Chronic Administration Of Valproic Acid Research Articles

Valproic acid attenuates the severity of astrogliosis in the hippocampus of animal models of temporal lobe epilepsy

Reactive astrogliosis is one of the most frequency neuropathological alterations in the hippocampus of animal models and patients with temporal lobe epilepsy (TLE). Valproic acid (VPA), a widely used antiepileptic drug (AED), acts by blocking ion channels and enhancing GABAergic activity. This study investigated the effects of VPA on hippocampal astrogliosis in a rat model of TLE. The results demonstrated that chronic administration of VPA at a dose of 200mg/kg significantly reduced the severity of astrogliosis and ameliorated neuronal loss in the hippocampus at the early and middle stages post-status epilepticus (SE), while also improving cognitive impairments at the middle and late stages in KA-SE rats. Long-term administration of VPA at 400mg/kg attenuated astrogliosis in the hippocampus at the middle stage post-SE, but lacked neuroprotective effects and exacerbated cognitive impairments at the late stage. These findings suggest that VPA at an appropriate dose could mitigate hippocampal astrogliosis, potentially offering a new antiepileptic mechanism for its long-term use.

Valproic Acid-Induced Anxiety and Depression Behaviors are Ameliorated in p39 Cdk5 Activator-Deficient Mice.

Valproic acid (VPA) is a drug used for the treatment of epilepsy, seizures, migraines, and bipolar disorders. Cyclin-dependent kinase 5 (Cdk5) is a Ser/Thr kinase activated by p35 or p39 in neurons and plays a role in a variety of neuronal functions, including psychiatric behaviors. We previously reported that VPA suppressed Cdk5 activity by reducing the expression of p35 in cultured cortical neurons, leaving p39 unchanged. In this study, we asked for the role of Cdk5 in VPA-induced anxiety and depression behaviors. Wild-type (WT) mice displayed increased anxiety and depression after chronic administration of VPA for 14days, when the expression of p35 was decreased. To clarify their relationship, we used p39 knockout (KO) mice, in which p35 is the only Cdk5 activator. When p39 KO mice were treated chronically with VPA, unexpectedly, they exhibited fewer anxiety and depression behaviors than WT mice. The effects were p39 cdk5r2 gene-dosage dependent. Together, these results indicate that Cdk5-p39 plays a specific role in VPA-induced anxiety and depression behaviors.

Chronic valproic acid administration enhances oxidative stress, upregulates IL6 and downregulates Nrf2, Glut1 and Glut4 in rat's liver and brain.

Valproic acid (VPA) is a powerful antiepileptic drug that was associated with several neurological and hepatic problems especially with increasing its dose and duration. These problems may be metabolic in origin and related to glucose homeostasis. So, the present study investigated the effect of different doses and durations of VPA on the expression of glucose transporters (Glut1 and Glut4), oxidative stress and inflammatory cytokine (IL-6) in the liver and specific brain regions. Seventy-two male Sprague-Dawley rats were randomly allocated into three equal groups: (1) saline group, (2) 200 mg VPA group and (3) 400 mg VPA group. By the end of experiments, the expressions of Glut1, Glut4 nuclear factor erythroid-like 2 related factor (Nrf2), IL-6 and oxidative stress markers [malondialdehyde (MDA) and glutathione (GSH)] in the liver, corpus striatum, prefrontal cortex (PFC) and cerebellum were assessed. We found that administration of VPA (200 mg and 400 mg) caused a significant decrease in the Glut1 and Glut4 expression in different tissues in a dose- and time-dependent manner (P < 0.01). Also, VPA (200 and 400 mg) caused a significant increase in MDA with a decrease in GSH in tissues at different times. Moreover, VPA (200 and 400 mg) caused significant upregulation in IL-6 expression and downregulation in Nrf2 expression (P < 0.01). The results suggest that increasing the dose and time of VPA therapy downregulates Glut1 and Glut4 in the liver and brain which may impair glucose uptake in these tissues. This effect was associated with enhanced oxidative stress, downregulation of nrf2 and upregulation of IL-6 in liver and brain tissues.

