingyi Xu
Epilepsy is characterized by repeated spontaneous seizures and remains untreatable due to its complicate pathogenesis. Low-dose hydrogen sulfide (H 2 S) has been shown to exert antiepileptic and protective effects in the central nervous system, but the administration of H 2 S gas to suppress seizures is difficult. In the present study, we synthesized a safe and efficient carbazole-based H 2 S donor from aldehydes with a one-pot procedure and characterized this specific H 2 S donor via proton nuclear magnetic resonance ( 1 HNMR), scanning electron microscopy (SEM), and absorption spectroscopy. In vitro and in vivo risk assessments demonstrated that the H 2 S donor (up to a 400-μM concentration) had sufficient biocompatibility and membrane permeability and suppressed epileptic seizures. Importantly, the suppression of seizures was determined in the brain when the H 2 S donor was injected into the lateral ventricle in a rat model of advanced seizures. Furthermore, the mechanism by which the H 2 S donor suppressed the expression of seizures may have been related to H 2 S donor-induced increases in the expressions of the ATP-sensitive potassium channel (K ATP ) subunits, Kir6.2 and SUR1. Taken together, these assays suggested that our novel H 2 S donor may represent a potential therapeutic strategy for ameliorating seizures in epilepsy.
研究领域:
神经科学
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药理学
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医学
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产品关联
DOI
高影响因子
JOURNAL OF NEUROSCIENCE RESEARCH
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2025
·Vol. 103
·期 7
·e70064
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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
ACS Chemical Neuroscience
·
2025
·
IF 3.9
Ying Sun,Yajun Bai,Bin Li,Peinan Fan,Haiyan Lu,Pu Jia,Ye Zhao,Yujun Bai,Shixiang Wang,Kechun Liu,Meng Jin,Tai-Ping Fan,Xiaohui Zheng
Developmental epileptic encephalopathies (DEEs), including Dravet syndrome (DS), require antiseizure medications (ASMs) that balance efficacy with developmental safety. There is an urgent clinical need for novel therapeutic agents that combine potent anticonvulsant activity with developmental safety. β-Asarone, an active constituent of Acorus plants, has demonstrated antiepileptic potential, but its toxicities severely limit clinical application. Notably, β-asaronol, a hydroxylated metabolite of β-asarone, may exhibit improved safety; however, its pharmacological properties and therapeutic potential remain systematically unelucidated. To evaluate the developmental safety and antiseizure efficacy of β-asaronol for pediatric refractory epilepsy, developmental toxicity, antiseizure activity, and neuroprotective effects were systematically assessed using zebrafish models (Tg vmat2:GFP, Tg lfabp:EGFP, pentylenetetrazole (PTZ)-induced seizures, and scn1lab–/– mutants). Electrophysiology, molecular docking, and biomarker analyses elucidated mechanisms. β-Asaronol (5–150 μM) exhibited no significant developmental toxicity in zebrafish, with normal hatching rate, mortality, malformation rate, and no abnormalities in neurotoxicity or hepatotoxicity indicators. Its lethal concentration 50 (LC50) value was 3.5-fold higher than that of the parent compound β-asarone. It prolonged seizure latency, suppressed PTZ-induced hyperactivity (150 μM restoring baseline locomotion), and reduced neuronal apoptosis (lactate dehydrogenase (LDH)/c-fos normalization). In scn1lab–/– mutants, β-asaronol outperformed stiripentol and cannabidiol, reducing epileptiform discharges by about 93%. Mechanistically, β-asaronol potentiated γ-aminobutyric acid type A (GABAA) receptor currents (EC50 = 20.8 μM) via benzodiazepine-binding site interactions. β-Asaronol combines superior developmental safety with potent antiseizure efficacy, positioning it as a promising candidate for Dravet syndrome and refractory epilepsy.
研究领域:
神经药理学
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发育毒理学
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癫痫研究
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民族药理学
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分子模拟
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神经科学
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产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2017
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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
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2025
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IF 8.4
Guo Qing,Gan Jun,Wang En-ze,Wei Yu-ming,Xu Jie,Xu Yun,Zhang Fei-fei,Cui Meng,Jia Meng-xing,Kong Ming-jian,Tang Qiong-yao,Zhang Zhe
Patients suffering epilepsy caused by the gain-of-function mutants of the hKCNT1 potassium channels are drug refractory. In this study, we cloned a novel human KCNT1B channel isoform using the brain cDNA library and conducted patch-clamp and molecular docking analyses to characterize the pharmacological properties of the hKCNT1B channel using thirteen drugs. Among cinchona alkaloids, we found that hydroquinine exerted the strongest blocking effect on the hKCNT1B channel, especially the F313L mutant. In addition, we confirmed the antitussive drug tipepidine was also a potent inhibitor of the hKCNT1B channel. Subsequently, we proved that these two drugs produced an excellent therapeutic effect on the epileptic model of KCNT1 Y777H mutant male mice; thus, both could be ready-to-use anti-epileptic drugs. On the other hand, we demonstrated that the activation of the KCNT1 channel by loxapine and clozapine was through interacting with pore domain residues to reverse the run-down of the KCNT1 channel. Taken together, our results provide new insights into the mechanism of the modulators in regulating the KCNT1 channel activity as well as important candidates for clinical tests in the treatment of KCNT1 mutant-associated epilepsy.
