Contribution of Calcium Ions to the Generation of Epileptic Activity and Antiepileptic Calcium Antagonism

Speckmann, E.-J.; Straub, H.; Köhling, Rüdiger

doi:10.1159/000118966

Cited by 32 publications

(13 citation statements)

References 10 publications

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“…Thus the other possible explanation for the anticonvulsant action of fluoxetine may be related to its inhibitory effect on ionic channels. Several reports indicated that altered activity of voltage-gated Na + and Ca 2+ channels was involved in the enhancement of neuronal discharges during epilepsy (51)(52)(53), and conventional anticonvulsant drugs were found to block voltage-dependent Na + and Ca 2+ channels (11,13,14,53). Our previous results demonstrating that fluoxetine was a considerably more potent inhibitor of Ca 2+ than Na + channels support the possibility that inhibition of Ca 2+ channels by fluoxetine may contribute to its anticonvulsant action (10).…”

Section: Discussionmentioning

confidence: 59%

Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues

et al. 2003

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Abstract. Racemic fluoxetine is a widely used SSRI antidepressant compound having also anticonvulsant effect. In addition, it was shown that it blocked several types of voltage gated ion channels including neural and cardiac calcium channels. In the present study the effects of enantiomers of fluoxetine (R(-)-fluoxetine and S(+)-fluoxetine) were compared on neuronal and cardiac voltage-gated Ca 2+ channels using the whole cell configuration of patch clamp techniques, and the anticonvulsant action of these enantiomers was also evaluated in a mouse epilepsy model. In isolated pyramidal neurons of the dorsal cochlear nucleus of the rat the effect of fluoxetine (S(+), R(-) and racemic) was studied on the Ca 2+ channels by measuring peak Ba 2+ current during ramp depolarizations. All forms of fluoxetine reduced the Ba

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Section: Discussionmentioning

confidence: 59%

Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues

et al. 2003

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“…This, however, could have been expected for verapamil, since voltage-operated Ca 2ϩ channels have been suggested as a pharmacotherapeutic drug target to correct the aberrant pathophysiology of epileptogenesis via a phenomenon known as "intrinsic burst firing" driven by an inward Ca 2ϩ current (Kulak et al, 2004). Several Ca 2ϩ channel antagonists were shown to possess anticonvulsant potential in experimental and clinical studies (De Sarro et al, 1988;Czuczwar et al, 1990;Larkin et al, 1992;Speckmann et al, 1993;Gasior et al, 1995Gasior et al, , 1996Swiader et al, 2002). However, systemic isradipine and verapamil administration per se or in combination with AEDs failed to display any anticonvulsant activity (Czuczwar et al, 1990;Borowicz et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Quantitative in Vivo Microdialysis Study on the Influence of Multidrug Transporters on the Blood-Brain Barrier Passage of Oxcarbazepine: Concomitant Use of Hippocampal Monoamines as Pharmacodynamic Markers for the Anticonvulsant Activity

