eLife
·
2024
·
IF 6.4
Tian Yuan,Yifan Wang,Yuchen Jin,Hui Yang,Shuai Xu,Heng Zhang,Qian Chen,Na Li,Xinyue Ma,Huifang Song,Chao Peng,Ze Geng,Jie Dong,Guifang Duan,Qi Sun,Yang Yang,Fan Yang,Zhuo Huang
Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine’s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6’s N- and C-termini binding to Slack’s C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of ‘Slack as an isolated target’ for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EPILEPSIA
·
2021
·Vol. 62
·期 1
·238-249
·
IF 5.866
Yi Zhao,Long An,Shupan Guo,Xiaoxing Huang,Huajie Tian,Li Liu,Tao Chen,Xun Sun,Qibing Mei,Rutao Wang
Objective LMR-101 is a bisphenol derivative of propofol, a short-acting general anesthetic, which is also used to manage status epilepticus (SE). We evaluated the sedative and anticonvulsant effects of LMR-101 to discover its potential to manage epilepsy and SE in the clinic. Methods Comparative studies between LMR-101 and propofol were performed in mice to elucidate an appropriate dose range for LMR-101 that produced anticonvulsant effects without significant sedation. Then, the anticonvulsive efficacy for LMR-101 was evaluated using seizure models induced by pentylenetetrazol and (+)-bicuculline. The ability of LMR-101 to inhibit SE was assessed using a rat model of SE induced by pilocarpine. Radioligand binding assay profiles for LMR-101 were performed to evaluate the potential mechanisms of action underlying its anticonvulsant properties. Results In the mouse study, LMR-101 exhibited greater anticonvulsant and lesser sedative effect compared with propofol. LMR-101 completely inhibited pentylenetetrazol-induced seizures at a dose of 50 mg/kg and exhibited heavy sedation at 300 mg/kg. Propofol anesthetized all mice and only decreased the seizure rate at 25 mg/kg. LMR-101 also suppressed seizure behaviors evoked by (+)-bicuculline in mice in a dose-dependent manner. In the pilocarpine-induced SE model, LMR-101 significantly decreased the maximum seizure score and seizure duration in a dose-dependent manner. The median effective dose for LMR-101 was 14.30 mg/kg and 121.87 mg/kg to prevent and inhibit sustained SE, respectively. In binding assays, LMR-101 primarily inhibited tert -[ 35 S] butylbicyclophosphorothionate binding to γ-aminobutyric acid type A (GABA A ) receptors (half-maximal inhibitory concentration = 2.06 μmol·L –1 ), but it did not affect [ 3 H] flunitrazepam or [ 3 H] muscimol binding. Significance It is anticipated that LMR-101 might play an essential role in the clinical management of epilepsy and SE. LMR-101 also might bind to a novel target site on the GABA A receptor that is different from existing antiepileptic drugs. Further study of the mechanisms of action of LMR-101 would be of considerable value in the search for new active drug sites on GABA A receptors.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Neuroscience Bulletin
·
2025
·
IF 5.8
Gu Yuang,Yao Yu,Lou Qiuwen,Zhu Xinyan,Lan Ju,Gao Chenshu,Wu Shuangshuang,Liang Jingjia,Xu Cenglin,Wang Yi,Cheng Heming,Chen Zhong
Epilepsy is one of the most prevalent and severe neurological disorders, and it is inadequately controlled with currently available medications. While cinnabar (mercury(II) sulfide)—a traditional Chinese medicine—has historical application in epilepsy treatment, its therapeutic efficacy and underlying mechanisms are unclear. In this study, we find that cinnabar exerts model-dependent antiseizure efficacy in mice. Specifically, it significantly attenuates acute seizures, enhances the termination of diazepam-resistant status epilepticus, and reduces spontaneous seizures in the kainic acid (KA)-induced seizure model. Conversely, no therapeutic effect was found in the maximal electroshock-, pentylenetetrazole-, or kindling-induced seizure model. Fiber photometry revealed that cinnabar normalizes KA-induced hippocampal neurotransmission imbalances by simultaneously decreasing glutamate hyperactivity and γ-aminobutyric acid hypoactivity. Furthermore, cinnabar has neuroprotective effects and alleviates comorbid anxiety-like behaviors, while showing no alterations in motor function. Our findings suggest cinnabar's potential as a therapeutic agent for seizure management, via a mechanism associated with the reversal of the hippocampal excitatory/inhibitory imbalance.
