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PubMedDate not supplied

The GABAergic control of prolactin release is not affected by insulin-dependent diabetes mellitus: evidence from studies with sodium valproate.

In order to evaluate the influence of the GABAergic system in the regulation of PRL secretion in patients with IDDM, serum PRL levels were measured in 7 diabetics and in 7 normal men with sodium valproate (400 mg per os), a drug capable of increasing cerebral GABA concentrations. A significant decrease of serum PRL concentrations was observed between 30 and 120 min after sodium valproate administration in both control and diabetic subjects. The time course and magnitude of the sodium valproate effect were similar in all subjects. These data confirm the inhibitory control of the GABAergic system on PRL secretion in man as evidenced by the GABAergic drug sodium valproate. It is suggested that this system is not altered in diabetic patients.

Adult↗

PubMed1999

Evidence of the activity of lithium on 5-HT1B receptors in the mouse forced swimming test: comparison with carbamazepine and sodium valproate.

The use of lithium in combination with various antidepressant drugs (e.g., heterocyclics and monoamine oxidase inhibitors) has been reported rapidly to improve antidepressant response in otherwise treatment-resistant patients. Carbamazepine and sodium valproate have also been shown to be effective in the treatment of several forms of affective disorders, such as treatment-resistant depression and bipolar depression. The present study, using the mouse forced swimming test, was undertaken to test the hypothesis of the action of lithium, carbamazepine or sodium valproate on some 5-HT receptor subtypes. Results showed that lithium significantly potentiated the anti-immobility effects of RU 24969 (P<0.01) and anpirtoline (P<0.01). Pretreatment with lithium did not induce any significant antidepressant-like effects when tested in combination with 8-OH-DPAT, NAN-190 or (+/-) pindolol. Pretreatment with carbamazepine provoked anti-immobility effects when tested in combination with RU 24969 (P<0.01) and 8-OH-DPAT (P<0.01), whereas prior administration of sodium valproate enhanced the antidepressant-like effects of (+/-) pindolol (P<0.01), 8-OH-DPAT (P<0.01) and RU 24969 (P<0.01). In conclusion, the results of the present study suggest that lithium may be acting through 5-HT1B receptors, whereas the action of carbamazepine and sodium valproate seems to involve 5-HT1A receptors in the mouse forced swimming test. However, considering the complexity of the actions of these compounds, it is possible that other neurotransmitter systems/receptors may be involved.

Animals↗

PubMed1997

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) triggered by valproate therapy.

UNLABELLED: We report in this study a patient who developed repeated convulsions as a result of valproate therapy. MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) was subsequently diagnosed and a nucleotide 3243 A-->G mutation was detected in the mitochondrial DNA. This mutation predisposes the patient to the detrimental effects of valproate on oxidative phosphorylation. CONCLUSION: We support the suggestion of Ponchaut et al. [14] that valproate should not be given to patients suspected of having mitochondrial diseases. In addition, for patients whose seizures worsen with valproate therapy, an inborn error of mitochondrial metabolism should be suspected. The underlying mitochondrial DNA defects should be sought for family screening and genetic counselling.

Anticonvulsants↗

PubMed2003

Lithium, but not valproate, induces the serine/threonine phosphatase activity of protein phosphatase 2A in the rat brain, without affecting its expression.

Protein phosphatase 2A (PP2A) regulates protein kinase cascades and thus plays an important role in the regulation of cell growth, gene expression and development. We examined the influence of lithium and valproate on the expression of PP2A and its serine/threonine phosphatase activity in the rat frontal cortex and hippocampus. Western blot and immunohistochemical analyses demonstrated that neither lithium nor valproate treatment had an effect on the levels of PP2A immunoreactivity in these brain regions. However, administration of lithium for 1 or 14 days significantly upregulated the activity of PP2A in the frontal cortex. Similarly, lithium administration tended to increase the activity of PP2A in the hippocampus. In contrast, neither a single nor repeated administration of valproate affected the activity of PP2A in these brain regions. These findings indicate that lithium, but not valproate, upregulated the activity of PP2A in the rat brain. It is suggested that the changes in neuronal functions induced by PP2A may be, at least in part, associated with the therapeutic action of lithium.

Animals↗

PubMed1988

Review of valproate monotherapy in the treatment of generalized tonic-clonic seizures.

Well-controlled prospective studies have shown the benefits of converting treatment for patients with epilepsy from polytherapy to monotherapy. Results of trials with valproate have demonstrated its efficacy as monotherapy in patients with generalized tonic-clonic seizures. Several studies have found no significant differences between valproate and phenytoin and carbamazepine in the treatment of partial seizures. In studies in which patients were diagnosed as having one of the primary generalized epilepsies, the response rate of tonic-clonic seizures to valproate establishes valproate as the drug of choice in the epilepsy syndromes with primary generalized tonic-clonic seizures.

