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PubMed1988

Valproate enhances GABA-A mediated inhibition of locus coeruleus neurones in vitro.

It has previously been claimed that the anticonvulsant valproate acts by augmenting GABA-ergic transmission, however, the data supporting this claim is controversial. Here we demonstrate that valproate strongly and reversibly potentiates the depressant effects of the GABA-A receptor agonist muscimol on locus coeruleus neurones recorded extracellularly from a midpontine slice preparation of the rat. The depressant effect of muscimol (2 microM) is augmented by bath applied valproate at concentrations of 50 microM, 100 microM and 1 mM. The effect of GABA is also potentiated by valproate. The potentiating effect is selective since the cell inhibition elicited by the GABA-B receptor agonist baclofen is not affected. Valproate on its own had no effect on the firing frequency.

Animals↗

PubMed1985

Effects of valproate on hyponeophagia in rats: competitive antagonism with picrotoxin and non-competitive antagonism with RO 15-1788.

The effects of valproate (30-500 mg/kg), alone and in combination with picrotoxin (1.5 mg/kg) or RO 15-1788 (10 mg/kg) were studied in two experiments on hyponeophagia in rats. Valproate reduced eating latency and increased eating time and amount eaten of novel food, except at 500 mg/kg which reduced feeding. Picrotoxin induced generally opposite actions alone and shifted valproate dose/response curves to the right. RO 15-1788 had no detectable intrinsic action, but prevented both the behavioural facilitation and inhibition produced by valproate. These findings are discussed in the context of the GABA hypothesis of benzodiazepine action, with the conclusions that they provide behavioural support for the hypothesis of a receptor complex with GABA and benzodiazepine binding sites, and that an optimal and submaximal level of activity at the benzodiazepine site is a necessary condition for anxiolytic actions of valproate.

Animals↗

PubMed1992

Interactions between valproate, glutamate, aspartate, and GABA with respect to uptake in astroglial primary cultures.

Astrocytes have been proposed to regulate the extracellular space in the brain, even if rather little is known about their specific functions. One possibility for obtaining more knowledge on the functions of astroglial cells is to examine how they respond on exposure to pharmacological agents. Na(+)-valproate is an anticonvulsive drug which is used in the treatment of several types of epilepsy. The mechanisms of action of the drug are not fully understood, but the GABA-ergic system, both in neurons and astrocytes, has been shown to be affected. In the present study, the effects of valproate were investigated on astroglial cells in primary cultures from newborn rat cerebral cortex. The transport of the drug itself and its effects on the transport of the amino acid transmitters glutamate, aspartate and gamma-aminobutyric acid (GABA) into astrocytes were examined. The [3H]valproate transport into the astrocytes was increased after exposure to L-glutamate but not L-aspartate. On the other hand, after acute exposure for the drug, the transport of [3H]L-glutamate and [3H]L-aspartate decreased, as also did the affinity but not the transport capacity for the [3H]GABA uptake. However, after 5 days chronic valproate exposure, no effects could be seen on the uptake kinetics of L-glutamate or L-aspartate. For GABA, the affinity decreased, while the transport capacity remained unchanged compared with controls. The results showed that valproate, glutamate, aspartate and GABA were capable of interacting significantly with each others transport into the astrocytes.

Animals↗

PubMed1995

The effect of sodium valproate on luteinizing hormone secretion in women with polycystic ovary disease.