研究领域:
神经病学
·
药理学
·
分子神经科学
·
转化医学
·
药物毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
·
2013
·
IF 2.608
Tao Yang,Bin Kong,Jian-Wen Gu,Yong-Qin Kuang,Lin Cheng,Wen-Tao Yang,Jing-Min Cheng,Yuan Ma,Xiao-Kun Yang
This study was designed to evaluate the anticonvulsant and sedative effects of paederosidic acid isolated from Paederia scandens (Lour.) Merrill. in mice and rats. In the present study, anticonvulsant activities of paederosidic acid were evaluated by maximal electroshock and pentylenetetrazole-induced seizures in male mice. Then, pentobarbital sodium-induced sleeping time and locomotor activity tests in mice were used to evaluate the sedative effects of paederosidic acid. Finally, the mechanism of paederosidic acid was explored by evaluating the contents of Glu and GABA in the brain, and Western blot was used to measure GAD65 expression in the mouse brain. Paederosidic acid (5, 10, 20, and 40 mg/kg, ip) had significant anticonvulsant and sedative effects. Moreover, paederosidic acid increased brain gamma-aminobutyric acid and decreased glutamic acid in the brain, and it up-regulated expressions of GAD 65. In conclusion, our results suggest that paederosidic acid may be a promising future therapeutic agent for treatment of epilepsy .
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
ARCHIV DER PHARMAZIE
·
2019
·Vol. 352
·期 8
·1800313
·
IF 2.145
Ming-Xia Song,Yuping Huang,Shiben Wang,Zeng-Tao Wang,Xian-Qing Deng
A novel series of benzoxazole derivatives containing 1,2,4-triazolone ( 5a-m ) was designed. These compounds were synthesized in order to screen their anticonvulsant activities by the maximal electroshock seizure (MES) model and the subcutaneous pentylenetetrazole (sc-PTZ) seizure model in mice. The rotarod test was used to evaluate their neurotoxicities. Most of the compounds showed anti-MES activities at 100 and 300 mg/kg. Compound 5f , which showed potential anticonvulsant activity in the MES model with ED 50 values of 22.0 mg/kg, was considered as the most promising one in this study. It exhibited greater safety than that of carbamazepine and valproate regarding neurotoxicity. The efficacy of compound 5f in inhibiting the tonic seizures and death induced by the convulsants 3-mercaptopropionic acid and BIC was also verified. In an enzyme-linked immunosorbent assay, compound 5f and the positive drug phenytoin significantly increased the γ-aminobutyric acid (GABA) level in the mouse brain. Further, pretreatment with an inhibitor of the GABA synthesizing enzyme dramatically raised the ED 50 value of 5f in the MES model. These results confirmed that the compound 5f plays its anticonvulsive action via regulating the GABA function in the brain. Also, a docking study of the compound 5f in the benzodiazepine (BZD) binding site of the GABA A receptor confirmed possible binding of the compound 5f with BZD receptors.
