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PubMed1995

Differential effects of phenytoin and sodium valproate on seizure-induced changes in gamma-aminobutyric acid and glutamate release in vivo.

The effects of intraperitoneal administration of the anticonvulsants phenytoin and sodium valproate were compared with ethosuximide on maximal electroshock seizure-related changes in rat hippocampal gamma-aminobutyric acid (GABA) and glutamate release in vivo as measured by microdialysis. There were immediate increases in GABA and glutamate in the 5 min post-ictal period, followed by a sustained reduction in GABA levels. Glutamate levels, however, were subsequently reduced until 20 min post-ictal before gradually increasing above basal. All animals displayed tonic hind-limb extension that was blocked by phenytoin (20 mg/kg) and sodium valproate (400 mg/kg) but not ethosuximide (150 mg/kg). Phenytoin attenuated the immediate post-ictal increase observed in glutamate whilst sodium valproate enhanced GABA release and prevented its secondary post-ictal inhibition. Ethosuximide was without effect on the post-ictal changes. These are the first data to show detailed seizure-induced amino acid changes and the in vivo effects of anticonvulsants on them in the seizure model.

Animals↗

PubMed1988

Hepatic hydrolysis of octanoyl-CoA and valproyl-CoA in control and valproate-fed animals.

1. Medium-chain acyl-CoA hydrolase activities were determined in liver from control and valproate-fed rats and rabbits. 2. Octanoyl-CoA was readily hydrolyzed by all control liver preparations. 3. Animals that had been fed diets containing 0.5 or 1.0% (w/w) valproic acid had significantly elevated octanoyl-CoA hydrolase activities. 4. The CoA ester of valproic acid, a branched-chain isomer of octanoic acid, was poorly hydrolyzed by liver preparations from both control and valproate-fed animals. 5. Livers from the valproate-fed animals contained high levels of medium-chain acyl-CoA; total CoA content was also increased. 6. The inefficiency of hepatic valproyl-CoA hydrolysis may play a role in the toxicity of valproic acid.

Acyl Coenzyme A↗

PubMed1987

The development of tolerance to the anticonvulsant effects of clonazepam, but not sodium valproate, in the amygdaloid kindled rat.

The effects of chronic treatment with clonazepam and sodium valproate were studied on kindled amygdaloid seizures in rats. Fully kindled rats were given an intraperitoneal (i.p.) injection of either vehicle (1.0 ml/kg), clonazepam (0.3 mg/kg) or sodium valproate (200 mg/kg) twice daily for 12 days. Each rat was stimulated through an amygdaloid electrode 30 min after the morning dose. While both drugs initially blocked and kindled seizure (P less than 0.01), the results showed a significant trend (P less than 0.02) in the development of tolerance to the anticonvulsant action of clonazepam but no significant tolerance to the action of valproate.

Amygdala↗

PubMed1988

Paradoxical enhancement of seizures in the gerbil after chronic treatment with sodium valproate.

Handling-induced seizures in male and female gerbils, at 1 year of age, were significantly increased following continuous administration of sodium valproate throughout postnatal life (600 mg/l in drinking fluid of gerbil dams and of the offspring after weaning; 82-111 mg/kg daily). The weight of the brain and gain in body weight of the valproate-treated gerbils were not significantly changed. Three components of the GABAA receptor complex were examined in cerebral cortical tissue from control gerbils and gerbils chronically treated with valproate. No significant differences were found in saturation binding of [35S]-t-butyl-bicyclophosphorothionate or [3H]flunitrazepam, or in the ability of GABA to stimulate the binding of [3H]flunitrazepam. Further studies of this enhancement of susceptibility to seizures are required since it may be of potential clinical relevance.

Animals↗

PubMed1993

Chronic treatment with valproate decreases the hypothermic response to clonidine.

Treatment with lithium (the prototype of an antimanic agent) attenuates responsiveness to the alpha 2-agonist clonidine in animal models. Valproate is now used to treat mania. The effect of treatment with this drug on responses mediated by an alpha 2-agonist have yet to be reported. The authors assessed the effect of a 14-day course of orally administered valproate on the rat's hypothermic response to clonidine. Treatment with valproate decreased this response.

Animals↗

PubMedDate not supplied

The use of sodium valproate, carbamazepine and oxcarbazepine in patients with affective disorders.

