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
Aim To investigate the synergistic effect of the combination of pinellia total alkaloid （PTA） and uncaria total alkaloid （UTA）, and explore the mechanism of anticonvulsant action. Methods Anticonvulsant and toxic ...Aim To investigate the synergistic effect of the combination of pinellia total alkaloid （PTA） and uncaria total alkaloid （UTA）, and explore the mechanism of anticonvulsant action. Methods Anticonvulsant and toxic effect profiles of combinations of PTA with UTA, alone and at three fixed ratios of 1：4, 1 ：1, 4：1, were evaluated in maximal electroshock （MES）-induced seizures and acute toxicity test in mice. Respective ED50 and LD50 were calculated with Bliss＇s method. Their synergistic effect were evaluated by isobolographic analysis and allowed the determination of benefit indices （BI） for respective combinations. The model of convulsive rats kindled by penicillin topically injected into cortex was used to investigated the content of Glu, Asp, Gly and GABA in hippocampus using high performance liquid chromatography （HPLC）. Results Combinations of PTA and UTA at the ratio of 4：1 were synergistic in MES test and antagonistic in acute toxicity test, showing the best profile for combinations of PTA with UTA. In contrast, the ratios of 1 ：4 and 1 ： 1, despite synergistic in MES test, were additive in acute toxicity test. The 4：1 combination and two drugs alone significantly decreased Glu level and increased GABA level in the hippocampus, but the GABA level in the 4：1 combination group was higher than that in the two drugs alone groups. They did not have significant influence on the levels of ASp and Gly. Conclusion Combinations of PTA and UTA at 4：1 ratio demonstrated synergistic effect in anticonvulsant action and antagonistic effect in toxicity. The anticonvulsant mechanism might be related to decreasing the excitability of Glutamatergic neurons and increasing the inhibition of GABAergic neurons.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(No 20041109).
文摘Aim To investigate the synergistic effect of the combination of pinellia total alkaloid （PTA） and uncaria total alkaloid （UTA）, and explore the mechanism of anticonvulsant action. Methods Anticonvulsant and toxic effect profiles of combinations of PTA with UTA, alone and at three fixed ratios of 1：4, 1 ：1, 4：1, were evaluated in maximal electroshock （MES）-induced seizures and acute toxicity test in mice. Respective ED50 and LD50 were calculated with Bliss＇s method. Their synergistic effect were evaluated by isobolographic analysis and allowed the determination of benefit indices （BI） for respective combinations. The model of convulsive rats kindled by penicillin topically injected into cortex was used to investigated the content of Glu, Asp, Gly and GABA in hippocampus using high performance liquid chromatography （HPLC）. Results Combinations of PTA and UTA at the ratio of 4：1 were synergistic in MES test and antagonistic in acute toxicity test, showing the best profile for combinations of PTA with UTA. In contrast, the ratios of 1 ：4 and 1 ： 1, despite synergistic in MES test, were additive in acute toxicity test. The 4：1 combination and two drugs alone significantly decreased Glu level and increased GABA level in the hippocampus, but the GABA level in the 4：1 combination group was higher than that in the two drugs alone groups. They did not have significant influence on the levels of ASp and Gly. Conclusion Combinations of PTA and UTA at 4：1 ratio demonstrated synergistic effect in anticonvulsant action and antagonistic effect in toxicity. The anticonvulsant mechanism might be related to decreasing the excitability of Glutamatergic neurons and increasing the inhibition of GABAergic neurons.
