Effects of various valproic acid derivatives on low-calcium spontaneous epileptiform activity in hippocampal slices

doi:10.1016/0920-1211(95)00044-5

Epilepsy Research

Volume 22, Issue 3, November 1995, Pages 185-192

https://doi.org/10.1016/0920-1211(95)00044-5 Get rights and content

Abstract

Lowering of extracellular calcium induces the development of spontaneous epileptiform activities in rat hippocampal slices. The antiepileptogenic effect of four new sugar-ester derivatives of valproic acid—dimethylenexylitol valproate, monoacetoneglucose valproate, diacetoneglucose valproate and glucose valproate—were investigated on such activity through 20-min bath applications and their effect compared to that of valproate, valpromide and phenytoin. Sodium valproate, 5 mM, did not completely suppress the spontaneous epileptiform activity. Valpromide, 2.5 mM, and phenytoin, 0.25 mM, produced complete cessation of seizure activity. Dimethylenexylitol valproate, 0.1 mM, completely suppressed spontaneous epileptiform activities. The other derivatives were less potent: concentrations of 0.25 mM of monoacetoneglucose valproate and 1 mM of diacetoneglucose valproate and glucose valproate were required for complete cessation of activity. The sugar carriers alone were devoid of effect. The data show that these molecules have a direct action on the nervous tissue and their antiepileptogenic efficacy in the low-calcium model is far larger than that of valproic acid itself. Such derivatives, especially dimethylenexylitol valproate, appear to be promising for development of new antiepileptic molecules.

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Cited by (13)

