Background:Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs.The presence of lamotrigine,at a very low dose,does not hamper kindling in mice;rather it modifies this ...Background:Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs.The presence of lamotrigine,at a very low dose,does not hamper kindling in mice;rather it modifies this epileptogenesis process into drug-resistant epilepsy.The lamotrigine-pentylenetetrazole kindled mice show resistance to lamotrigine,phenytoin,and carbamazepine.It may also be possible that other licensed antiseizure drugs,like the mentioned drugs,remain ineffective in this model;therefore,this was the subject of this study.Methods:Swiss albino mice were kindled with pentylenetetrazole for 35 days in the presence of either methylcellulose vehicle or lamotrigine(subtherapeutic dose,ie,5 mg/kg).Vehicle vs lamotrigine-kindled mice were compared in terms of(a)resistance/response toward nine antiseizure drugs applied as monotherapies and two drug combinations;(b)lamotrigine bioavailability in blood and brain;(c)blood-brain barrier integrity;and(d)amino acids and monoamines in the cerebral cortex and hippocampus.Results:Lamotrigine vs vehicle-kindled mice are similar(or not significantly different P>.05 from each other)in terms of(a)response toward drug combinations;(b)lamotrigine bioavailability;and(c)blood-brain barrier integrity except for,significantly(P<.05)reduced taurine and increased glutamate in the cerebral cortex and hippocampus.Aside from these,lamotrigine-kindled mice show significant(P<.05)resistant to lamotrigine(15 mg/kg),levetiracetam(40 mg/kg);carbamazepine(40 mg/kg),zonisamide(100 mg/kg),gabapentin(224 mg/kg),pregabalin(30 mg/kg),phenytoin(35 mg/kg),and topiramate(300 mg/kg).Conclusion:Lamotrigine-pentylenetetrazole kindling takes longer to develop(~5 weeks)in comparison to lamotrigine-amygdale(~4 weeks)and lamotriginecorneal(~2 weeks)kindling models.However,drug screening through this model may yield superior drugs with novel antiseizure mechanisms.展开更多
Background Curcumin can reduce the severity of seizures induced by kainate acid （KA）, but the role of curcumin in amygdaloid kindled models is still unknown. This study aimed to explore the effect of curcumin on the...Background Curcumin can reduce the severity of seizures induced by kainate acid （KA）, but the role of curcumin in amygdaloid kindled models is still unknown. This study aimed to explore the effect of curcumin on the development of kindling in amygdaloid kindled rats. Methods With an amygdaloid kindled Sprague-Dawley （SD） rat model and an electrophysiological method, different doses of curcumin （10 mg·kg^-1·d^-1 and 30 mg·kg^-1·d^-1 as low dose groups, 100 mg·kg^-1·d^-1 and 300 mg·kg^-1·d^-1 as high dose groups） were administrated intraperitoneally during the whole kindling days, by comparison with the course of kindling, afterdischarge （AD） thresholds and the number of ADs to reach the stages of class I to V seizures in the rats between control and experimental groups. One-way or two-way ANOVA and Fisher＇s least significant difference post hoc test were used for statistical analyses. Results Curcumin （both 100 mg·kg^-1·d^-1 and 300 mg·kg^-1·d^-1 ） significantly inhibited the behavioral seizure development in the （19.80±2.25） and （21.70±2.21） stimulations respectively required to reach the kindled state. Rats treated with 100mg·kg^-1·d^-1 curcumin 30 minutes before kindling stimulation showed an obvious increase in the stimulation current intensity required to evoke AD from （703.3±85.9） μA to （960.0±116.5） μA during the progression to class V seizures. Rats treated with 300 mg·kg^-1·d^-1 curcumin showed a significant increase in the stimulation current intensity required to evoke AD from （735.0±65.2） μA to （867.0±93.4） μA during the progression to class V seizures. Rats treated with 300mg·kg^-1·d^-1 curcumin required much more evoked ADs to reach the stage of class both IV （as （199.83±12.47） seconds） and V seizures （as （210.66±10.68） seconds）. Rats treated with 100 mg·kg^-1·d^-1 curcumin required much more evoked ADs to reach the stage of class V seizures （as （219.56±18.24） seconds）. Conclusion Our study suggests that curcumin has a potential antiepileptogenic effect on kindling-induced epileptogenesis.展开更多