A Long-Term Treatment with Arachidonyl-2'-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy.

Rational polytherapy in the treatment of refractory epilepsy has been the main therapeutic modality for several years. In treatment with two or more antiepileptic drugs (AEDs), it is of particular importance that AEDs be selected based on their high anticonvulsant properties, minimal side effects, and impact on the formation of new neurons. The aim of the study was to conduct an in vivo evaluation of the relationship between treatments with synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA) alone or in combination with valproic acid (VPA) and hippocampal neurogenesis in a mouse pilocarpine model of epilepsy. All studies were performed on adolescent male CB57/BL mice with using the following drugs: VPA (10 mg/kg), ACEA (10 mg/kg), phenylmethylsulfonyl fluoride (PMSF—a substance protecting ACEA against degradation by fatty acid hydrolase, 30 mg/kg), pilocarpine (PILO, a single dose of 290 mg/kg) and methylscopolamine (30 min before PILO to stop peripheral cholinergic effects of pilocarpine, 1 mg/kg). We evaluated the process of neurogenesis after a 10-day treatment with ACEA and VPA, alone and in combination. We observed a decrease of neurogenesis in the PILO control group as compared to the healthy control mice. Furthermore, ACEA + PMSF alone and in combination with VPA significantly increased neurogenesis compared to the PILO control group. In contrast, VPA 10-day treatment had no impact on the level of neurons in comparison to the PILO control group. The combination of ACEA, PMSF and VPA considerably stimulated the process of creating new cells, particularly neurons, while chronic administration of VPA itself had no influence on neurogenesis in the mouse pilocarpine model of epilepsy. The obtained results enabled an in vivo evaluation of neurogenesis after treatment with antiepileptic drugs in an experimental model of epilepsy.

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells.

Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

Effects of chronic administration of valproic acid to epileptic patients on coagulation tests and primary hemostasis.

Valproic acid (VPA) is an antiepileptic drug that has been associated with impaired hemostasis and increased risk for postsurgical bleeding. However, the published reports provide controversial results. We measured parameters of primary hemostasis in VPA-treated patients with epilepsy, focusing on adenosine nucleotide-dependent platelet responses, which play a central role in primary hemostasis. We enrolled 20 cases (epileptic patients receiving treatment with VPA) and 20 controls (12 epileptic patients receiving treatment with drugs different from VPA and 8 healthy subjects). Measurements included prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count, platelet function analyzer (PFA)-100 closure times, plasma von Willebrand factor levels, platelet content of ADP, ATP, and serotonin (all stored in platelet dense granules), and platelet shape change and aggregation induced by ADP and other platelet agonists, including the ATP analog α,β-methylene-ATP. The plasma concentration of VPA was in the therapeutic range in 17 patients and slightly above the upper limit in 3 patients. There were no statistically significant differences in any of the studied parameters in cases versus controls. Our thorough controlled study failed to show that chronic treatment with VPA induces significant abnormalities of coagulation and primary hemostasis. Therefore, VPA, when present in the circulation in the therapeutic range, does not impair hemostasis.

Valproic acid downregulates Cdk5 activity via the transcription of the p35 mRNA

The cyclin-dependent kinase 5 (Cdk5) is a neuron-specific Ser/Thr kinase that is activated by the regulatory subunit p35. Overactivation of Cdk5, which is induced by the cleavage of p35 by calpain, is implicated in neuronal death in various neurodegenerative diseases. In contrast, depletion of the Cdk5 activity renders neurons vulnerable to stresses. Recent reports suggest the involvement of Cdk5 in mental disorders. We hypothesized that perturbation of Cdk5 activity is related to mental conditions. To verify this hypothesis, we investigated the effect of valproic acid (VPA), which is a drug of choice for psychiatric disorders, on Cdk5 activity. VPA decreased the expression of p35 at both the protein and mRNA levels in cultured neurons, resulting in a decrease of Cdk5 activity. VPA decreased the p35 mRNA via histone deacetylase inhibition. The chronic administration of VPA also downregulated p35 in mouse brains. These results indicate that VPA regulates Cdk5 activity in neurons via p35 transcription mediated by HDAC inhibition.

