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PubMed1988

Sodium valproate decreases synaptic potentiation and epileptiform activity in hippocampus.

The actions of sodium valproate (NaVP) were studied in the in vitro hippocampus using extracellular, intracellular and voltage-clamp recording techniques. In the CA1 region, concentrations of 30-200 microM NaVP reduced the amplitude but not the time course of post-tetanic potentiation (PTP) of dendritic field excitatory postsynaptic potentials (EPSPs). Epileptiform discharges were studied intracellularly in CA3 cells after pharmacological blockade of synaptic inhibition and repeated tetanic stimulation. NaVP (100 microM) blocked evoked paroxysmal depolarizing shift (PDS) discharges through a mechanism of increasing the threshold for burst-firing. When the PDS current was studied under voltage-clamp, application of NaVP (100 microM) resulted in a graded reduction of the PDS waveform. All of the actions of NaVP may result from inhibition of excitatory synaptic transmission following repetitive cell firing. A hypothesis is proposed that NaVP may act to decrease excitatory synaptic potentiation necessary for network synchronization.

Action Potentials↗

PubMed1989

Valproate enhances GABA turnover in the substantia nigra.

The effects of the antiepileptic drug, valproate (VPA), on regional turnover of gamma-aminobutyric acid (GABA) in the rat brain were studied by determining the rate of GABA accumulation following complete inhibition of GABA degradation by aminooxyacetic acid (AOAA). VPA was administered at a dose of 200 mg/kg 5, 15 and 30 min prior to injection of AOAA, 100 mg/kg. In most of the 12 regions examined, VPA did not alter the AOAA-induced GABA accumulation. However, significant increases in GABA accumulation were found in corpus striatum and, more marked, in substantia nigra. Since the substantia nigra has been identified as a substrate for the anticonvulsant action of GABAergic drugs, the data may indicate that the effect of VPA on GABA synthesis rate in this region may be involved in its mechanism of anticonvulsant action.

Aminooxyacetic Acid↗

PubMed1991

Valproate suppresses N-methyl-D-aspartate-evoked, transient depolarizations in the rat neocortex in vitro.

Effects of the antiepileptic drug sodium valproate (VPA) were studied on neocortical pyramidal cells (layer II/III) of the rat in vitro by intracellular recording. VPA (0.1-1 mM) in a dose-related manner suppressed the characteristic transient depolarizations induced by N-methyl-D-aspartate (NMDA) applied iontophoretically Higher concentrations of VPA (5-10 mM) also reduced L-glutamate responses. At these concentrations VPA increased the duration of orthodromically evoked inhibitory postsynaptic potentials and reduced repetitive spike firing induced by depolarizing currents. All effects were fully reversible within about 30 min. These results suggest that an essential mode of action for the anticonvulsant VPA is the attenuation of NMDA receptor-mediated excitation.

Animals↗

PubMed1992

The effect of sodium valproate on extracellular GABA and other amino acids in the rat ventral hippocampus: an in vivo microdialysis study.

We report the effects of i.p. administration of sodium valproate (VPA) on extracellular concentrations of various amino acids in the rat ventral hippocampus studied using in vivo microdialysis, followed by HPLC with fluorometric detection. At the doses used (100, 200 and 400 mg/kg), VPA had no effect on extracellular aspartate, glutamine and taurine, whilst inducing a small, but not statistically significant increase in glutamate at 200 and 400 mg/kg. In contrast, VPA administration produced a biphasic effect on extracellular GABA levels which was dependent on the dose used. At 100 mg/kg, VPA reduced GABA concentrations by 50% when compared to basal. 200 mg/kg VPA had virtually no effect, whilst 400 mg/kg VPA raised extracellular GABA levels to 200% of basal. The results are discussed in relation to the known pharmacological and anticonvulsant actions of VPA.

Amino Acids↗

PubMed1995

Reduction in firing rate of substantia nigra pars reticulata neurons by valproate: influence of different types of anesthesia in rats.

