MOLECULES
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2018
·Vol. 23
·期 4
·756
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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
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神经科学
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药物化学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2018
·Vol. 15
·期 1
·1-12
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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
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药理学
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炎症研究
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
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2025
·Vol. 50
·期 5
·1-12
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IF 3.8
Huang Manqian,Tang Meiling,Liu Lu
Epilepsy is a chronic neurological disorder featured by abnormal neural discharges that can lead to cognitive impairment. Salidroside (Sal), a biologically active component, protects neurons against various insults. The current study aims to explore the therapeutic potential of Sal in epilepsy and elucidate the mechanisms underlying its effects. We established a rat model of status epilepticus (SE) using pentylenetetrazol-kindling. SE rats were treated with Sal. Assessment of seizure latency and epileptic stage scores were performed. Cognitive function of rats was evaluated using a novel object recognition test and a Morris water maze test. Neuronal damage and hippocampal pathology were examined, alongside microglial and astrocyte activation, complement C3-C3a receptor (C3-C3aR) pathway involvement, and inflammatory factor levels. Sal prolonged seizure latency, decreased epilepsy stage scores, and improved cognitive performance compared to untreated SE rats. Furthermore, Sal suppressed the activation of C3-C3ar, microglia, and astrocytes, while decreasing the levels of inflammatory factors, which ameliorated hippocampal damage and neuronal loss. Sal may attenuate epilepsy and cognitive dysfunction by downregulating complement C3-C3aR pathway-mediated activation of microglia and astrocytes.
研究领域:
神经病学
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药理学
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神经药理学
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免疫学
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分子生物学
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神经科学
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DOI
PubMed
高影响因子
Pharmacognosy Magazine
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2017
·
IF 1.069
An Wu,Xia Ye,Qiang Huang,Wei-Min Dai,Jian-Min Zhang
Objective: This work aimed to investigate the anti-epileptic effects of valepotriate isolated from Valeriana jatamansi Jones and studied its possible mechanisms. Methods: The anti-epileptic effects of valepotriate were studied using maximal electroshock-induced seizure (MES), pentylenetetrazole (PTZ)-induced epilepsy, and pentobarbital sodium-induced sleeping model in mice. The possible anti-epileptic mechanisms of valepotriate were investigated by analyzing the expressions of GABA A , GABA B , glutamic acid decarboxylase (GAD65), Bcl-2, and caspase-3 in the brain using Western blot assay. Results: The results indicated that valepotriate showed significant anti-epileptic activity against MES- and PTZ-induced epilepsy at doses of 5, 10, and 20 mg/kg, and ED 50 values for MES- and PTZ-induced epilepsy were 7.84 and 7.19 mg/kg, respectively. Furthermore, valepotriate (10 and 20 mg/kg) can significantly prolong sleeping time and shorten the latency time on the pentobarbital sodium-induced sleeping time test. Furthermore, valepotriate (5, 10, and 20 mg/kg) could significantly up-regulate the expression of GABA A , GAD65, and Bcl-2 and down-regulate the expression of caspase-3, but had no significant effect on the expression of GABA B . Conclusion: The results indicated that valepotriate had anti-epileptic activity and the mechanisms might be associated with regulation of GABA and inhibition of neuronal apoptosis. SUMMARY Anti-epileptic effect of valepotriate was investigated for the 1 st time Valepotriate showed notable anti-epileptic activity Valepotriate can significantly increase the expression of GABA A , glutamic acid decarboxylase 65, and Bcl-2 and reduce the expression of caspase-3. Open in a separate window
研究领域:
药理学
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神经科学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2015
·Vol. 29
·期 7
·996-1003
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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
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神经科学
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生物化学
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PubMed
高影响因子
Neural Regeneration Research
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2022
·Vol. 18
·期 8
·1763
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IF 6.058
Yang Li-Xiang,Yao Yuan-Yuan,Yang Jiu-Rong,Cheng Hui-Lin,Zhu Xin-Jian,Zhang Zhi-Jun
Destruction of the blood-brain barrier is a critical component of epilepsy pathology. Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity. However, its effect on blood-brain barrier permeability in epileptic mice remains unclear. In this study, we prepared pilocarpine -induced status epilepticus models and pentylenetetrazol -induced epilepsy models in C57BL/6 mice. S1P1 expression was increased in the hippocampus after status epilepticus, whereas tight junction protein expression was decreased in epileptic mice compared with controls. Intraperitoneal injection of SEW2871, a specific agonist of sphingosine-1-phosphate receptor 1, decreased the level of tight junction protein in the hippocampus of epileptic mice, increased blood-brain barrier leakage, and aggravated the severity of seizures compared with the control. W146, a specific antagonist of sphingosine-1-phosphate receptor 1, increased the level of tight junction protein, attenuated blood-brain barrier disruption, and reduced seizure severity compared with the control. Furthermore, sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1β and tumor necrosis factor-α and caused astrocytosis. Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline, a neuroinflammation inhibitor. Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy -associated depression-like behaviors. Additionally, specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage, seizure severity, and epilepsy -associated depression-like behaviors. Taken together, our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation .
研究领域:
神经科学
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药理学
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病理生理学
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PubMed
高影响因子
Oncotarget
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2017
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IF 5.168
Qin Yang,Yi-Da Hu,Xue-Feng Wang,Fang-Shuo Zheng
Epilepsy is the most prevalent chronic neurological disorder, and its pathological mechanism indicates that an imbalance between excitatory and inhibitory neurotransmission leads to neuronal hyperexcitability. Previous studies have suggested that dl-3n-butylphthalide (NBP) regulates the excitatory neurotransmitter glutamate in the brains of epileptic mice, however, the mechanisms are unknown. We investigated behavioral and electrophysiological factors in rats using NBP. In an in vivo pentylenetetrazole (PTZ)-induced epileptic seizure animal model, NBP decreased the generalized tonic-clonic seizure (GTCS) severity. In an acute hippocampal slice 4-aminopyridine (4-AP) epilepsy model in vitro , NBP decreased the epileptiform activity and miniature excitatory postsynaptic current (mEPSC) amplitude; there was no change in the miniature inhibitory postsynaptic current (mIPSC) amplitude or frequency. This effect suggested changes in excitatory synaptic transmission, which was altered through postsynaptic GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs). These findings showed that NBP suppressed epileptiform activity in these epilepsy models and provided the first detailed electrophysiological analysis of the impact of NBP in epilepsy models, which may be employed in future experimental or clinical therapies for patients with epilepsy.
研究领域:
神经科学
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药理学
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电生理学
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产品关联
DOI
PubMed
高影响因子
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