During recent years alternatives to lithium prophylaxis have been developed using primary dipropylacetamide and, later on, sodium valproate, as a mono-therapy as well as in combination with low-dosage lithium treatment. It has been shown in a placebo-controlled ABA design that sodium valproate exerts an acute antimanic effect and a prophylactic action of sodium valproate has also been established. Carbamazepine represents another important contribution to the arsenal of drugs to be used as alternatives for the prophylactic treatment in patients not responding to lithium and/or experiencing too many side effects. The keto-derivative of carbamazepine, oxcarbazepine, has been shown to exert acute antimanic effects in a similar way to carbamazepine itself.

Anticonvulsants↗

PubMed1985

Combined lithium and valproate treatment and subsequent withdrawal: serotonergic mechanism of their interaction in discrete brain regions.

Rats were administered with lithium carbonate (1 mmole/kg), valproate (300 mg/kg) and their combination for 12 days. Rats in the withdrawal group were treated for 10 days, followed by saline for 2 days. Mid-brain tryptophan levels increased in all the groups except lithium-treated rats. The administration of lithium together with valproate decreased tryptophan hydroxylase activity and 5-hydroxytryptamine levels in certain brain regions compared to either treatment alone. Also, the magnitude of valproate-induced 5-hydroxyindoleacetic acid elevation was decreased after combined treatment. Most of the changes observed after combined exposure persisted even after 2 days of treatment withdrawal. It appears from the data that combined administration of the two drugs produces persistent decrease in 5-hydroxytryptamine synthesis and turnover in the brain.

Animals↗

PubMed1992

Studies on valproate-induced perturbations of neurulation in the explanted chick embryo.

The effect of the anticonvulsant sodium valproate on in vitro neurulation of the chick embryo, explanted after a 25-h in ovo incubation period, is described. Sodium valproate, at concentrations of 0.5-1.5 mM did not appear to have any profound effect on embryo growth when assessed by light microscopy. However scanning electron microscopy revealed a dose-dependent increase in the incidence of open anterior and posterior neuropores after 20 h of in vitro development (Stage 11). Concentrations of sodium valproate which were greater than 1.5 mM markedly increased the number of gross malformations, which were manifested as a complete disruption of the neural tube along its entire length. Failure of neuropore closure could not be attributed to a drug-induced neurodevelopmental delay as these defects were still apparent following 27 h of in vitro culture, a time coincident with the onset of embryo torsion.

Animals↗

PubMed1995

Myo-inositol monophosphatase: diverse effects of lithium, carbamazepine, and valproate.

The therapeutic molecular sites of action for the mood-stabilizing medications are unknown. Myo-inositol monophosphatase (E.C. 3.1.3.25) is a major enzyme of the inositol signaling system that has previously been shown to be inhibited by clinically relevant concentrations of lithium, implicating this enzyme as a potential therapeutic site of action in manic-depressive disorder. Inhibition of myo-inositol monophosphatase (IMPase), which converts myo-inositol monophosphates to myo-inositol, results in increased levels of myo-inositol monophosphates and decreased myo-inositol available for the resynthesis of inositol phospholipids. In addition to lithium, carbamazepine and valproate are also used medically to treat manic-depressive disorder. It is of considerable interest to determine whether inhibition of IMPase activity is a common unifying mechanism for mood-stabilizing medications. Using a partially purified myo-inositol monophosphatase preparation derived from bovine brain, we examined the effects of lithium, carbamazepine, and valproate on the IMPase reaction. These results demonstrate that (1) lithium inhibited IMPase activity in the low millimolar range, (2) carbamazepine stimulated the IMPase reaction beginning in the low-micromolar range, and (3) valproate did not demonstrate any stimulation or inhibition of IMPase. We conclude that inhibition of IMPase is not a common neurochemical mechanism for mood-stabilizing medications.

Animals↗

PubMed1990

Cognitive effects of valproate.

The effects of valproate on cognition are usually considered to be minimal, but few formal neuropsychological studies are available. We studied the psychomotor performances of 20 seizure-free epileptics during fixed valproate monotherapy and after its withdrawal. Our findings suggest some adverse effects of valproate which appear to be completely reversible after withdrawal.

Adult↗

PubMedDate not supplied

Pteroylpolyglutamate pool modifications in rat liver after chronic administration of phenobarbitone and valproate.