Nondopaminergic, presumably GABAergic neurons in the substantia nigra pars reticulata (SNR) are thought to function as a gating mechanism for seizure propagation. Systemic administration of anticonvulsant doses of the antiepileptic drug valproate (VPA) has previously been reported to inhibit the firing of nondopaminergic SNR neurons in anesthetized but not in awake, paralyzed and locally anesthetized rats, suggesting that the findings in anesthetized rats were due to an interaction between VPA and the general anesthetic used. In the present study, we determined the influence of different anesthetic measures on the effect of an anticonvulsant dose of VPA (100 mg/kg) on extracellularly recorded spontaneous single unit activity of nondopaminergic SNR neurons in rats. Rats were anesthetized by continuous infusion of the general anesthetic chloral hydrate, the dissociative anesthetic ketamine or the narcotic opioid fentanyl, or were only locally anesthetized and paralyzed. VPA significantly reduced SNR firing in all groups with a time course that matched its anticonvulsant time course in rodents. However, VPA's inhibitory effect on SNR firing was significantly less marked under anesthesia with chloral hydrate than in any of the other groups, indicating that this anesthetic suppresses the action of VPA, which may be related to an interaction with GABA-related processes in the SNR. The closest approximation to the effect of VPA in awake rats was obtained under anesthesia with ketamine, while VPA's inhibitory action on SNR neuronal firing seemed to be enhanced in the fentanyl group, which exhibited the highest baseline firing rates of all groups. Determination of VPA in the SN showed that the difference in VPA's inhibitory effect on SNR neurons was not secondary to differences in local drug concentrations. The data demonstrate that VPA is capable of significantly slowing the spontaneous activity of nondopaminergic SNR neurons, but that the magnitude of this effect depends on the anesthetic measures used. In view of the presumed role of SNR neurons in seizure propagation and the finding that VPA consistently inhibits these neurons at an anticonvulsant dose, the present data suggest that suppression of spontaneous SNR neuronal firing may be an important mechanism through which VPA exerts its anticonvulsant properties.

Anesthetics↗

PubMed1977

A rapid and sensitive gas-liquid chromatographic procedure for the micro determination of sodium valproate (sodium di-N-propylacetate) in plasma or serum.

A gas-liquid chromatographic procedure for the micro determination of sodium valproate is described. Valproic acid is extracted from acidified plasma or serum into n-heptane containing an internal standard (octanoic acid) and after phase separation an aliquot is analysed by gas-liquid chromatography. The procedure is rapid, reliable, sensitive and specific. It requires 25--50 microliter sample for a single estimation, has a detection threshold of less than 10 mumol/l, and is suitable for routine clinical use.

Chromatography, Gas↗

PubMed1981

Suppression by sodium valproate of gamma-vinyl GABA-induced facilitation of visual evoked potentials in rats.

A single dose (500 mg/kg, i.p.) of GABA-transaminase inhibitor, gamma-vinyl GABA (GVG), administered to Wistar rats caused time-related 2--3-fold enhancement of the slow negative wave (SNW) and sensory after-discharge (SAD) of the VEP. This effect was detectable at 1 h, reached plateau at 3--4 h and remained at this level 7 h after GVG. Sodium valproate (VPA, di-n-propylacetic acid), which is also believed to block GABA-transaminase and succinic semialdehyde dehydrogenase, when administered in a dose of 200 mg/kg (i.p.) 3 h after GVG reversibly antagonized the SNW-SAD hypersynchronization. The time-course of this effect was similar to that obtained after VPA administration alone. These findings are interpreted as suggesting that VPA acts via a mechanism using a transmitter intimately connected to but not identical with GABA.

4-Aminobutyrate Transaminase↗

PubMed1983

Sodium valproate-induced hyperammonemia in the rat: role of the kidney.

The intravenous injection of sodium valproate (VPA) 200 mg/kg provoked in fasting rats a 100% increase in the arterial NH+4 concentration by the 10th min. The increase persisted at this level for at least 100 min. Simultaneous measurements of NH+4 and glutamine concentrations in the carotid artery, renal vein and suprahepatic vein showed that there were increases in the release of NH+4 and the uptake of glutamine by the kidney while the [NH+4] of suprahepatic venous blood remained stable. In binephrectomized rats injected with VPA, NH+4 levels did not change. These results suggest that the VPA-induced arterial hyperammonemia depended on the accelerated catabolism or possibly the reduced synthesis of glutamine by the kidneys. The liver of fasting rats does not seem to play a preponderant role in the VPA-induced hyperammonemia.

Ammonia↗

PubMedDate not supplied

Inhibition of oxidative phosphorylation in hepatic and cerebral mitochondria of sodium valproate-treated rats.

Rats were treated with intraperitoneal injections of sodium valproate (VPA), either acutely, one injection VPA 200 mg/kg, or chronically, VPA 600 mg/kg/day for 5 days, and the oxygen consumption, MO2, of isolated hepatic and cerebral mitochondria measured. For hepatic mitochondria, Stade IV MO2 decreased by more than 20%, and Stage III MO2 by more than 50%, in the presence of succinate or glutamate-malate substrates. A decoupling agent intensified this inhibition. With cerebral mitochondria, the effects were similar but weaker, for pyruvate-malate or glutamate-malate substrates. These findings suggest that VPA, a short-chain fatty acid, may affect the properties of the internal mitochondrial membrane, although an action on substrate carriers, or on indispensable mitochondrial metabolites, is not excluded. Inhibition of oxidative phosphorylation cannot, however, alone account for hepatotoxicities seen in VPA-treated subjects. These are rare, whereas inhibition of mitochondrial respiration by VPA is consistently observed.