Long-lasting antiseizure effects of chronic intrasubthalamic convection-enhanced delivery of valproate
2023, Neurobiology of Disease
Intracerebral drug delivery is an experimental approach for the treatment of drug-resistant epilepsies that allows for pharmacological intervention in targeted brain regions. Previous studies have shown that targeted pharmacological inhibition of the subthalamic nucleus (STN) via modulators of the GABAergic system produces antiseizure effects. However, with chronic treatment, antiseizure effects are lost as tolerance develops. Here, we report that chronic intrasubthalamic microinfusion of valproate (VPA), an antiseizure medication known for its wide range of mechanisms of action, can produce long-lasting antiseizure effects over three weeks in rats. In the intravenous pentylenetetrazole seizure-threshold test, seizure thresholds were determined before and during chronic VPA application (480 μg/d, 720 μg/d, 960 μg/d) to the bilateral STN. Results indicate a dose-dependent variation in VPA-induced antiseizure effects with mean increases in seizure threshold of up to 33%, and individual increases of up to 150%. The lowest VPA dose showed a complete lack of tolerance development with long-lasting antiseizure effects. Behavioral testing with all doses revealed few, acceptable adverse effects. VPA concentrations were high in STN and low in plasma and liver. In vitro electrophysiology with bath applied VPA revealed a reduction in spontaneous firing rate, increased background membrane potential, decreased input resistance and a significant reduction in peak NMDA, but not AMPA, receptor currents in STN neurons. Our results suggest an advantage of VPA over purely GABAergic modulators in preventing tolerance development with chronic intrasubthalamic drug delivery and provide first mechanistic insights in intracerebral pharmacotherapy targeting the STN.
Valproic acid potently inhibits interictal-like epileptiform activity in prefrontal cortex pyramidal neurons
2019, Neuroscience Letters
Citation Excerpt :
It has been found in a zero-magnesium model that 3 mM valproate (a concentration that greatly exceeds the therapeutic level) reduces the frequency of interictal epileptic events in entorhinal cortex neurons by approximately one half [20]. In a different study, the frequency of interictal discharges induced in hippocampal neurons in a low-calcium, elevated potassium model was reduced by valproic acid concentration as high as 5 mM [21]. The fact that authors applied such a high concentration of the drug suggests that lower (therapeutic) levels are not effective.
Valproic acid has a long-standing reputation of effectively treating the symptoms of not only epilepsy but also psychiatric conditions. In the latter, the exact mechanism by which valproate exerts its effect remains unclear. In this study, epileptiform bursts were recorded from pyramidal neurons in the prefrontal cortex (the brain region thought to be involved in psychiatric disorders) using the patch-clamp technique. An extracellular solution with no magnesium ions and elevated potassium levels that is known to induce epileptiform activity in vitro was used. Because of their short durations, the epileptiform bursts were regarded as interictal-like epileptiform activity, which is believed to be involved in cognitive impairment. Interictal discharges occur in many neuropsychiatric disorders as well as in healthy population.
Epileptic activity in prefrontal cortex pyramidal neurons was potently inhibited by two therapeutic concentrations of valproic acid (20 μM and 200 μM). Moreover, valproate suppressed spontaneous excitatory postsynaptic potentials. Epileptiform bursts were fully inhibited by NMDA receptor antagonist, which suggests that epileptiform activity is driven by NMDA receptors. The inhibition of excitability in prefrontal cortex pyramidal neurons by valproate was also shown.
This study shows that it is possible to evoke NMDA-dependent epileptiform activity in prefrontal cortex pyramidal neurons in vitro.
We suggest that the prefrontal cortex is a good region for studying the influence of drugs on interictal epileptiform activity.
The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABA<inf>B</inf> class C G protein-coupled receptors
2011, Neuropharmacology
Citation Excerpt :
Indeed, the EC50 for Ca2+ on GABAB receptor is 37 μM (Galvez et al., 2000). Such a low extracellular Ca2+ concentration can be reached only in some pathological conditions, like epileptic seizure, then offering a way for GABAB receptor to act differently under such conditions (Armand et al., 1995; Heinemann et al., 1986). In the case of the GPRC6 receptor, the amino acid-induced response could also be augmented by divalent cations, like Ca2+ and Mg2+, at physiological concentrations (Pi et al., 2005), although the mechanism remains to be determined precisely.
In the human genome, 22 genes are coding for the class C G protein-coupled receptors that are receptors for the two main neurotransmitters glutamate and γ-aminobutyric acid, for Ca²⁺ and for sweet and amino acid taste compounds. In addition to the GPCR heptahelical transmembrane domain responsible for G-protein activation, class C receptors possess a large extracellular domain that is responsible for ligand recognition. Recent studies had revealed that class C receptors are homo- or heterodimers with unique mechanism of activation. In the present review, we present an up-to-date view of the structures and activation mechanism of these receptors in particular the metabotropic glutamate and GABA_B receptors. We show how the complexity of functioning of these transmembrane proteins can be used for the development of therapeutics to modulate their activity. We emphasize on the new approaches and drugs that could potentially become important in the future pharmacology of these receptors.
Sodium valproate at the therapeutic concentration inhibits the induction but not the maintenance phase of long-term potentiation in rat hippocampal CA1 area
2010, Biochemical and Biophysical Research Communications
Citation Excerpt :
The critical event leading to the induction of LTP is approved to be the influx of calcium ions into the postsynaptic spine, and the elevation of postsynaptic calcium concentration is necessary and sufficient for the induction of hippocampal LTP [13]. Meanwhile there are some reports that contributing to the anticonvulsant action VPA reduced the T-type Ca2+ currents [11,26,27]. Therefore maybe VPA suppressed LTP induction through inhibiting Ca2+ diffusing into the postsynaptic neurons.
Sodium valproate (VPA) is currently one of the major antiepileptic drugs and has been reported to impair the induction of long-term potentiation (LTP) in rat hippocampal. However, there are discrepancies when used at therapeutic dose and few researches to study the effects of VPA on the maintenance of LTP. Here we investigated the effects of VPA at therapeutic concentration on two LTP phases: induction and maintenance in CA1 region. We found (1) VPA inhibited field excitatory postsynaptic potentials (fEPSPs) without modifying paired-pulse facilitation (PPF) solely occured presynaptically as a form of synaptic plasticity. (2) Pretreatment with VPA before high-frequency stimulation (HFS) decreased the fEPSPs slope. (3) There were no significant changes in fEPSPs slope with VPA applied in maintenance phase of LTP. These results indicate that VPA inhibited the induction of LTP postsynaptically without modifying presynaptic neurotransmitter release and had no significant influence on the two maintenance phase of LTP.
Crystal structure and anticonvulsant activity of (±)-1,2:4,5-di-O-isopropylidene-3,6-di-O-(2-propylpentanoyl)-myo-inositol
2007, Carbohydrate Research
Citation Excerpt :
This hypothesis is supported by the molecular geometry, the observation that the carbonyl carbon is sterically hindered by both the valproate group and the myo-inositol ring also suggests that the molecules of 2 could not be easily hydrolyzed. Furthermore, the results of Armand et al.9 and Redecker et al.10 are in line with our findings. These authors suggested that other VPA sugar-alcohol esters analyzed by them do not represent prodrugs of VPA.
The biological activity and crystal structure of (±)-1,2:4,5-di-O-isopropylidene-3,6-di-O-(2-propylpentanoyl)-myo-inositol have been investigated. This compound shows better anticonvulsant activity than valproic acid (VPA) in the MES test as measured in mice. Its structure, determined from single-crystal X-ray diffraction measurements, shows that the inositol ring deviates from the ideal chair conformation and that the two 2-propylpentanoyl groups are located on opposite ring positions. This molecular conformation lets carbonyl and hydroxyl oxygen atoms to be available for hydrogen-bonding interactions, hinders carbonyl carbon atoms, preventing metabolic enzymatic hydrolysis, and helps to rationalize the observed inactive profile in the PTZ test. The anticonvulsant activity profile suggests a mechanism different from that of VPA.
Epileptiform activity of veratridine model in rat brain slices: Effects of antiepileptic drugs
2000, Epilepsy Research
The effects of the antiepileptic drugs valproic acid (VPA), phenytoin (PHT), and ethosuximide (ESM) on evoked and spontaneous seizure-like (epileptiform) activity were studied in the veratridine epileptiform model in rat brain slices, using conventional electrophysiological intracellular recording techniques. The veratridine model is generated by treatment of brain slices with a low concentration (0.3 μM) of the alkaloid veratridine. The drug modifies sodium channel function so that a brief current injection in hippocampal CA1 pyramidal neurons evokes bursts of epileptiform activity. Therapeutic concentrations of VAP (50–200 μM) inhibited both evoked and spontaneous bursting in a voltage-dependent manner without affecting membrane resting potential or input resistance. Similarly, therapeutic concentrations of PHT (4–15 μM) inhibited both evoked and spontaneous bursting in a voltage-dependent fashion with no apparent change in the membrane resting potential. However, PHT increased the membrane input resistance and elevated the firing threshold of neurons. The antiepileptic drug ESM failed to inhibit evoked or spontaneous bursting even at high concentrations. The results suggest that the veratridine model of epileptiform activity is sensitive only to antiepileptic drugs that primarily affect the sodium channels.

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Research reportEffects of various valproic acid derivatives on low-calcium spontaneous epileptiform activity in hippocampal slices

Abstract

Prog. Neurobiol.

Brain Res.

Brain Res.

Brain Res.

Neurosci. Lett.

Neurosci. Lett.

Epilepsy Res.

Epilepsy Res.

Brain Res.

Synthèses, études toxicologique et pharmacologique de nouveaux esters valproïques derivés de saccharides et d'itols

Research report
Effects of various valproic acid derivatives on low-calcium spontaneous epileptiform activity in hippocampal slices