研究领域:
神经生物学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Wang Fei,Wang Yu,Zhang Qing-yang,Hu Ke-yu,Song Ying-jie,Yang Lin,Fei Fan,Xu Ceng-lin,Cui Sun-liang,Ruan Ye-ping,Wang Yi,Chen Zhong
Status epilepticus (SE), a serious and often life-threatening medical emergency, is characterized by abnormally prolonged seizures. It is not effectively managed by present first-line anti-seizure medications and could readily develop into drug resistance without timely treatment. In this study, we highlight the therapeutic potential of CZL80, a small molecule that inhibits caspase-1, in SE termination and its related mechanisms. We found that delayed treatment of diazepam (0.5 h) easily induces resistance in kainic acid (KA)-induced SE. CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic time window to 3 h following SE, and also protected against neuronal damage. Interestingly, the effect of CZL80 on SE termination was model-dependent, as evidenced by ineffectiveness in the pilocarpine-induced SE. Further, we found that CZL80 did not terminate KA-induced SE in Caspase-1 −/− mice but partially terminated SE in IL1R1 −/− mice, suggesting the SE termination effect of CZL80 was dependent on the caspase-1, but not entirely through the downstream IL-1β pathway. Furthermore, in vivo calcium fiber photometry revealed that CZL80 completely reversed the neuroinflammation-augmented glutamatergic transmission in SE. Together, our results demonstrate that caspase-1 inhibitor CZL80 terminates diazepam-resistant SE by blocking glutamatergic transmission. This may be of great therapeutic significance for the clinical treatment of refractory SE.
研究领域:
神经科学
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药理学
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神经炎症
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癫痫
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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
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DOI
PubMed
高影响因子
EBioMedicine
·
2019
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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
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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
NEUROSCIENCE LETTERS
·
2017
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IF 2.18
Tingting Yang,Zhenzhou Lin,Ling Xie,Yao Wang,Suyue Pan
Vasogenic edema induced by blood brain barrier disruption and neuronal loss play an important role in the epileptogenic process. 4,4′- diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) is a commonly used anion channel inhibitor that has been reported to exert an anticonvulsant effect in rat hippocampus in vitro. The present study aimed to investigate whether DIDS could prevent epileptogenic process in rat lithium-pilocarpine model of temporal lobe epilepsy. The tight junction proteins and serum extravasation were examined in the piriform cortex 3 days after status epilepticus. The findings showed that status epilepticus induced vasogenic edema. Based on these findings, rats were intracerebroventricularly infused with saline and DIDS 1 week after surgery, DIDS reduced vasogenic edema and prevented neuronal loss following status epilepticus in the piriform cortex. Moreover, spontaneous recurrent seizures were recorded by continuous video monitoring. DIDS significantly reduced the frequency and duration of spontaneous recurrent seizures from day 28 to day 42 post status epilepticus. These findings demonstrated that DIDS attenuated vasogenic edema and neuronal apoptosis and might exert disease-modifying effect in animal model of temporal lobe epilepsy. These results explored a novel therapeutic strategy for treatment of epilepsy.