Anticonvulsants↗

PubMed1988

Valproate monotherapy in partial seizures.

Results of a retrospective study in 30 patients indicate that, contrary to the findings of some earlier studies, valproate monotherapy is highly effective in the treatment of partial seizures, especially those that become secondarily generalized. In 22 of these 30 patients (73 percent), valproate monotherapy either abolished seizures (12 patients) or reduced their frequency by at least 51 percent (10 patients), whereas eight patients experienced minimal or no reduction in seizure frequency. All these patients had previously experienced treatment failure with carbamazepine, phenytoin, or phenobarbital--either alone or combined--because of lack of efficacy or unacceptable side effects. In these patients, failure to have a response to valproate therapy appeared to be related to the type of seizure (simple partial seizures alone/complex partial seizures alone, without secondarily generalized tonic-clonic seizures) and longer duration of uncontrolled seizures. Although these results cannot be generalized to all patients with partial seizures, they do indicate that a double-blind randomized trial of valproate in patients with all types of partial seizures is warranted.

Adolescent↗

PubMed1982

Effects of sodium valproate and acetazolamide on cerebral respiration.

The effects of sodium valproate and acetazolamide on the oxygen uptake of guinea pig brain cortex slices were investigated. In calcium-free medium, sodium valproate inhibited the oxygen uptake appreciably in the presence of glucose and glutamic acid. Acetazolamide, on the other hand, was more effective in inhibiting oxygen uptake in the presence of glucose than in the presence of glutamic acid. Addition of 0.2 mM CaCl2 in the medium containing 5 mM KCl could appreciably reverse the inhibition of oxygen uptake by acetazolamide in the presence of glucose. The inhibition of oxygen uptake by these drugs in the presence of glucose, however, could be completely reversed by increasing the dose of K+ ions (100 mM) in the medium which had no effect on the inhibition of oxygen uptake in the presence of glutamic acid. When the concentration of Ca2+ ions in the medium was elevated to 0.75 mM, the inhibitory effects of these drugs on the oxygen uptake in the presence of both glucose and glutamic acid could be completely abolished. Sodium valproate also inhibited the endogenous respiration of guinea pig brain cortex slices, whereas acetazolamide was almost without any effect. Increase in the concentration of Ca2+ ions in the medium failed to counteract the inhibition of endogenous respiration of guinea pig brain cortex slices by sodium valproate.

Acetazolamide↗

PubMed1985

Peroxisomal beta-oxidation and sodium valproate.

The influence of sodium valproate on peroxisomal beta-oxidation was investigated in rats, by evaluating in vivo changes in hepatic H2O2 production, using a combination of the catalase inhibitor 3-amino-1,2,4-triazole, and methanol. In rats starvation causes an increased flux of fatty acids through the peroxisomal beta-oxidation pathway. Valproate inhibits the formation of 3-hydroxybutyrate but not increased H2O2 production during starvation. There is no inhibitory effect of valproate on the peroxisomal oxidase. At low valproate concentrations it is possible that peroxisomes partially take over impaired mitochondrial function.

Animals↗

PubMed1989

Neuronal activity, amino acid concentration and amino acid release in the substantia nigra of the rat after sodium valproate.

The effects of sodium valproate on extracellularly recorded spontaneous neuronal activity and striatal-evoked inhibition in the substantia nigra zona reticulata of the rat were compared with its effects on the tissue concentration of endogenous amino acids and their spontaneous release into perfusates of this region obtained with a push-pull cannula. Valproate (200 mg/kg i.p.) produced a rapid and sustained reduction in the firing rate of all reticulata neurones tested and a concomitant increase in the duration of striatal-evoked inhibition. No change in the spontaneous release of any amino acid was observed. A significant elevation of nigral gamma-aminobutyric acid concentration was seen in both anaesthetized and non-anaesthetized animals, but this occurred only after 60 minutes. Valproate produced a rapid decline in nigral aspartate in non-anaesthetized but not in anaesthetized animals. The results of this study suggest that the acute depressant effect of valproate is unrelated to its ability to alter the concentration of GABA or aspartate in brain and is most likely due to a postsynaptic action.

Action Potentials↗

PubMed1986

The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids.

Patients taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine together with their oral contraceptive steroid may suffer contraceptive failure because of the enzyme-inducing properties of these anticonvulsants. We have examined, in six women, the effect of sodium valproate, an effective broad spectrum anticonvulsant, on the area under the plasma concentration versus time profile (AUC) of ethinyloestradiol (EE2) and levonorgestrel (Ng). Prior to sodium valproate therapy the mean AUC for EE2 was 880 +/- 109 pg/ml X h (+/- S.E.) and for levonorgestrel it was 29.1 +/- 2.9 ng/ml X h (n = 4). Between two and four months after sodium valproate therapy the mean AUC figures had not changed significantly, the figure for EE2 being 977 +/- 130 pg/ml X h and for levonorgestrel 29.2 +/- 1.9 ng/ml X h (p greater than or equal to 0.1 in each case). We conclude that sodium valproate in the dose used (200 mg b.d.) does not interact with oral contraceptive steroids.