The aim of this study was to examine whether modulation of the GABA-ergic system (with sodium valproate) affects gonadotropin secretory frequency and amplitude in women with polycystic ovarian syndrome (PCOS). Six women aged 25 +/- 2 years with diagnosed PCOS and six healthy women aged 26 +/- 2 years at day 7-11 of menstrual cycle were included in the study. Sodium valproate 1200 mg p.o./day (600 mg t.i.d.) was administered for five days in both groups. Efficacy of treatment was assessed in women with PCOS by measuring six hour LH pulsatility (every .10 min), and by GnRH tests before and after treatment. Basal serum steroids were assessed as well. Hormones were determined by radioimmunoassay and pulse detection was carried out by the program PULSAR. The administration of valproate did not change basal serum LH concentration (9.1 +/- 0.6 vs 9.0 +/- 0.8 IU/L p > 0.05) nor LH pulse frequency (7.3 +/- 0.5 vs 6.3 +/- 0.5 p > 0.05) or the LH pulse amplitude (3.0 +/- 0.5 vs 3.5 +/- 0.4 p > 0.05). LH response to GnRH (mean peak 43.6 +/- 5.2 vs 44.1 +/- 6.0 IU/L p > 0.05) did not change either. Valproate did not affect the LH secretory activity in women with PCOS. There was no change in FSH, and prolactin secretion. In five patients with PCOS valproate caused further increase in serum testosterone level but this did not reach significance in the group as a whole (5.6 +/- 1.0 vs 9.1 +/- 2.0 nmol/L p > 0.05).

Adult↗

PubMed1988

Valproate monotherapy in children.

Seizures are more common in children than in adults. Since most pediatric epilepsies can be controlled with a single antiepileptic drug, children with epilepsy should receive monotherapy when possible or switch from polytherapy to monotherapy. More than half of the epileptic patients receiving multiple antiepileptic drugs will have better seizure control as well as fewer side effects with monotherapy. Most of the pediatric epilepsies occur as primary generalized seizures, for which valproate is a preferred drug. Children can begin to receive valproate treatment in a dosage of 20 to 30 mg/kg per day in two or three divided doses. After several days, plasma levels may be useful in adjusting the dosage. The major adverse effect of valproate in children is fatal hepatotoxicity. The risk of this complication is considerably lower with valproate monotherapy (one per 10,000 patients) than with polytherapy. Other advantages of valproate monotherapy, compared with polytherapy, include the avoidance of drug interactions, lower cost, and reduced potential for impaired cognitive function, which is particularly important in children.

Anticonvulsants↗

PubMed1982

The effects of sodium valproate on gamma-aminobutyrate metabolism and behaviour in naive and ethanolamine-O-sulphate pretreated rats and mice.

Sodium valproate was injected acutely (400 mg/kg i.p.) into naive and ethanoloamine-O-sulphate chronically pretreated rats and mice, in an attempt to gain further insight into the effects of this anticonvulsant on GABA metabolism. Sodium valproate significantly enhanced the activity of GAD in the medulla and pons, cerebellum and midbrain regions of rats, and partially relieved the suppression of GAD activity caused by chronic GABA-transaminase inhibition in whole mouse brain. In combination with EOS, sodium valproate caused behavioural excitation in mice which was similar to that sometimes seen with high doses of some GABA-T inhibitors. Pretreatment with EOS potentiated the characteristic abstinence behaviour caused by sodium valproate in rats, though no further significant rise in cerebral GABA levels was observed. In view of the neuronal location of GAD, the elevation of cerebral GABA levels at least in part by potentiation of GAD activity could be involved in the mediation of the anticonvulsant activity of sodium valproate.

Animals↗

PubMed1983

The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats.

Valproate is a valuable anticonvulsant which is associated with hepatotoxicity in some patients. In concentrations in the range found in man during valproate therapy (0.1-1.0 mM), it inhibited pyruvate and palmitate oxidation, urea synthesis and gluconeogenesis by 30-50% in isolated rat hepatocytes. Valproate (100 mg/kg body weight) is also hypoglycaemic and hypoketonaemic in fasted rats. All these inhibitions can be explained in terms of the accumulation of valproyl-CoA and its further metabolites in the matrix of hepatic mitochondria. Although these inhibitions are only partial, and normally well tolerated, they could significantly impair liver function when there is an additional insult, such as may occur with multiple drug therapy or if there is already an inborn error of metabolism. Such an association with inborn errors may explain the higher incidence of valproate-associated toxicity in children. It may be of more value to measure blood urea and ammonia concentrations routinely shortly after starting valproate therapy than to do conventional liver function tests.

Animals↗

PubMed1993

Effect of valproate on lipogenesis in neonatal rat brain.