Background Glucocorticoid receptor （GR） is believed to be a major factor in brain maturation and in modulation of a series of brain activity. Hippocampal neurons are abundant in glucocorticoid receptor, and there is...Background Glucocorticoid receptor （GR） is believed to be a major factor in brain maturation and in modulation of a series of brain activity. Hippocampal neurons are abundant in glucocorticoid receptor, and there is significant change in GR expression under certain pathological state. Epilepsy is a special pathological state of the central nervous system. This study aimed to explore the role of GR in epilepsy by observing the change and functions of GR in hippocampus with a basolateral amygdale-electrical kindled rat epilepsy model. Methods Firstly, we established the basolateral amygdale-electrical kindled rat epilepsy model. Then GR mRNA expression in the hippocampus was assayed by semi-quantitative reverse transcription-PCR in this experiment. In addition, the processes of epileptic seizures were observed and electroencephalograms were recorded. One-way analysis of variance （ANOVA） was employed for comparing means of multiple groups, followed Fisher＇s least significant difference （LSD） for paired comparison. Results The rats were successfully kindled after an average of （13.50＋3.99） times electrical stimulation, in which it was showed that GR mRNA expression reduced obviously as compared with the control group and the sham groups （P 〈0.001）. The down-regulation of GR mRNA expression was abated or reversed by some anti-epilepsy drugs （P 〈0.001 compared with the epilepsy group）, accompanied by attenuation of seizures and improvement of electroencephalograms. Conclusions Down-regulation of hippocampal GR mRNA expression may be related to the kindling. Anti-epilepsy drugs exposure can retard this change.展开更多
The antiepileptic effect of pinellia total alkaloids（PTA） on penicillin（PNC） chronically kindled rats was investigated. We investigated the effects of PTA on Glu,Asp,Gly andγ-aminobutyric acid（GABA） concentrati...The antiepileptic effect of pinellia total alkaloids（PTA） on penicillin（PNC） chronically kindled rats was investigated. We investigated the effects of PTA on Glu,Asp,Gly andγ-aminobutyric acid（GABA） concentrations and the expression level of cerebral GABA_A receptor in hippocampus.The influence of PTA on epilepsy seizure latency and degree in PNC chronically kindled rats were observed.High performance liquid chromatography（HPLC） was adopted to measure the concentrations of Glu, Asp,Gly and GABA in hippocampus. Reverse transcriptase-polymerase chain reaction （RT-PCR） was used to determine the expression of cerebral GABAA receptor mRNA. Compared with normal rats, the levels of GABA and Gly decreased obviously while the level of Glu and Asp increased significantly in model rats. The cerebral GABAA receptor mRNA level was also decreased at the same time. The difference was statistically different compared to the control group. PTA could prolong the latent period of the penicillin induced seizure and weaken the extent of seizure, compared with the model group without PTA treatment. Moreover, PTA increased the level of GABA and the expression level of GABAA receptor, while decreased the level of Glu significantly. However, it had no obvious effect on the level of Gly and Asp. Pre-treatment of PTA can also increase the GABAA receptor mRNA level. In conclusion, PTA could alleviate the PNC chronically kindled rat seizure. It increased the GABA level and the expression of GABAA receptor, and it decreased the Glu concentration.展开更多
Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characte...Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses,respec-tively,on corneal kindling-induced generalized seizures and behavioral alterations.Furthermore,observed convulsive frequency and behavioral changes were corre-lated to post-kindling-induced changes in the activity of markers of oxidative stress.Methods:Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz elec-trical stimulations(3 mA)for 3 s for 12 days until animals reached a fully kindled state.After the kindling procedure,animals were tested using a set of behavioral tests,and neurochemical alterations were assessed.Results:Corneal-kindled animals exhibited intense generalized convulsions,altered behavioral phenotypes typified by positive symptoms(hyperlocomotion),negative symptoms(anxiety and anhedonia),and deficits in semantic and working memory.BRV 10+RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4–5 seizures and improved phenotypical deficits,that is,anxiety,depression,and memory impairments.Moreover,this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult.Conclusion:Based on our outcomes,this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.展开更多
Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in ...Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in combination was tested in corneal kindling model in mice,which is a cost-effective mechanism for screening of antiseizure drugs.Methods:The impact of lacosamide(5 mg/kg)and perampanel(0.125 mg/kg)alone and their combination was tested in corneal kindling process(3-mA current for 3 s applied twice daily for consecutive 12 days)in male BALB/c mice.Post-kindling,mice were subjected to a battery of behavioral tests assessing anxiety,memory,and depression-like behaviors.Brain tissues were then harvested for analysis of oxidative stress biomarkers.Results:Our results showed that the combination therapy of lacosamide and perampanel was more effective in reducing seizure progression than monotherapy of these drugs.Animals treated with combination therapy showed significant behavioral improvements,as reduced anxiety and depression were noticed,and their cognitive abilities were notably better compared to animals of all other groups.Moreover,biochemical assays of isolated brains from combination-treated group revealed lesser amount of oxidative stress.In addition,outcomes of dual regime were comparable to the phenytoin in seizure control but showed superior benefits in mitigation of kindling-prompted behavioral dysfunction and oxidative stress.Conclusions:This study suggests that the lacosamide and perampanel combination therapy worked noticeably better in halting the corneal kindling process in mice and improved the epilepsy-associated psychiatric disorders that might be due to antioxidant effects of both drugs.展开更多
文摘Background:Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs.The presence of lamotrigine,at a very low dose,does not hamper kindling in mice;rather it modifies this epileptogenesis process into drug-resistant epilepsy.The lamotrigine-pentylenetetrazole kindled mice show resistance to lamotrigine,phenytoin,and carbamazepine.It may also be possible that other licensed antiseizure drugs,like the mentioned drugs,remain ineffective in this model;therefore,this was the subject of this study.Methods:Swiss albino mice were kindled with pentylenetetrazole for 35 days in the presence of either methylcellulose vehicle or lamotrigine(subtherapeutic dose,ie,5 mg/kg).Vehicle vs lamotrigine-kindled mice were compared in terms of(a)resistance/response toward nine antiseizure drugs applied as monotherapies and two drug combinations;(b)lamotrigine bioavailability in blood and brain;(c)blood-brain barrier integrity;and(d)amino acids and monoamines in the cerebral cortex and hippocampus.Results:Lamotrigine vs vehicle-kindled mice are similar(or not significantly different P>.05 from each other)in terms of(a)response toward drug combinations;(b)lamotrigine bioavailability;and(c)blood-brain barrier integrity except for,significantly(P<.05)reduced taurine and increased glutamate in the cerebral cortex and hippocampus.Aside from these,lamotrigine-kindled mice show significant(P<.05)resistant to lamotrigine(15 mg/kg),levetiracetam(40 mg/kg);carbamazepine(40 mg/kg),zonisamide(100 mg/kg),gabapentin(224 mg/kg),pregabalin(30 mg/kg),phenytoin(35 mg/kg),and topiramate(300 mg/kg).Conclusion:Lamotrigine-pentylenetetrazole kindling takes longer to develop(~5 weeks)in comparison to lamotrigine-amygdale(~4 weeks)and lamotriginecorneal(~2 weeks)kindling models.However,drug screening through this model may yield superior drugs with novel antiseizure mechanisms.
文摘Background Curcumin can reduce the severity of seizures induced by kainate acid （KA）, but the role of curcumin in amygdaloid kindled models is still unknown. This study aimed to explore the effect of curcumin on the development of kindling in amygdaloid kindled rats. Methods With an amygdaloid kindled Sprague-Dawley （SD） rat model and an electrophysiological method, different doses of curcumin （10 mg·kg^-1·d^-1 and 30 mg·kg^-1·d^-1 as low dose groups, 100 mg·kg^-1·d^-1 and 300 mg·kg^-1·d^-1 as high dose groups） were administrated intraperitoneally during the whole kindling days, by comparison with the course of kindling, afterdischarge （AD） thresholds and the number of ADs to reach the stages of class I to V seizures in the rats between control and experimental groups. One-way or two-way ANOVA and Fisher＇s least significant difference post hoc test were used for statistical analyses. Results Curcumin （both 100 mg·kg^-1·d^-1 and 300 mg·kg^-1·d^-1 ） significantly inhibited the behavioral seizure development in the （19.80±2.25） and （21.70±2.21） stimulations respectively required to reach the kindled state. Rats treated with 100mg·kg^-1·d^-1 curcumin 30 minutes before kindling stimulation showed an obvious increase in the stimulation current intensity required to evoke AD from （703.3±85.9） μA to （960.0±116.5） μA during the progression to class V seizures. Rats treated with 300 mg·kg^-1·d^-1 curcumin showed a significant increase in the stimulation current intensity required to evoke AD from （735.0±65.2） μA to （867.0±93.4） μA during the progression to class V seizures. Rats treated with 300mg·kg^-1·d^-1 curcumin required much more evoked ADs to reach the stage of class both IV （as （199.83±12.47） seconds） and V seizures （as （210.66±10.68） seconds）. Rats treated with 100 mg·kg^-1·d^-1 curcumin required much more evoked ADs to reach the stage of class V seizures （as （219.56±18.24） seconds）. Conclusion Our study suggests that curcumin has a potential antiepileptogenic effect on kindling-induced epileptogenesis.