Adenosine Diphosphate↗

PubMed1983

[Sodium valproate: a hyperammonemic drug. Study in the epileptic and healthy volunteer].

Sodium valproate (VPA) consistently induces an arterial hyperammonemia in epileptics tolerant of this drug and in normal subjects. The hyperammonemia appears with the first oral or intravenous dose of the drug, 15-25 mg/kg, and is established within minutes following drug absorption. In 20 epileptics treated with VPA alone for 4 days, the mean arterial ammonemia measured 2-3 h after breakfast and the day's first VPA dose was 72 +/- 9 mumols/l in non-alcoholics, and 77 +/- 7 mumols/l in alcoholics. Hyperammonemia persisted during chronic treatment; in 10 epileptics who had had received only VPA for over a month, the mean hyperammonemia was 87 +/- 6 mumols/l (normal value means +/- 2 SD = 28 +/- 12 mumols/l). The ammonemia varied in the course of the day; sharp peaks 7 or more times the base value were observed. These variations, differing among subjects, depended on the VPA plasma concentration, and above all on the meal composition and the relative timing of the meal and the drug administration. No secondary effects were seen; in particular, hepatic and pancreatic tests were normal. The hyperammonemia would seem to be due to physiopathological mechanisms other than those giving rise to the hepatic complications occasionally observed with VPA. The permanence and the extent of the hyperammonemia raise questions as to its origin, its relation to the stuporous states induced by VPA, and its eventual repercussions on the functioning of neurons.

Ammonia↗

PubMed1985

Decrease of valproate-induced hyperammonemia in normal subjects by lipid ingestion.

Sodium valproate (VPA), a branched short-chain fatty acid, always causes a hyperammonemia of renal origin in fasting man. The intake of medium-length, straight-chain fatty acids abolishes the VPA-induced hyperammonemia, and VPA free fraction increases concomitantly. Accordingly, fatty acids could be useful in preventing and treating hyperammonemia-accompanied stuporous states which are complications of VPA medication.

Ammonia↗

PubMed1982

Benzodiazepine antagonists abolish electrophysiological effects of sodium valproate in the rat.

A hypothesis was considered that anti-epileptic potency of sodium valproate (VPA) may be associated with its action via the benzodiazepine system. The ability of anti-petit mal drugs to suppress the slow secondary negative wave (SNW) of the visually evoked potential was used as a sensitive electrophysiological "tag" for comparison of VPA (200 mg/kg, i.p.) and Diazepam (5 mg/kg, i.p.) effects. Both drugs induced a profound inhibition of the SNW. Benzodiazepine antagonists Ro 5-3663 (2 mg/kg, i.p.) and Ro 15-1788 (5 mg/kg, i.p.) caused recovery of the SNW amplitude within several minutes of injection. Both antagonists abolished immobility and sedation produced by VPA and Diazepam. The possibility should be considered that therapeutic effects of VPA are mediated through the benzodiazepine receptor coupled to GABA.

Animals↗

PubMed1985

Diurnal oscillations of CSF valproate in monkey.

Valproate (VPA) was administered to four rhesus monkeys by constant-rate intravenous infusion for two weeks under controlled conditions. Plasma and CSF samples were collected for a period of 27 hours at 3-hour intervals during steady-state and post-infusion periods. The mean correlation coefficient between total plasma and CSF VPA concentrations was found to be 0.78 +/- 0.09. The CSF VPA levels reflected the changes in free VPA in plasma but the two were not equivalent. Diurnal fluctuations in CSF VPA concentration were similar to those found in plasma but the inter-animal variation was greater in CSF than in plasma.

Animals↗

PubMed1987

3'-5' cyclic-guanosine monophosphate increase in rat brain hippocampus after gamma-hydroxybutyrate administration. Prevention by valproate and naloxone.

An increase (123%) of cyclic GMP (cGMP) was observed in the hippocampus of the rat killed by microwave irradiation 45 min after administration of 500 mg/kg gamma-hydroxybutyrate (GHB) IP. This increase is time and dose dependent. No modification in cyclic nucleotide content was observed in striatum and in cerebellum. As the role of GHB has been implicated in neurotransmission, the fact that this compound increases cyclic GMP accumulation in hippocampus in vivo may represent a mechanism by which the actions of GHB are mediated at the cellular level. Valproate (400 mg/kg) or naloxone (10 mg/kg) pretreatment completely abolish the cGMP increase due to GHB. A GABAergic and/or opiate phenomenon may be involved in the mechanism of GHB induced increase of cGMP.