Adolescent↗

PubMed1986

Benzodiazepine cross-tolerance in mice extends to sodium valproate.

Slow intravenous infusion of pentylenetetrazol was used to measure the convulsive threshold in mice. The anticonvulsant effects of clobazam, clonazepam, diazepam, lorazepam, sodium phenobarbitone and sodium valproate were assessed in naive animals and compared with the effects of the same compounds in animals which had been pretreated (twice daily for 3 days) with one of the benzodiazepines or sodium valproate. Cross-tolerance was observed between all the benzodiazepines but not between benzodiazepines and sodium phenobarbitone. Animals pretreated with the benzodiazepines were cross-tolerant to valproate, but the converse was not true; nor did sodium valproate induce tolerance to itself.

Animals↗

PubMed1990

Voltage-dependent action of valproate on potassium channels in frog node of Ranvier.

The influence of the anti-epileptic drug, valproate, on K conductance (gK) was investigated in voltage-clamped Ranvier nodes of Xenopus laevis. A double pulse method was used in order to eliminate the effect of accumulation of potassium ions in the perinodal space, thus enabling the determination of the 'true' magnitude of gK. Valproate (2.4 mM) had a voltage-dependent action on the magnitude of gK. With small step depolarizations more negative than about -50 mV, valproate increased gK (20 ms after the step) to approximately 12% of the maximal gK, an increase which disappeared due to a relatively rapid (less than 200 ms) inactivation process. However, with step depolarizations more positive than about -50 mV, valproate markedly reduced gK (20 ms after the step) at greater depolarizations, with a maximum of about 40% of the maximal gK. Moreover, at these voltages gK was inactivated completely (less than or equal to 10 s), whereas under control conditions the inactivation was only partial. Both the temporary increase and the steady state decrease of gK could contribute to an anti-epileptic effect by increasing the action potential threshold and by preventing excessive depolarizations of the nerve during epileptic seizures, respectively.

Animals↗

PubMed1988

Valproate enhances fluid consumption suppressed by shock or neophobia, but not by partial satiation or d-amphetamine, in rats.

The effects of sodium valproate (100 and 300 mg/kg) on fluid consumption in water deprived rats were assessed. Drinking was inhibited to approximately equal extents by a water pre-load, by d-amphetamine (1.5 mg/kg), by neophobia and by shock at mild (0.3mA) or moderate (0.5mA) intensities, the latter condition having an enhanced level of deprivation also. At both doses valproate significantly enhanced drinking in the neophobia, mild shock and moderate shock conditions but failed to increase drinking suppressed by pre-load or d-amphetamine. It is concluded that the increases in drinking suppressed by neophobia or shock which valproate induces are due to anxiolytic actions of the drug and not non-specific enhancement of fluid consumption. The present results also constitute a further parallel between the actions of valproate and those of benzodiazepines.

Animals↗

PubMed1984

Effects of chlordiazepoxide and of valproate on hyponeophagia in rats. Evidence for a mutual antagonism between their anxiolytic properties.

The effects of chlordiazepoxide (0,2.5 and 7.5 mg/kg), of valproate (0,100 and 300 mg/kg), and of combinations of these drugs, on hyponeophagia in rats, were studied using a food preference test. Chlordiazepoxide alone reduced the latency for eating, and also enhanced the time of eating and the amount of familiar food eaten at the smaller dose, and of novel food eaten at the larger dose. Valproate alone reduced the latency of eating and enhanced time of eating and the amount of novel food eaten, especially at 300 mg/kg. However, valproate antagonised the effects of chlordiazepoxide on all behavioural measures. These findings are discussed in the context of the GABA hypothesis of the actions of benzodiazepines, with the conclusion that valproate has an atypical pharmacological profile amongst putative GABA agonists, and may have partial agonist activity at the proposed benzodiazepine/GABA receptor complex.

Animals↗

PubMed1986

Differential effect of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurones and astrocytes.