Chronic valproic acid administration impairs contextual memory and dysregulates hippocampal GSK-3β in rats

Valproic acid (VPA), a long-standing anti-epileptic and anti-manic drug, exerts multiple actions in the nervous system through various molecular mechanisms. Neuroprotective properties have been attributed to VPA in different models of neurodegeneration, but contrasting results on its improvement of learning and memory have been reported in non-pathologic conditions. In the present study, we have tested on a hippocampal-dependent learning test, the contextual fear conditioning, the effect of chronic VPA administration through alimentary supplementation that allows relatively steady concentrations to be reached by a drug otherwise very rapidly eliminated in rodents. Contextual fear memory was significantly impaired in rats chronically treated with VPA for 4weeks. To understand the cellular and molecular correlates of this amnesic effect with particular regard to hippocampus, we addressed three putatively memory-related targets of VPA action in this brain area, obtaining the following main results: i) chronic VPA promoted an increase of post-translational modifications of histone H3 (acetylation and phosphorylation) known to favor gene transcription; ii) adult neurogenesis in the dentate gyrus, which has been controversially reported to be affected by VPA, was unchanged; and iii) GSK-3β, a kinase playing a key role in hippocampal plasticity, as well as in learning and memory, was dysregulated by VPA treatment. These results point at GSK-3β dysregulation in the hippocampus as an important parameter in the amnesic effect of VPA. The VPA amnesic effect in the animal model here reported is also supported by some observations in patients and, therefore, it should be taken into account and monitored in VPA-based therapies.

Extracellular-derived calcium does not initiate in vivo neurotransmission involving docosahexaenoic acid

In vitro studies show that docosahexaenoic acid (DHA) can be released from membrane phospholipid by Ca(2+)-independent phospholipase A(2) (iPLA(2)), Ca(2+)-independent plasmalogen PLA(2) or secretory PLA(2 (sPLA2)), but not by Ca(2+)-dependent cytosolic PLA(2) (cPLA2), which selectively releases arachidonic acid (AA). Since glutamatergic NMDA (N-methyl-D-aspartate) receptor activation allows extracellular Ca(2+) into cells, we hypothesized that brain DHA signaling would not be altered in rats given NMDA, to the extent that in vivo signaling was mediated by Ca(2+)-independent mechanisms. Isotonic saline, a subconvulsive dose of NMDA (25 mg/kg), MK-801, or MK-801 followed by NMDA was administered i.p. to unanesthetized rats. Radiolabeled DHA or AA was infused intravenously and their brain incorporation coefficients k*, measures of signaling, were imaged with quantitative autoradiography. NMDA or MK-801 compared with saline did not alter k* for DHA in any of 81 brain regions examined, whereas NMDA produced widespread and significant increments in k* for AA. In conclusion, in vivo brain DHA but not AA signaling via NMDA receptors is independent of extracellular Ca(2+) and of cPLA(2). DHA signaling may be mediated by iPLA(2), plasmalogen PLA(2), or other enzymes insensitive to low concentrations of Ca(2+). Greater AA than DHA release during glutamate-induced excitotoxicity could cause brain cell damage.

Chronic Administration of Valproic Acid Inhibits Activation of Mouse Hepatic Stellate Cells in Vitro and in Vivo

Hepatic stellate cell (HSC) activation is a pivotal step in the pathogenesis of liver fibrosis. The clarification of this transdifferentiation process is therefore important for the development of effective therapies for fibrosis. We analyzed the effect of a histone deacetylase inhibitor, valproic acid (VPA), on mouse HSC transdifferentiation in vitro and in vivo. The exposure of freshly isolated mouse HSCs to 2.5 mM VPA led to increased histone H4 acetylation and inhibited cell proliferation. Expression of stellate cell activation markers analyzed by quantitative polymerase chain reaction and western blotting revealed that treatment with VPA inhibited the induction of activation markers such as Acta2, Lox, Spp1, and Myh11. Treatment of mice with VPA decreased collagen deposition and in vivo activation of stellate cells in the livers of CCl(4)-treated mice. Class I histone deacetylase silencing through RNA interference in mouse HSCs only partially mimicked treatment with VPA. Chronic administration of VPA results in a marked decrease in stellate cell activation both in vitro and in vivo. We hypothesize that the VPA effect results partially from class I histone deacetylase inhibition, but that also non-histone deacetylase class I VPA targets are involved in the stellate cell activation process.