The effect of valproate on lipogenesis in brain slices from early neonatal rats was studied. The rate of lipid synthesis from lactate and 3-hydroxybutyrate, but not from glucose, was decreased significantly by 1 mM valproate. Separation by high performance liquid chromatography of brain lipids showed that valproate inhibited the synthesis of major phospholipids (phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine) from lactate and major sterols (desmosterol, cholesterol and lanosterol) from lactate and 3-hydroxybutyrate. Valproate did not affect sterol synthesis but slightly enhanced phospholipid synthesis from glucose. However, the ratio of phosphatidylserine/phosphatidylethanolamine synthesis was decreased from lactate, glucose and 3-hydroxybutyrate, suggesting that valproate changes phospholipid composition of brain structures. These changes may contribute to the pharmacological action of the drug.

3-Hydroxybutyric Acid↗

PubMed1991

The anticonvulsant valproate teratogen restricts the glial cell cycle at a defined point in the mid-G1 phase.

Direct cell counting and extent of [3H]thymidine incorporation demonstrated valproate to inhibit C6 glioma proliferation rate in a dose-dependent manner with a 1 mM concentration achieving 50% inhibition. The antiproliferative effect was reversible and could not be attributed to cytotoxicity at the valproate concentrations employed. The site of valproate action within the cell cycle was determined to be in the G1 phase, at a point 6-6.5 h prior to S phase, by estimating the time to increased [3H]thymidine incorporation following release from a 70% proliferative arrest. Synchronised cells obtained by a mitotic selection procedure required 11-12 h to enter S phase and demonstrated the valproate restriction point to be 5 h into the G1 phase of the C6 cell cycle. Exposure of valproate to the part of the G1 period which follows the restriction point was without effect on cell entry into S phase.

Animals↗

PubMed1987

Bepridil and valproate retard Na+ reactivation in Myxicola.

Two drugs were examined, each causing a similar specific modification of Na+ channel inactivation gating when internally applied to voltage-clamped Myxicola giant axons. Bepridil is an antianginal-antiarrhythmic agent with vasodilator and direct cardiac inotropic effects. Sodium valproate has anticonvulsant activity and causes use-dependent inhibition of repetitive firing in CNS neurons. Bepridil and sodium valproate caused a dose-dependent decrease in maximum Na+ conductance (KD = 25 microM for bepridil; KD = 0.5 mM for valproate). More importantly, at half-maximal blocking concentrations both drugs shifted steady state Na+ inactivation in the hyperpolarizing direction (by 30 mV for bepridil; 15 mV for valproate) and slowed the recovery of Na+ channels from inactivation (by 300% for bepridil; 60% for valproate). There was no effect on the K+ conductance, voltage-dependence of Na+ activation, or the time-dependence of inactivation of conducting channels. Neither produced non-inactivating Na+ current during long depolarizing steps.

Animals↗

PubMed1993

Magnesium valproate attenuates hyperactivity induced by dexamphetamine-chlordiazepoxide mixture in rodents.

A mixture of dexamphetamine and chlordiazepoxide induces hyperactivity in both mice and rats. This type of hyperactivity has been proposed as an animal model of mania. Magnesium valproate itself had little influence on the activity of normal mice and rats. Acute pretreatment of mice with magnesium valproate (75-300 mg/kg p.o., 37.5-150 mg/kg i.v.) attenuated the mixture-induced hyperactivity. Pretreatment of rats with a single dose of magnesium valproate (75-300 mg/kg, p.o. or i.p.) also counteracted the locomotor hyperactivity caused by the mixture. The effects of magnesium valproate in the mixture-treated mice and rats could be abolished by bicuculline and picrotoxin, but not isoniazid. These findings suggest that the antimanic effect of valproate may be related to its ability to enhance the postsynaptic effects of gamma-aminobutyric acid (GABA).

Analysis of Variance↗

PubMed1991

Study of bioequivalence of magnesium and sodium valproates.