A preferential effect of valproate on gamma-aminobutyric acid (GABA) in the nerve terminal compartment has been proposed. Gamma-vinyl GABA, an irreversible inhibitor of GABA-transaminase (GABA-T) causes a preferential increase in the GABA compartment of the non-nerve terminal. The aim of the present study was to investigate further this apparent differential effect on GABA-T of these compounds in neurones and glia. The investigations were undertaken in neurones and astrocytes, cultured separately. After incubation with valproate, the IC50 value for astrocytes was found to be 1202 microM of valproate and for neurones 634 microM. Assuming regional differences of concentrations of valproate in the brain, the observed IC50 values might be clinically relevant. Culturing the cells in the presence of gamma-vinyl GABA demonstrated IC50 values for astrocytes and neurones of 89 and 24 microM, respectively. The (S)isomer of gamma-vinyl GABA was the most active inhibitor of GABA-T in both glia and neurones. After withdrawal of gamma-vinyl GABA from the culture media of the cells, in neurones 50% of the activity of GABA-T was regained within 2-4 days. In astrocytes a similar time course was observed. These findings are in agreement with clinical data: the IC50 values correspond to clinically-relevant serum levels of gamma-vinyl GABA in humans only the (S)isomer showed an antiepileptic effect in animal models of epilepsy a delayed antiepileptic effect, after withdrawal of gamma-vinyl GABA, has been established in clinical studies.

4-Aminobutyrate Transaminase↗

PubMed1990

Valproate potentiates and picrotoxin antagonizes the anxiolytic action of ethanol in a nonshock conflict task.

The purpose of this study was to examine the effects of the indirect GABA agonist valproate and the indirect GABA antagonist picrotoxin on the anxiolytic (anti-conflict) activity of ethanol in a behavioral conflict task that does not employ electroshock. This task (negative contrast) quantifies how animals respond to an abrupt, unexpected reduction in reward. Treatment with valproate alone did not elevated depressed behavior engendered by abrupt reduction in reward. However, when administered together with a sub-effective dose of ethanol (0.5 g/kg), valproate (50-200 mg/kg) dose-dependently potentiated the anxiolytic action of ethanol. Picrotoxin (2 mg/kg) antagonized the anxiolytic effects of a larger dose of ethanol (1.0 g/kg) given alone, as well as the ability of valproate to enhance the anxiolytic effects of smaller dose of ethanol (0.5 g/kg). As such, these data support a role for GABA in mediating the anxiolytic activity of ethanol.

Animals↗

PubMed1989

Chlordiazepoxide and valproate enhancement of saline drinking by nondeprived rats: effects of bicuculline, picrotoxin and Ro15-1788.

Drinking of 0.85% saline by nondeprived rats was significantly enhanced by chlordiazepoxide (5 or 10 mg/kg) and by valproate (100 or 300 mg/kg), drug effects being strongest in the earlier parts of a 30-minute test. When given alone, both bicuculline and picrotoxin significantly reduced saline drinking at 2.5 mg/kg, but not 1.5 mg/kg. Administration of valproate at either dose or of chlordiazepoxide (10 mg/kg) completely prevented bicuculline action and 5 mg/kg chlordiazepoxide reduced it. Picrotoxin, however, largely prevented the actions of both chlordiazepoxide and valproate. The increase in saline drinking induced by valproate (300 mg/kg) was also blocked by RO15-1788 (10 or 25 mg/kg). These findings are discussed in the context of the three-site model of the GABA/benzodiazepine receptor complex. It is concluded that drugs acting at the benzodiazepine site or the chloride ion channel affect saline drinking, but that there is little evidence of an important functional role for the GABAa site at present.

Animals↗

PubMed1995

Effects of valproate and lorazepam on experimental anxiety: tolerance, withdrawal, and role of clonidine.

The anxiolytic-like effects tolerance and withdrawal from chronic treatment with sodium valproate [200, 300, and 400 mg/kg, intraperitoneally (i.p.)] were compared with those of a known anxiolytic drug, lorazepam (0.025, 0.05, and 0.10 mg/kg, i.p.), in the light-dark aversion test in mice. Furthermore, we investigated whether acute treatment with clonidine, 0.03 mg/kg i.p., an alpha 2-adrenoceptor agonist, could reduce the increased anxiety on withdrawal from chronic treatment. Mice were given 14 daily i.p. injections of valproate, lorazepam, or vehicle and were tested in the light-dark aversion test 30 min or 24 or 48 h after the last drug or vehicle administration. Results showed that both acute and chronic valproate treatment reduced the aversion of mice for the light area, as well as increased the number of transitions, thus indicating an anxiolytic-like potential. Furthermore, in contrast to lorazepam, tolerance to the anxiolytic-like effects of valproate did not occur, and withdrawal from chronic treatment (300 mg/kg, i.p.) in our behavioral paradigm was not associated with any behavioral disturbances referring to an increased anxiety state. Finally, low doses of clonidine (0.03 mg/kg, i.p.) were shown to have anxiolytic properties and to reverse the anxiogenic effects of lorazepam on withdrawal.

Adrenergic alpha-Agonists↗