研究领域:
神经科学
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药理学
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癫痫研究
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DOI
PubMed
高影响因子
NEUROSCIENCE
·
2024
·
IF 2.9
Xuejing Hou,Shanshan Xiao,Xiaohong Xu,Mingze Qin,Xuebing Cheng,Xiangping Xu
Epilepsy is a progressive neurodegenerative disease highlighted by recurrent seizures, neuroinflammation, and the loss of neurons. Microglial dysfunction is commonly found in epileptic foci and contributes to neuroinflammation in the initiation and progression of epilepsy. Glycoprotein non-metastatic melanoma protein B (GPNMB), a transmembrane glycoprotein, has been involved in the microglial activation and neuroinflammation response. The present study investigated the functional significance of GPNMB in epilepsy. A proven model of epilepsy was established by intraperitoneal injection of pilocarpine to male Sprague Dawley rats. Lentivirus vectors carrying GPNMB or GPNMB short hairpin RNA (shGPNMB) were injected into the hippocampus to induce overexpression or knockdown of GPNMB. GPNMB expression was significantly upregulated and overexpression of GPNMB in the hippocampus reduced seizure activity and neuronal loss after status epilepticus (SE). We here focused on the effects of GPNMB deficiency on neuronal injury and microglia polarization 28 days after SE. GPNMB knockdown accelerated neuronal damage in the hippocampus, evidenced by increased neuron loss and neuronal cell apoptosis. Following GPNMB knockdown, M1 polarization (iNOS) and secretion of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α were increased, and M2 polarization (Arg1) and secretion of anti-inflammatory cytokines IL-4, IL-10, and TGF-β were decreased. BV2 cells were used to further confirm the regulatory role of GPNMB in modulating phenotypic transformations and inflammatory cytokine expressions in microglia. In conclusion, these results indicated that GPNMB suppressed epilepsy through repression of hippocampal neuroinflammation, suggesting that GPNMB might be considered the potential neurotherapeutic target for epilepsy management and play a protective role against epilepsy by modulating the polarization of microglia.
研究领域:
神经科学
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神经病学
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免疫学
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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
Frontiers in Bioengineering and Biotechnology
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2024
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IF 4.3
Han Meiqi,Wang Yu,Jing Luyi,Yang Gucheng,Liu Yaoyao,Mo Fan,Xu Zhaojie,Luo Jinping,Jia Qianli,Zhu Yuxin,Cao Hanwen,Cai Xinxia,Liu Juntao
The striatum plays a crucial role in studying epilepsy, as it is involved in seizure generation and modulation of brain activity. To explore the complex interplay between the striatum and epilepsy, we engineered advanced microelectrode arrays (MEAs) specifically designed for precise monitoring of striatal electrophysiological activities in rats. These observations were made during and following seizure induction, particularly three and 7 days post-initial modeling. The modification of graphene oxide (GO)/poly (3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)/platinu-m nanoparticles (PtNPs) demonstrated a marked reduction in impedance (10.5 ± 1.1 kΩ), and maintained exceptional stability, with impedance levels remaining consistently low (23 kΩ) even 14 days post-implantation. As seizure intensity escalated, we observed a corresponding increase in neuronal firing rates and local field potential power, with a notable shift towards higher frequency peaks and augmented inter-channel correlation. Significantly, during the grand mal seizures, theta and alpha bands became the dominant frequencies in the local field potential. Compared to the normal group, the spike firing rates on day 3 and 7 post-modeling were significantly higher, accompanied by a decreased firing interval. Power in both delta and theta bands exhibited an increasing trend, correlating with the duration of epilepsy. These findings offer valuable insights into the dynamic processes of striatal neural activity during the initial and latent phases of temporal lobe epilepsy and contribute to our understanding of the neural mechanisms underpinning epilepsy.
研究领域:
神经科学
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电生理学
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生物医学工程
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材料科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2013
·Vol. 14
·期 12
·23751-23761
·
IF 2.464
Jun Xiang,Yugang Jiang
Our present study aimed to determine the antiepileptic activity of matrine, and explore the possible molecular mechanism. To evaluate the antiepileptic activity of matrine, seizures in mice induced by PTZ and MES were established, then the pentobarbital sodium-induced anaesthetizing time and locomotor activity tests in mice were also carried out. For the molecular mechanism investigations, contents of aspartic acid (Asp), gamma-aminobutyric acid (GABA), glutamic acid (Glu), glycine (Gly) in seizures mice were determined; then, the chronic seizures rats induced by PTZ were prepared, and western blotting was used to determine the expressions of GAD 65, GABAAand GABABin the brains. In the results, matrine showed significant antiepileptic effects on seizures mice induced by MES and PTZ. Moreover, the pentobarbital sodium-induced anaesthetizing time and locomotor activity tests were also demonstrated that matrine had obvious antiepileptic effects. Additionally, our results revealed that after treatment with matrine, contents of GABA can be elevated, and the contents of Glu were obviously decreased. Furthermore, western blotting revealed that the mechanism regarding the antiepileptic effect of may be related to the up-regulations of GAD 65 and GABAAin the brain. Collectively, we suggested that matrine can be developed as an effective antiseptic drug.Keywords:antiepileptic;matrine;gamma-aminobutyric acid;glutamic acid
研究领域:
药理学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）