Flunarizine inhibits both calcium-dependent and -independent release of glutamate from synaptosomes and cultured neurones

Cousin, Michael A.; Nicholls, David G.; Pocock, Jennifer M.

doi:10.1016/0006-8993(93)90989-z

Cited by 42 publications

(30 citation statements)

References 30 publications

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“…This action, which is unlikely to be mediated by high-affinity a binding sites, may play a role in the anticonvulsant and neuroprotective activities of some of the compounds. Indeed, the broad spectrum of activity of the compounds tested in the present experiments at HVA Ca2" channels resembles that of flunarizine, which is able to inhibit responses mediated by Ca2" flux through dihydropyridinesensitive and -insensitive Ca2" channels (Tytgat et al, 1991), blocks Ca2"-dependent glutamate release (Cousin et al, 1993) and possesses both anticonvulsant and neuroprotective efficacy in vivo (Deshpande & Wieloch, 1986;Czuczwar et al, 1992). Finally, it is noteworthy that rimcazole, an atypical antipsychotic agent, was one of the more potent Ca2" channel blockers examined in the present experiments.…”

Section: Electrophysiological Studiesmentioning

confidence: 69%

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

Church

Fletcher

1995

British J Pharmacology

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1 The effects of a series of structurally-dissimilar ai site ligands were examined on high voltage-activated Ca2`channel activity in two preparations of cultured hippocampal pyramidal neurones. 2 In mouse hippocampal neurones under whole-cell voltage-clamp, voltage-activated Ca2`channel currents carried by barium ions (IB.) were reduced with the rank order (IC" values in (18)>opipramol (32)>carbetapentane (40) (42)>caramiphen (47)>dextromethorphan (73). At the highest concentrations tested, the compounds almost abolished IB. in the absence of any other pharmacological agent.3 The current-voltage characteristics of the whole-cell IB. were unaffected by the test compounds. The drug-induced block was rapid in onset and offset, with the exceptions of carbetapentane and caramiphen where full block was achieved only after two to three voltage-activated currents and was associated with an apparent increase in the rate of inactivation of IB.4 In rat hippocampal neurones loaded with the Ca2"-sensitive dye Fura-2, rises in intracellular free Ca2+ concentration evoked by transient exposure to 50 mM K+-containing medium, either in the absence or in the presence of 10 pM nifedipine (to block L-type high voltage-activated Ca2`channels), were also reversibly attenuated by the ai ligands. The rank order potencies for the compounds in these experimental paradigms were similar to that observed for blockade of IB, in the electrophysiological studies. 5These results indicate that, at micromolar concentrations, the compounds tested block multiple subtypes of high voltage-activated Ca2" channels. These actions, which do not appear to be mediated by high-affinity a binding sites, may play a role in some of the functional effects previously described for the compounds.

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Section: Electrophysiological Studiesmentioning

confidence: 69%

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

Church

Fletcher

1995

British J Pharmacology

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“…Indirect effects of calcium antagonists (e.g. through glutamate release) [51] or contingent, Ca-independent effects cannot be excluded in principle. Although peculiarly sensitive to changes in the neuronal membrane and synaptic function and successfully applied in the study of neuropsychoactive compounds, the EEG is not specific with respect to the pharmacological characteristics and mechanisms of action of most compounds.…”

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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“…Flunarizine protects cells from the effects of Ca 2+ overload without interfering with the normal cellular Ca 2+ homeostasis, and protects the endothelium by blocking the entry of excessive Ca 2+ into the cell [1,4,16].…”

Section: Introductionmentioning

confidence: 99%

Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats

Matthew

Sils

2000

Pflügers Arch - Eur J Physiol

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Previous work has established that there is an increase in endothelial permeability in hyperthermic rats. This work assessed the potential of the calcium channel blocker (E)-1-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine) as a pretreatment to ameliorate this extravasation. Five groups of male rats (n=12 rats per group, 400-500 g) were given 0, 0.3, 1, 2, or 3 mg/kg flunarizine (FL0, FL0.3, FL1, FL2, and FL3, respectively) by gavage 30 min prior to induction of hyperthermia. Hyperthermia was achieved by placing unrestrained animals in their own cages in a chamber maintained at 41.5 degrees C until a core temperature (Tc) of 42.6 degrees C was attained. Then, 25 mg/kg of Evans blue in saline was administered via a jugular cannula. After 15 min the animals were anesthetized, exsanguinated, tissues removed and washed in saline, and Evans blue extracted with formamide. As the dose of flunarizine was increased, there was a significant (P<0.05) reduction of Evans blue recovered from the liver, kidney, lung, spleen, and intestinal tissue. Endurance time in the heat to reach a Tc of 42.6 degrees C increased significantly from 194+/-39 min (mean+/-SD) with FL0 to 275+/-33 min with FL1, but decreased again with FL2 (206+/-42) and FL3 (199+/-60). Thus, flunarizine pretreatment attenuated hyperthermia-induced extravasation, and 1 mg/kg flunarizine markedly increased the tolerance time to heat exposure.

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Flunarizine inhibits both calcium-dependent and -independent release of glutamate from synaptosomes and cultured neurones

Cited by 42 publications

References 30 publications

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

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

Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats

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Flunarizine inhibits both calcium-dependent and -independent release of glutamate from synaptosomes and cultured neurones

Cited by 42 publications

References 30 publications

Blockade by sigma site ligands of high voltage‐activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones

Blockade by sigma site ligands of high voltage‐activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones

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

Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats

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Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones

Blockade by sigma site ligands of high voltage‐activated Ca²⁺ channels in rat and mouse cultured hippocampal pyramidal neurones