Clinckers¹,

Smolders²,

Meurs³

et al. 2005

J Pharmacol Exp Ther

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Various antiepileptic drugs were shown to be substrates for multidrug transporters at the level of the blood-brain barrier. These ATP-dependent efflux pumps actively limit brain accumulation of xenobiotics and drugs. Intrahippocampal oxcarbazepine perfusion in rat was previously shown to exert anticonvulsant effects associated with increases in extracellular dopamine and serotonin levels. In contrast, preliminary studies in our laboratory revealed that no anticonvulsant or monoaminergic effects could be obtained after systemic oxcarbazepine administration. The present in vivo microdialysis study was conducted to investigate the impact of the transport kinetics of oxcarbazepine across the blood-brain barrier on the observed treatment refractoriness. More precisely, the influence of intrahippocampal perfusion of verapamil, a P-glycoprotein inhibitor, and probenecid, a multidrug resistance protein inhibitor, on the blood-brain barrier passage and anticonvulsant properties of oxcarbazepine were investigated in the focal pilocarpine model for limbic seizures. Simultaneously, the effects on hippocampal monoamines were studied as pharmacodynamic markers for the anticonvulsant activity. Although systemic oxcarbazepine administration alone failed in preventing the animals from developing seizures, coadministration with verapamil or probenecid offered complete protection. Concomitantly, significant increases in extracellular hippocampal dopamine and serotonin levels were observed within our previously defined anticonvulsant monoamine range. The present data indicate that oxcarbazepine is a substrate for multidrug transporters at the bloodbrain barrier. Coadministration with multidrug transporter inhibitors significantly potentiates the anticonvulsant activity of oxcarbazepine and offers opportunities for treatment of pharmacoresistant epilepsy.Oxcarbazepine (OXC) is the 10,11-keto analog of carbamazepine (CBZ). Like CBZ, it is considered to exert its antiepileptic effects by stabilization of the Na ϩ channels in a voltage-, frequency-, and time-dependent manner. OXC can also block high-threshold Ca 2ϩ currents and increase K ϩ channel conductance (McLean et al., 1994). Previously, we showed that increases in hippocampal dopamine (DA) and serotonin (5-HT) levels can have important anticonvulsant effects in the focal pilocarpine model for limbic psychomotor seizures (Clinckers et al., 2004a). These anticonvulsant effects were restricted to a well defined anticonvulsant concentration range and were proven to be mediated by D 2 and 5-HT 1A receptor stimulation. Anticonvulsant activity against pilocarpine-induced seizures can also be achieved by intrahippocampal perfusion of OXC (unpublished data). From the anticonvulsant threshold concentration (i.e., 100 M) onward, significant increases in extracellular (EC) hippocampal DA and 5-HT levels were observed, within the previously determined anticonvulsant monoamine ranges. These monoaminergic neurotransmitter increases were again shown to importantly contribute to the ant...

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“…Calcium ions (Ca2+), ubiquitous second messengers in vertebrate cells, are involved in the pathology of epileptic seizures (Speckmann et al, 1993). This assumption is supported by the findings that burst firing of neurons (the best electrophysiological manifestation of seizures) may be triggered by a large influx of Ca 2+ (Schwartzkroin and Wyler, 1980).…”

Section: Introductionmentioning

confidence: 95%

Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice

Gąsior

Kamiński

Brudniak

et al. 1996

J. Neural Transmission

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Among three calcium channel inhibitors, only nicardipine (10-40 mg/kg) significantly inhibited clonic seizures induced by pentylenetetrazol administered at its CD97 (convulsive dose 97%) of 81 mg/kg, subcutaneously. Nimodipine and flunarizine (both up to 80 mg/kg) did not suppress pentylenetetrazol-induced clonic seizures per se. Co-administration of nicardipine (5 mg/kg) resulted in a significant enhancement of the protective potency of either ethosuximide (50 mg/kg) or valproate (100 mg/kg) against clonic seizures in this test. Similar effects were noted in case of combined treatment of nimodipine (20-40 mg/kg) with these antiepileptics. On the contrary, flunarizine (up to 20 mg/kg) did not modify the anticonvulsive action of these antiepileptic drugs. Moreover, none of the studied calcium channel inhibitors influenced the protective activity of clonazepam (0.01 mg/kg). The antiepileptic drugs, administered alone in above doses, were ineffective against pentylenetetrazol-induced clonic convulsions. In case of ethosuximide and valproate, the motor performance in the chimney test was worsened by co-administration of nimodipine (40 mg/kg). We found no pharmacokinetic interactions (at least in relation to the plasma levels of ethosuximide and valproate) that could explain the observed results. Thus, we conclude that a combination of some calcium channel inhibitors and antiepileptic drugs may provide more efficient protection against experimental seizures which may bear a potential clinical significance.

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Contribution of Calcium Ions to the Generation of Epileptic Activity and Antiepileptic Calcium Antagonism

Cited by 32 publications

References 10 publications

Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues

Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues

Quantitative in Vivo Microdialysis Study on the Influence of Multidrug Transporters on the Blood-Brain Barrier Passage of Oxcarbazepine: Concomitant Use of Hippocampal Monoamines as Pharmacodynamic Markers for the Anticonvulsant Activity

Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice

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