文摘Background Glucocorticoid receptor （GR） is believed to be a major factor in brain maturation and in modulation of a series of brain activity. Hippocampal neurons are abundant in glucocorticoid receptor, and there is significant change in GR expression under certain pathological state. Epilepsy is a special pathological state of the central nervous system. This study aimed to explore the role of GR in epilepsy by observing the change and functions of GR in hippocampus with a basolateral amygdale-electrical kindled rat epilepsy model. Methods Firstly, we established the basolateral amygdale-electrical kindled rat epilepsy model. Then GR mRNA expression in the hippocampus was assayed by semi-quantitative reverse transcription-PCR in this experiment. In addition, the processes of epileptic seizures were observed and electroencephalograms were recorded. One-way analysis of variance （ANOVA） was employed for comparing means of multiple groups, followed Fisher＇s least significant difference （LSD） for paired comparison. Results The rats were successfully kindled after an average of （13.50＋3.99） times electrical stimulation, in which it was showed that GR mRNA expression reduced obviously as compared with the control group and the sham groups （P 〈0.001）. The down-regulation of GR mRNA expression was abated or reversed by some anti-epilepsy drugs （P 〈0.001 compared with the epilepsy group）, accompanied by attenuation of seizures and improvement of electroencephalograms. Conclusions Down-regulation of hippocampal GR mRNA expression may be related to the kindling. Anti-epilepsy drugs exposure can retard this change.
基金Natural Science Foundation of Shanxi Province (Grant No.20041109).
文摘The antiepileptic effect of pinellia total alkaloids（PTA） on penicillin（PNC） chronically kindled rats was investigated. We investigated the effects of PTA on Glu,Asp,Gly andγ-aminobutyric acid（GABA） concentrations and the expression level of cerebral GABA_A receptor in hippocampus.The influence of PTA on epilepsy seizure latency and degree in PNC chronically kindled rats were observed.High performance liquid chromatography（HPLC） was adopted to measure the concentrations of Glu, Asp,Gly and GABA in hippocampus. Reverse transcriptase-polymerase chain reaction （RT-PCR） was used to determine the expression of cerebral GABAA receptor mRNA. Compared with normal rats, the levels of GABA and Gly decreased obviously while the level of Glu and Asp increased significantly in model rats. The cerebral GABAA receptor mRNA level was also decreased at the same time. The difference was statistically different compared to the control group. PTA could prolong the latent period of the penicillin induced seizure and weaken the extent of seizure, compared with the model group without PTA treatment. Moreover, PTA increased the level of GABA and the expression level of GABAA receptor, while decreased the level of Glu significantly. However, it had no obvious effect on the level of Gly and Asp. Pre-treatment of PTA can also increase the GABAA receptor mRNA level. In conclusion, PTA could alleviate the PNC chronically kindled rat seizure. It increased the GABA level and the expression of GABAA receptor, and it decreased the Glu concentration.
基金The authors extend their appreciation to the Distinguished Scientist Fellowship program at King Saud University,Riyadh,Saudi Arabia,for funding this work through Research Supporting Project Number RSP2024R131.
文摘Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses,respec-tively,on corneal kindling-induced generalized seizures and behavioral alterations.Furthermore,observed convulsive frequency and behavioral changes were corre-lated to post-kindling-induced changes in the activity of markers of oxidative stress.Methods:Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz elec-trical stimulations(3 mA)for 3 s for 12 days until animals reached a fully kindled state.After the kindling procedure,animals were tested using a set of behavioral tests,and neurochemical alterations were assessed.Results:Corneal-kindled animals exhibited intense generalized convulsions,altered behavioral phenotypes typified by positive symptoms(hyperlocomotion),negative symptoms(anxiety and anhedonia),and deficits in semantic and working memory.BRV 10+RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4–5 seizures and improved phenotypical deficits,that is,anxiety,depression,and memory impairments.Moreover,this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult.Conclusion:Based on our outcomes,this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.
基金The authors extended their appreciation to Distinguished Scientist Fellowship program at King Saud University,Riyadh,Saudi Arabia,for funding this work through research supporting project number(RSP2024R131).
文摘Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in combination was tested in corneal kindling model in mice,which is a cost-effective mechanism for screening of antiseizure drugs.Methods:The impact of lacosamide(5 mg/kg)and perampanel(0.125 mg/kg)alone and their combination was tested in corneal kindling process(3-mA current for 3 s applied twice daily for consecutive 12 days)in male BALB/c mice.Post-kindling,mice were subjected to a battery of behavioral tests assessing anxiety,memory,and depression-like behaviors.Brain tissues were then harvested for analysis of oxidative stress biomarkers.Results:Our results showed that the combination therapy of lacosamide and perampanel was more effective in reducing seizure progression than monotherapy of these drugs.Animals treated with combination therapy showed significant behavioral improvements,as reduced anxiety and depression were noticed,and their cognitive abilities were notably better compared to animals of all other groups.Moreover,biochemical assays of isolated brains from combination-treated group revealed lesser amount of oxidative stress.In addition,outcomes of dual regime were comparable to the phenytoin in seizure control but showed superior benefits in mitigation of kindling-prompted behavioral dysfunction and oxidative stress.Conclusions:This study suggests that the lacosamide and perampanel combination therapy worked noticeably better in halting the corneal kindling process in mice and improved the epilepsy-associated psychiatric disorders that might be due to antioxidant effects of both drugs.
