Calcium channel blocking agents and potassium-stimulated release of glutamate from cerebellar slices

Dickie, Brian G.M.; Davies, John A.

doi:10.1016/0014-2999(92)90291-b

Cited by 26 publications

(14 citation statements)

References 8 publications

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“…Veratridine stimulates the release of neurotransmitters by preventing the inactivation of sodium channels and TTX, through blockade of sodium channels, is effective in preventing this release (Levi et al ., 1980; Minchin, 1980; Dickie & Davies, 1992). Antiepileptics such as lamotrigine, which have been shown to block veratridine‐stimulated release but not potassium‐stimulated release, are thought to act by maintaining the inactivation of sodium channels (Leach et al ., 1986).…”

Section: Discussionsupporting

confidence: 87%

“…The mechanism by which potassium stimulates release is secondary to changes in the transmembrane potential which results in the opening of voltage‐sensitive calcium channels leading to exocytosis. The release of neurotransmitters in response to potassium does not involve sodium channels as tetrodotoxin (TTX) is ineffective in reducing this release (Dickie & Davies, 1992). Although losigamone has been shown to block sodium channels (Schmitz et al ., 1995) this action is therefore probably not involved in the reduced release seen in these present experiments.…”

Section: Discussionmentioning

confidence: 99%

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The anticonvulsant effects of the enantiomers of losigamone

Jones

Davies

1999

British J Pharmacology

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1 Losigamone is a novel anticonvulsant undergoing phase III clinical trials in patients with partial and secondary generalized seizures. This study investigated the eects of the S(+)-and R(7)-enantiomers of losigamone on endogenous amino acid release from BALB/c mouse cortical slices, spontaneous depolarizations in the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in DBA/2 mice. 2 S(+)-losigamone (100 and 200 mM) signi®cantly reduced both potassium-and veratridine-elicited release of glutamate and aspartate from cortical slices. R(7)-losigamone had no eect on release at concentrations up to 400 mM. 3 Cortical wedges exhibit spontaneous depolarizations when perfused with magnesium-free arti®cial cerebrospinal¯uid. S(+)-losigamone signi®cantly reduced these depolarizations at 50 ± 200 mM whilst R(7)-losigamone had a signi®cant eect at 200 ± 800 mM. 4 DBA/2 mice are susceptible to audiogenic seizures and S(+)-losigamone dose-dependently (5, 10 and 20 mg kg 71 , i.p.) signi®cantly inhibited clonic/tonic convulsions with 91% of the mice protected at 20 mg kg 71 . There was no protection at 20 mg kg 71 with R(7)-losigamone. 5 These results, from both in vitro and in vivo experiments, con®rm that the pharmacological activity pro®les of the two losigamone enantiomers are not identical and suggest further that excitatory amino acid-mediated processes are involved in the mode of action of S(+)-losigamone whereas R(7)-losigamone does not possess such properties. For the treatment of neurological conditions involving exaggerated excitatory amino acid function the use of S(+)-losigamone might therefore be more eective clinically than losigamone or its R(7)-enantiomer.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

The anticonvulsant effects of the enantiomers of losigamone

Jones

Davies

1999

British J Pharmacology

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“…The release of neurotransmitters in response to potassium does not involve sodium channels as tetrodotoxin, a potent sodium channel blocker, has been shown to be ineffective in inhibiting this release (Dickie & Davies, 1992). The inhibition of potassiumstimulated release of glutamate and aspartate by FPL 12495AA and dizocilpine is probably as a result of blockade of the NMDA receptor.…”

Section: Resultsmentioning

confidence: 99%

The effect of the desglycinyl metabolite of remacemide hydrochloride (FPL 12495AA) and dizocilpine (MK‐801) on endogenous amino acid release from mouse cortex

Srinivasan

Richens

Davies

1995

British J Pharmacology

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1 In this study the effect of FPL 12495AA, the desglycinyl metabolite of remacemide hydrochloride and dizocilpine (MK-801), on potassium-and veratridine-stimulated release of neurotransmitter amino acids from mouse cortical slices was investigated.2 Veratridine (20 gM) and potassium (60 mM) produced a preferential release of glutamate and aspartate. Potassium-stimulated release was calcium-dependent, while veratridine-stimulated release was only partially affected by removal of calcium from the medium. 3 FPL 12495AA significantly inhibited veratridine-and potassium-stimulated release of glutamate and aspartate. Lower concentrations of FPL 12495AA were needed to inhibit veratridine-stimulated release of glutamate (12.5 gM) than potassium-stimulated release (100 gM).4 Dizocilpine significantly inhibited veratridine-and potassium-stimulated release of glutamate and aspartate at concentrations of 100 gM and above. 5 FPL 12495AA and dizocilpine both have an affinity for the ion channel subsite of the N-methyl-Daspartate (NMDA) receptor. The reduction of potassium-stimulated release of glutamate and aspartate by FPL 12495AA and dizocilpine is probably due to NMDA receptor blockade. 6 FPL 12495AA inhibited veratridine-stimulated release at a concentration of 12.5 uM while dizocilpine was effective only at a concentration of 100 gM. This difference in efficacy is probably due to the higher affinity of FPL 12495AA compared to dizocilpine at the veratridine-binding site on the sodium channel.

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“…[8,9,11,12,19,27,[44][45][46][47]. All these neuronal functions also serve as basic mechanisms in the generation and regulation of brain activity, including the rhythmic activities concurring in the generation of the EEG and their cortical/subcortical modulation.…”

Section: Discussionmentioning

confidence: 99%

Plasma Concentration and CNS Effects of Ca Antagonists Darodipine and Nimodipine after Single-Dose Oral Administration to Healthy Volunteers

Sannita¹,

Garbarino

Gesino

et al. 1999

Neuropsychobiology

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The dynamics at the brain level (quantitative EEG), plasma kinetics and effects on blood pressure and heart rate of the Ca antagonists, darodipine (slow-release, 50– 200 mg) and nimodipine (30 mg), were compared in a double-blind cross-over study on healthy volunteers during a 9-hour period following single drug/placebo administration. Increased EEG total power was observed after 100 and 200 mg daropidine; a concomitant decrease of 14.5–32.0 Hz relative power was observed at 100 mg. The 50-mg dose proved ineffective. These effects were correlated with the darodipine plasma concentration only at the 100-mg dose, with indications of an active concentration interval at approximately 5–10 ng/ml; a reduction in diastolic blood pressure and increased heart rate proved to be linearly correlated with the drug plasma concentration throughout the entire concentration range. Comparable EEG effects were observed after nimodipine, but they did not correlate with the plasma concentration. Implications of the predictability of the brain effect from the drug plasma concentration and differential thresholds for the brain action and effects on (peripheral) circulation are suggested.

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Calcium channel blocking agents and potassium-stimulated release of glutamate from cerebellar slices

Cited by 26 publications

References 8 publications

The anticonvulsant effects of the enantiomers of losigamone

The anticonvulsant effects of the enantiomers of losigamone

The effect of the desglycinyl metabolite of remacemide hydrochloride (FPL 12495AA) and dizocilpine (MK‐801) on endogenous amino acid release from mouse cortex

Plasma Concentration and CNS Effects of Ca Antagonists Darodipine and Nimodipine after Single-Dose Oral Administration to Healthy Volunteers

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