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
MOLECULES
·
2022
·Vol. 27
·期 23
·8315
·
IF 4.927
Qinglei Wang,Rong Wang,Cheng Zheng,Linlin Zhang,Hong Meng,Yi Zhang,Linke Ma,Bilian Chen,Juanjuan Wang
Bombyx batryticatus(BB) is an anticonvulsant animal medicine in traditional Chinese medicine (TCM) and acts on the central nervous system. This research aimed to study the anticonvulsant effects of different polarity fractions of extracts from BB and to explore the components conferring anticonvulsant activity. Materials and methods: Crude extracts of BB at 20 g/kg were divided into different polarity fractions (petroleum ether, chloroform, ethyl acetate, water) and were administered to groups of mice before injecting pentylenetetrazol (PTZ) to induce convulsions. The animals were placed in chambers, and their behaviors were recorded for 30 min following the injection. Latency time, percent of protection, convulsion, convulsion rate, and convulsion score were determined for these mice. The compounds present in the different fractions were analyzed, and those from the fraction that conferred anticonvulsant activity were identified by high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF MS) and molecular networking (MN). The chloroform extract fractions (B-C) clearly increased the seizure latency time and protection percentage and decreased the convulsion percentage compared to the control group. The anticonvulsant effect of other extract fractions was not significant. Our study shows that the chloroform extract fractions (B-C) of BB have a significant anticonvulsant effect. We also identified 17 compounds including lumichrome, pheophorbide A, and episyringaresinol 4′-O-beta-d-glucopyranose that were found for the first time. The results of this study may lay the groundwork for studying compounds derived fromBombyx batryticatusand their anticonvulsant effect.Keywords:Bombyx batryticatus;anticonvulsant activity;different polar fractions;UHPLC-Q-TOF-MS/MS;molecular networking
研究领域:
药理学
·
中药学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2018
·Vol. 23
·期 4
·756
·
IF 3.098
Ming-Xia Song,Zhen-Yuan Wang,Shi-Hui He,Sheng-Wang Yu,Shi-Long Chen,Dong-Fu Guo,Wen-Hao Zhao,Xian-Qing Deng
In this study, a novel series of 4-(2-(alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (4a–m) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound4gwas considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED50values of 23.7 and 18.9 mg/kg, respectively. The TD50value of4gwas 284.0 mg/kg, which resulted in a higher protective index (PI = TD50/ED50) value than that of carbamazepine and valproate. In an ELISA test, compound4gsignificantly increased the γ-aminobutyric acid (GABA) content in mouse brain. In addition, pretreatment with thiosemicarbazide (an inhibitor of the GABA synthesizing enzyme) significantly decreased the activity of4gin the MES model, which suggests that the mechanism through which compound4gelicits its anticonvulsive action is at least in part through increasing the GABA level in the brain.Keywords:anticonvulsant;maximal electroshock;pentylenetetrazole;benzoxazole;triazolone
研究领域:
药理学
·
神经科学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2020
·
IF 4.831
Shiben Wang,Hui Liu,Kang Lei,Guangyong Li,Jun Li,Yuyu Wei,Xuekun Wang,Renmin Liu
In this study, a series of 3,4-dihydroquinolin-2(1 H )-one derivatives were designed and synthesized using two experimental models, namely maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), to test the anticonvulsant activity of the target compound in vivo (i.p. in Kunming mice). The neurotoxicity (NT) of the target compound was measured by the rotating rod method (i.p. in Kunming mice). Six compounds with potential activity were selected from the two experimental models to test the 50% effective dose (ED 50 ). In vitro binding experiments with the GABA A receptor were also performed. The results of the pharmacological experiments showed that compound 7-((5-(pentylthio)-1,3,4-oxadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1 H )-one ( 5b ) showed the best anticonvulsant activity (MES, ED 50 = 10.1 mg/kg; scPTZ, ED 50 = 9.3 mg/kg), which was superior to activities shown by carbamazepine and ethosuximide, and it also exhibited the most potent binding affinity to GABA A receptors (IC 50 = 0.12 μM). The GABA content in Wistar rat brains (i.p.) was also investigated, and the results showed that compound 5b may have a certain effect on the GABA system, as it increased the GABA concentration in the brain of rats. Molecular docking was used to study the binding mode of compound 5b and the GABA A receptor. Compound 5b showed significant interactions with residues at the benzodiazepines binding site on the GABA A receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.0.
研究领域:
药理学
·
神经科学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 16
·3400
·
IF 4.6
Lina Hu,Mengjiao Li,Zheng Liu,Hui Yan,Xuekun Wang,Shiben Wang
To discover novel, potent anticonvulsant compounds, a series of compounds containing triazole structural fragments were synthesized and evaluated for their anticonvulsant activity. Compounds6f(maximal electroshock (MES), 50% effective dose (ED50) = 13.1 mg/kg; subcutaneous pentylenetetrazole (scPTZ), ED50= 19.7 mg/kg) and6l(MES, ED50= 9.1 mg/kg;scPTZ, ED50= 19.0 mg/kg) showed the best activity in MES andscPTZ tests. The results of an affinity test showed that the potent compounds had better binding to the GABAAreceptors. The results of an inhibitory neurotransmitter GABA content test in brain tissue indicated that compounds6fand6lexerted anticonvulsant activity which may be associated with the increase of GABA content in the rat brain. Elevated plus maze (EPM) assay results showed that compounds6fand6lpossessed anxiolytic effects, and their effects correlated with the binding sites of benzodiazepines (BZs) in the GABAAreceptors. Molecular docking was performed to investigate the interactions of the studied compound6lwith the GABAAreceptors on the molecular level.