Chronic intraperitoneal administration of low doses of phenobarbitone and valproate caused different alterations in hepatic percentage distribution of pteroylpolyglutamate derivatives without modification of total folate content. Phenobarbitone treatment caused a significant decrease of the percentage content of reduced unsubstituted and methylene-substituted derivatives, while valproate produced an increase of the percentage content of methenyl-, formyl- and formimino-substituted derivatives and a concomitant percent increase of hexaglutamates. The modified ratios of various pteroylpolyglutamates, both in phenobarbitone- and in valproate-treated animals, probably contribute to influencing the partitioning of the one-carbon pool through the various areas of one-carbon metabolism.

Animals↗

PubMed2005

Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania.

Bipolar disorder is a psychiatric condition characterised by episodes of mania, depression, and underlying mood instability. Anticonvulsant drugs have an established place in the treatment of the disorder, but identifying novel drugs in this class is complicated by the absence of validated animal models. We have evaluated the efficacy of three anticonvulsant mood stabilising drugs (lamotrigine, valproate, and carbamazepine) in a model of mania, in which hyperactivity is induced by the combination of D-amphetamine and chlordiazepoxide. All three drugs were effective at preventing the hyperactivity. Lower doses of valproate and carbamazepine were required to prevent hyperactivity compared to doses required to block tonic-clonic seizures induced by pentylenetetrazole. Lamotrigine was equipotent in the two models. However, the complex pharmacology of the D-amphetamine/chlordiazepoxide model means that there may be several mechanisms by which hyperactivity can be reduced, and these may have more or less relevance to the treatment of bipolar disorder. To address this issue, we also evaluated effects of the three anticonvulsants on baseline locomotion, on activity in the presence of chlordiazepoxide alone, or on activity induced by D-amphetamine alone. Based on the results, we propose that hyperactivity induced by D-amphetamine/chlordiazepoxide may arise through dopaminergic drive coupled with disinhibition caused by low doses of the benzodiazepine. The efficacy of lamotrigine may then arise through a reduction in neuronal excitability or increased glutamate transmission, these latter a consequence of the disinhibition. Carbamazepine may also reduce excitability and glutamate release, but its broader pharmacology, manifested by sedation at higher doses complicates interpretation of its efficacy and reflects its poorer tolerability in the clinic. Valproate may be effective, at least in part, through an enhancement of GABAergic transmission. The predictive validity of the D-amphetamine/chlordiazepoxide model for efficacy in bipolar disorder remains to be established, and research with a wider range of clinically tested drugs is warranted to help validate the model further. In the meantime, the model may be useful for distinguishing novel anticonvulsant drugs with different mechanisms of action.

Animals↗

PubMed2005

Microarray analysis of rat brain gene expression after chronic administration of sodium valproate.

Valproic acid has been used to treat mania and bipolar disorder, but its mechanism of action is not agreed on. We used rat genome U34A Affymetrix oligonucleotide microarrays, containing 8799 known probesets, to determine the effect of 30-day daily intraperitoneal administration of valproate (200mg/kg) on rat brain gene expression. We found 87 down-regulated genes and 34 up-regulated genes of at least a 1.4-fold change in valproate-treated compared to control rats. The experiments were done on five independent samples for each group, each in duplicate. The genes affected are known to be involved in a variety of pathways, including synaptic transmission, ion channels and transport, G-protein signaling, lipid, glucose and amino-acid metabolism, transcriptional and translational regulation, phosphoinositol cycle, protein kinases and phosphatases, and apoptosis. Our results suggest that the therapeutic effect of valproate may involve the modulation of multiple signaling pathways.

Animals↗

PubMed2005

Sodium Valproate versus Propranolol in paediatric migraine prophylaxis.

In a randomized clinical trial the effect of Sodium Valproate in pediatric migraine prophylaxis was compared with that of Propranolol. One hundred and twenty patients with common migraine (migraine without aura) aged from 3 to 15 years who met the defined criteria enrolled into the study. Randomly the patients were divided in two groups of A and B, treating with sodium Valproate and Propranolol, respectively. Three phases of baseline period (phase I), titration and adjustment period (phases II) and fixed -dose treatment period (phase III) have been designed. A total of 57 patients in group A, and 58 patients in group B completed all phases of the trial. Seventy two percent of patients in group A and 69% of patients in group B have responded to Sodium Valproate and Propranolol, respectively, as a reduction of more than 50% in headache frequency per month. Further more both drugs have shown efficacy in reducing the severity and duration of headache and also better response to rescue medications (p value <0.01). There was no significant difference in all previously mentioned therapeutic effects between two groups (p value <0.05).