The in vivo bioavailability of magnesium valproate (500 and 1000 mg) enteric-coated tablets has been compared with that of sodium valproate (Depakine) (500 and 1000 mg) enteric-coated tablets. The two preparations were found to be bioequivalent; magnesium valproate appeared to be a drug without bioavailability problems and with reduced inter-subject variability, compared with that of sodium valproate. A reversed-phase HPLC method for the determination of valproates is described.

Administration, Oral↗

PubMedDate not supplied

Short term effects of valproate on infantile spasms.

Although valproic acid (VPA) is used to treat infantile spasms, VPA's efficacy in infantile spasms has not been determined in a controlled study. This study evaluated the effect of VPA on infantile spasms in patients who had not responded to adrenocorticotropin (ACTH) and corticosteroid therapy. The hypotheses were tested using a double-blind, randomized controlled crossover design. Twenty-one patients were randomly assigned to either the baseline-valproate-placebo treatment or the baseline-placebo-valproate treatment groups. Based on a repeated measures analysis of variance test, the valproate group had lower total mean spasm frequency levels than the placebo group. However, this difference did not remain after the crossover; the difference was due to the initial administration of valproate and placebo. When the spasm index was analyzed, the valproate treatment was found to have lower mean spasm index scores than the baseline treatments (p less than 0.03). No short-term toxic effects were observed in any patient. We conclude that short-term VPA therapy has a beneficial effect even on chronic infantile spasm patients who have failed to respond to ACTH/corticosteroid therapy.

Clinical Trials as Topic↗

PubMedDate not supplied

Expanded therapeutic range of valproate.

Twenty-five pediatric patients with serum valproate levels above 100 micrograms/ml (therapeutic range: 50-100 micrograms/ml) are reviewed for nondose-related side effects and seizure control. The dose of valproate varied from 50-100 mg/kg/day. All patients had generalized or mixed seizure disorders which were difficult to control. Seizure frequency decreased by more than 50% in 14 patients. For those patients with improved control, valproate levels ranged from 111-196 micrograms/ml. Patients were carefully monitored for side effects; nondose-related side effects were not encountered. Random valproate levels were between 100-200 micrograms/ml. The clinical response to valproate can be augmented by increasing it to the maximum tolerated dose.

Adolescent↗

PubMedDate not supplied

Effects of sodium valproate on development and social behaviour in the Mongolian gerbil.

Sodium valproate is an anticonvulsant widely prescribed because of its broad spectrum of activity. While acute toxicity from high doses is well recognized, there have been few animal studies of its chronic toxicity at therapeutic dose levels. Sodium valproate given continuously in drinking fluid (600 mg/l) throughout pregnancy and lactation to breeding gerbils caused developmental delay of the self-righting reflex in their pups. Dams ingested 97 mg/kg daily during gestation and 151 mg/kg on average during lactation, a dose in the lower range of anticonvulsant effectiveness. Reproductive performance, birth weights and subsequent growth of the pups remained normal, as did brain weights in adulthood. Drug-treated offspring, continuing to receive valproate as drinking fluid after weaning (600 mg/l; 82 to 111 mg/kg) showed negligible behavioural alteration at 6 weeks of age as assessed by ethological procedures, although behavioural change did occur at 20 weeks in the female animals. These females were characterised by significant enhancement of exploration and scanning during dyadic encounters in an unfamiliar cage, and showed a concomitant reduction of other nonsocial activities. Short-term administration of this dose of the drug did not affect behaviour. These results suggest an increased reactivity to the environment which becomes evident only after long-term treatment with valproate and to which female animals are more susceptible than males. These findings of developmental delay and of modifications to behaviour later in life points to the need for more detailed clinical assessments of the effects of valproate in human patients.

Administration, Oral↗

PubMed2004

Valproate prevents the induction, but not the expression of morphine sensitization in mice.