研究领域:
药物化学
·
药理学
·
神经科学
·
有机合成
✓ 已验证
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2018
·Vol. 15
·期 1
·1-12
·
IF 5.193
Gao Bo,Wu Yu,Yang Yuan-Jian,Li Wei-Zu,Dong Kun,Zhou Jun,Yin Yan-Yan,Huang Da-Ke,Wu Wen-Ning
Background Epilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs). Inflammation is considered to be a critical factor in the pathophysiology of epilepsy. Sinomenine (SN), a bioactive alkaloid with anti-inflammatory effect, exerts neuroprotective activity in many nervous system diseases. However, little is known about the effect of SN on epilepsy.Methods The chronic epilepsy model was established by pentylenetetrazole (PTZ) kindling. Morris water maze (MWM) was used to test spatial learning and memory ability. H.E. staining and Hoechst 33258 staining were used to evaluate hippocampal neuronal damage. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA) kits.Results SN (20, 40, and 80 mg/kg) dose-dependently disrupts the kindling acquisition process, which decreases the seizure scores and the incidence of fully kindling. SN also increases the latency of seizure and decreases the duration of seizure in fully kindled rats. In addition, different doses of SN block the hippocampal neuronal damage and minimize the impairment of spatial learning and memory in PTZ kindled rats. Finally, PTZ kindling increases the expression of NLRP1 inflammasome complexes and the levels of inflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α, which are all attenuated by SN in a dose- dependent manner.Conclusion sSN exerts anticonvulsant and neuroprotective activity in PTZ kindling model of epilepsy. Disrupting the kindling acquisition, which inhibits NLRP1 inflammasome-mediated inflammatory process, might be involved in its effects.
研究领域:
神经病学
·
药理学
·
炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2015
·Vol. 29
·期 7
·996-1003
·
IF 2.66
Hao Liu,Zhi Song,Da-Guang Liao,Tian-Yi Zhang,Feng Liu,Kai Zhuang,Kui Luo,Liang Yang,Jing He,Jian-Ping Lei
This paper was designed to investigate anticonvulsant and sedative effects of eudesmin isolated from Acorus tatarinowii . The eudesmin (5, 10, and 20 mg/kg) was administered intraperitoneally (i.p.). The maximal electroshock test (MES) and pentylenetertrazole (PTZ)-induced seizures in male mice were used to evaluate anticonvulsant activities of eudesmin, and sedative effects of eudesmin were evaluated by pentobarbital sodium-induced sleeping time (PST) and locomotor activity in mice. Finally, the mechanisms of eudesmin were investigated by determining contents of glutamic acid (Glu) and gamma-aminobutyric acid (GABA) in epileptic mice, and expressions of glutamate decarboxylase 65 (GAD65), GABA A , Bcl-2, and caspase-3 in the brain of chronic epileptic rats. Results of MES and PTZ tests revealed that eudesmin possesses significant anticonvulsant effects, and the PST and locomotor activity tests demonstrated that eudesmin has significant sedative effects. Furthermore, our study revealed that after treatment with eudesmin, GABA contents increased, whereas Glu contents decreased, and ratio of Glu/GABA decreased. Our results also indicated that expressions of GAD65, GABAA, and Bcl-2 were up-regulated by treating with eudesmin, whereas the caspase-3 obviously was down-regulated. In conclusion, eudesmin has significant anticonvulsant and sedative effects, and the mechanism of eudesmin may be related to up-regulation of GABA A and GAD65 expressions, and anti-apoptosis of neuron the in brain. Copyright © 2015 John Wiley & Sons, Ltd.
研究领域:
药理学
·
神经科学
·
生物化学
✓ 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）