Animals↗

PubMed1996

Ursodeoxycholate improves hepatobiliary dysfunction induced by valproate-carbamazepine treatment in the rat.

Carbamazepine (CBZ) and valproate (VPA) are commonly used antiepileptic drugs. These drugs, either alone or combined, may produce hepatotoxicity. We report results of a biochemical and histological study of the liver in rats treated for eight days with VPA (500 mg/Kg/day), CBZ (200 mg/Kg/day) and VPA plus CBZ. A hepatoprotective bile salt, ursodeoxycholate (UDC, 60 mg/Kg/day) was given as a supplement to rats treated with the VPA+CBZ combination. VPA strongly modified the biliary biochemical parameters inducing hypercholeresis and hyposecretion of phospholipids. Microscopically, hepatocytes showed intense vacuolation of the peripheral cytoplasm and alterations of the mitochondrial matrix. CBZ produced increased choleresis but had no effect on biliary lipid parameters. Ultrastructurally, CBZ induced marked proliferation of the smooth endoplasmic reticulum of hepatocytes. The VPA+CBZ association produced a combination of the alterations induced independently by each drug. In both bile and plasma, increased CBZ-epoxide and decreased VPA levels were observed. The addition of UDC restored the biliary phospholipid secretion, decreased cytoplasmic vacuoles and mitochondrial alterations, and diminished the hypertrophy of smooth endoplasmic reticulum, indicating a clear beneficial effect of UDC on hepatobiliary dysfunction induced by the VPA+CBZ combination. Furthermore, the supplementation with UDC did not significantly change the plasma levels of the antiepileptic drugs.

Animals↗

PubMed1985

Effect of valproate on brain GABA: comparison with various medium chain fatty acids.

The antiepileptic valproic acid increases brain GABA levels, and interferes with intermediate metabolism. We have therefore evaluated the effects of a number of other medium chain fatty acids on brain GABA. Propionate, isovalerate, pent-4-enoate and diallylacetate all increased whole-brain GABA levels in mice, but only diallylacetate possessed some anticonvulsant activity. Hyperammonaemia is a common side effect observed with these acids, but artificially induced hyperammonaemia through injections of ammonium chloride did not alter brain GABA. These results suggest that high doses of valproate may increase brain GABA by interfering with intermediate metabolism, possibly at the level of medium chain acyl CoA. However alterations in brain GABA did not correlate with anticonvulsant activity.

Ammonia↗

PubMed1981

Pharmacologic analysis of sodium valproate-induced suppression of secondary components of visual evoked potentials in albino rats.

Sodium Valproate (VPA) administered to rats in a dose of 10 or 200 mg/kg IP suppressed the slow negative wave (SNW) and photically-induced afterdischarge (SAD) of VEP (when they were present) within 15-30 min. The recovery of VEP amplitude began at 3 hr. This effect was antagonized by subconvulsive doses of convulsant benzodiazepine RO 5-3663 (2 mg/kg) and metrazol (15 mg/kg) but not by picrotoxin (2 mg/kg) and naloxone (10 mg/kg). The SNW suppression may be attributed to a disinhibitory action of a system located presynaptically on recurrent collaterals of the output neurons, or nerve terminals of inhibitory interneurons or both. Alternative conjecture suggests that VPA depolarizes the dendritic tree masking thereby somatic inhibition produced by recurrent circuits.

Animals↗

PubMed1986

Effects of chlordiazepoxide and sodium valproate in two tests of spatial behaviour.

The effects of chlordiazepoxide (CDP) and sodium valproate (VPA) were studied in rats trained to asymptotic performance on two tests of spatial behaviour, the 8-arm radial maze and the 8-choice arena. The task in the 8-arm maze was to locate a single food pellet at the end of each arm. Both CDP and VPA caused an increase in errors, an increase in performance time, and the utilization of a non-spatial response strategy. The task in the 8-choice arena was to locate a single water bottle from an octagonal array of eight otherwise empty bottles. For one group the goal bottle remained in the same place from trial to trial; for a second group the position of the goal bottle was cued by a black card over the nozzle; for the third group the goal bottle was uncued and moved randomly from trial to trial. VPA had no effect on performance, but CDP impaired performance in all three groups. These patterns of effects suggest that VPA may specifically disrupt working memory, but that the impairment of spatial performance by CDP probably results from a non-specific perceptual or attentional deficit.

Animals↗