Repetitive exposure to opioids elicits sensitization to its locomotor stimulating effects. Several lines of evidence have shown that the central GABAergic system is involved in behavioral sensitization induced by morphine. Valproate, a clinically widely used anticonvulsant and mood stabilizer, can mainly inhibit gamma-aminobutyric acid (GABA) transaminase and activate glutamic acid decarboxylase, which result in decrease in the degradation and increase in the synthesis of GABA, and then the elevation of extracellular GABA in the central nervous system. However, the effects of valproate on behavioral sensitization to morphine have not been documented. Herein, we investigated the effects of valproate on the induction and the expression of behavioral sensitization to morphine. Mice treated daily for 7 days with 10 mg/kg morphine and challenged with the same dose after 7 days of washout showed increased locomotor activity. Co-administration of valproate (37.5, 75, 150 mg/kg, intraperitoneal (i.p.)), at doses that did not affect the spontaneous activity, 30 min prior to morphine dose-dependently inhibited the induction of morphine sensitization. However, neither single nor multiple administration (37.5, 75, 150 mg/kg x 7 injections) of valproate had any effect on the expression of morphine sensitization once it developed. Our results indicated that GABA plays an important role in the induction, but not in the expression of morphine sensitization in mice.

Analysis of Variance↗

PubMed2005

Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice.

BACKGROUND: Reelin and GAD(67) expression is downregulated in cortical interneurons of schizophrenia (SZ) patients. This downregulation is probably mediated by epigenetic hypermethylation of the respective promoters caused by the selective increase of DNA-methyltransferase 1 in GABAergic neurons. Mice receiving methionine (MET) provide an epigenetic model for neuropathologies related to SZ. We studied whether MET-induced epigenetic reelin promoter hypermethylation and the associated behavioral alterations can be reduced by valproate in doses that inhibit histone deacetylases (HDACs). METHODS: Mice treated with either methionine (MET) (5.2 mmol/kg/SC/twice daily) or valproate (1.5 mmol/kg/SC/twice daily) or MET+ valproate combination were tested for prepulse inhibition of startle (PPI) and social interaction (SI). S-adenosylmethionine, acetylated histone 3, reelin promoter methylation, and reelin mRNA were assayed in the frontal cortex. RESULTS: Valproate enhances acetylated histone 3 content, and prevents MET-induced reelin promoter hypermethylation, reelin mRNA downregulation, and PPI and SI deficits. Imidazenil, a positive allosteric modulator at GABA(A) receptors containing alpha(5) subunits but inactive at receptors including alpha(1) subunits, normalizes MET-induced behavioral changes. CONCLUSION: This MET-induced epigenetic mouse models the neurochemical and behavioral aspects of SZ that can be corrected by positively modulating the action of GABA at alpha(5)-containing GABA(A) receptors with imidazenil or by inhibiting HDACs with valproate, thus opening exciting new avenues for treatment of epigenetically modified chromatin in SZ morbidity.

Aggression↗

PubMed2006

Homeostatic effects of plasma valproate levels on corticospinal excitability changes induced by 1Hz rTMS in patients with juvenile myoclonic epilepsy.

OBJECTIVE: The preliminary results of noninvasive brain stimulation for epilepsy treatment have been encouraging, but mixed. Two important factors may contribute to this heterogeneity: the altered brain physiology of patients with epilepsy and the variable presence of antiepileptic drugs. Therefore, we aimed to study the effects of 1 Hz rTMS on corticospinal excitability in patients with juvenile myoclonic epilepsy (JME) in two different conditions: low- or high-plasma valproate levels. METHODS: Fifteen patients with JME and 12 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS was assessed in JME patients with low- and high-plasma valproate levels; and these results were compared with those in healthy subjects. RESULTS: In patients with chronic use of valproate and low-plasma concentrations, 1 Hz rTMS had a similar significant inhibitory effect on corticospinal excitability as in healthy subjects. However, in the same patients when the serum valproate concentration was high, 1 Hz rTMS increased the corticospinal excitability significantly. In addition, there was a significant positive correlation between plasma valproate levels and the motor threshold changes after 1 Hz rTMS. CONCLUSIONS: Our findings can be accounted for by mechanisms of homeostatic plasticity and illustrate the dependency of the modulatory effects of rTMS on the physiologic state of the targeted brain cortex. SIGNIFICANCE: The therapeutic use of rTMS in epilepsy should take into consideration the interaction between rTMS and drugs that change cortical excitability.

Adolescent↗