Adolescent↗

PubMed2006

The effects of chronic valproate and diazepam in a mouse model of posttraumatic stress disorder.

To better understand neurochemical and psychopharmacological aspects of post-traumatic stress disorder (PTSD), it is necessary establish an animal model of PTSD in which behavioral changes persist for a long time after the initial traumatization. The present study aimed to characterize long-term behavioral alterations in male ICR mice as an animal model of PTSD consisting of a 2-day foot shock (0.8 mA, 10 s) followed by 3 weekly situational reminders (SR), and to evaluate the effects of repeated administration of valproate and diazepam on behavioral deficits of this animal model. The results showed that the aversive procedure induced several long-term behavioral deficiencies: increased freezing behavior and anxiety level, reduced time spent in an aversive like context. Repeated treatment with valproate (100-400 mg/kg, i.p.) induced a dose-dependent reduction of these behavioral changes. In contrast, diazepam at a low dose (0.25 mg/kg) but not at a high dose (4 mg/kg) reduced the behavioral deficiencies. These results demonstrate that exposure to intense foot shock associated with repeated situational reminders elicits long-term disturbances that last about 4 weeks after the foot shock exposure. These behavioral deficits can be ameliorated by repeated administration of valproate or diazepam at some special dose ranges.

Animals↗

PubMed2005

Toxic epidermal necrolysis with combination lamotrigine and valproate in bipolar disorder.

Toxic epidermal necrolysis (TEN) is the most severe and potentially life-threatening cutaneous reaction associated with lamotrigine. The risk of developing TEN during lamotrigine therapy is low and previously reported cases most involved epileptic patients. However, the risk of TEN with combination lamotrigine and valproate is greater than with monotherapy. We present here the emergence of TEN in a 32-year-old bipolar woman who was concomitantly treated with lamotrigine and valproate. The patient developed high fever, pharyngitis, cervical lymphadenopathy, mucosal sloughing, generalized erythematous eruptions and more than 40% epidermal detachment of the total body surface area (TBSA) after we added lamotrigine to her medications of valproate and trazodone. The patient's illness course was protracted and accompanied with hepatitis, pneumonitis and hematologic abnormalities. In the beginning of her illness course, our patient did not respond to antihistamine treatment. However, she made a full recovery without any sequela after she had received systemic corticosteroid and intensive resuscitation. Our case suggests that early use of systemic corticosteroid might be beneficial in treating TEN patients, if there is not any clinical contraindication.

Adult↗

PubMed2004

Valproate as an adjunct to antipsychotics for schizophrenia: a systematic review of randomized trials.

Randomized controlled trials comparing valproate (as a sole, or as an adjunctive compound) to placebo for patients with schizophrenia or schizophrenia-like disorders were summarized in a metaanalysis. It was possible to include only five trials (n = 379) examining valproate as add-on to antipsychotics in this review. Some of the single studies showed inconsistent beneficial effects on some aspects of response, but no overall superiority of valproate augmentation at study endpoints was shown.

Anticonvulsants↗

PubMed2004

Ethosuximide and valproate display high efficacy against lindane-induced seizures in mice.

Both lindane (gamma-hexachlorocyclohexane), an organochlorine ectoparasiticide and pentylenetetrazol, used as a model of experimental epilepsy, produce convulsive seizures resulting from the blockade of the gamma-aminobutyric acid (GABAA) receptor. In the present study we established the protective effects of ethosuximide and valproate against seizures induced by lindane and compared them with the well-known protective effects of these drugs against pentylenetetrazol-induced seizures in mice. Both ethosuximide and valproate afforded complete and dose-dependent protection against seizures induced by lindane. However, the potencies of these drugs were lower than those obtained against pentylenetetrazol seizures. Nevertheless, the protective efficacy of ethosuximide and valproate against experimentally induced lindane seizures may suggest possible efficacy of these drugs against seizures in lindane-poisoned patients.

Animals↗