Chronic Dietary Administration of Valproic Acid Protects Neurons of the Rat Nucleus Basalis Magnocellularis from Ibotenic Acid Neurotoxicity

Valproic acid (VPA) has been used for many years as a drug of choice for epilepsy and mood disorders. Recently, evidence has been proposed for a wide spectrum of actions of this drug, including antitumoral and neuroprotective properties. Valproic acid-mediated neuroprotection in vivo has been so far demonstrated in a limited number of experimental models. In this study, we have tested the neuroprotective potential of chronic (4 + 1 weeks) dietary administration of VPA on degeneration of cholinergic and GABAergic neurons of the rat nucleus basalis magnocellularis (NBM), injected with the excitotoxin, ibotenic acid (IBO), an animal models that is relevant for Alzheimer's disease-like neurodegeneration. We show that VPA treatment significantly protects both cholinergic and GABAergic neurons present in the injected area from the excitotoxic insult. A significant level of neuroprotection, in particular, is exerted towards the cholinergic neurons of the NBM projecting to the cortex, as demonstrated by the substantially higher levels of cholinergic markers maintained in the target cortical area of VPA-treated rats after IBO injection in the NBM. We further show that chronic VPA administration results in increased acetylation of histone H3 in brain, consistent with the histone deacetylase inhibitory action of VPA and putatively linked to a neuroprotective action of the drug mediated at the epigenetic level.

Valproic Acid Inhibits the Growth of Cervical Cancer both In Vitro and In Vivo

Valproic acid (VPA), a well-known anti-convulsant, is currently under extensive evaluation as an anti-cancer agent. It is known to exert its anti-cancer effect mainly by inhibiting the enzyme histone deacetylase I. In our study, we investigated the effects of VPA on cervical cancer both in vitro and in vivo cancer models. We examined the effects of acute VPA (0, 1.2, 2.4, 5.0 mM) treatment on cell proliferation in cervical cancer cell lines HeLa, SiHa and Ca Ski and histone acetylation, p21 and p53 gene expression in HeLa cell line. We also investigated the effect of chronic VPA administration in tumour xenograft growth studies. Our results show that with acute treatment, VPA can increase the expression of net histone H3 acetylation and up-regulate p21 expression with no effect on p53 expression. Chronic administration of VPA had a net cytostatic effect that resulted in a statistically significant reduction of tumour growth and improved survival advantages in tumour xenografts studies. Furthermore, we also demonstrated that VPA has a direct anti-angiogenic effect in tumour studies and could potentially be a promising candidate for further cervical cancer trails.

Chronic administration of valproic acid reduces brain NMDA signaling via arachidonic acid in unanesthetized rats.

Evidence that brain glutamatergic activity is pathologically elevated in bipolar disorder suggests that mood stabilizers are therapeutic in the disease in part by downregulating glutamatergic activity. Such activity can involve the second messenger, arachidonic acid (AA, 20:4n - 6). We tested this hypothesis with regard to valproic acid (VPA), when stimulating glutamatergic N-methyl-D: -aspartate (NMDA) receptors in rat brain and measuring AA and related responses. An acute subconvulsant dose of NMDA (25 mg/kg i.p.) or saline was administered to unanesthetized rats that had been treated i.p. daily with VPA (200 mg/kg) or vehicle for 30 days. Quantitative autoradiography following intravenous [1-(14)C]AA infusion was used to image regional brain AA incorporation coefficients k*, markers of AA signaling. In chronic vehicle-pretreated rats, NMDA compared with saline significantly increased k* in 41 of 82 examined brain regions, many of which have high NMDA receptor densities, and also increased brain concentrations of the AA metabolites, prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)). VPA pretreatment reduced baseline concentrations of PGE(2) and TXB(2), and blocked the NMDA induced increases in k* and in eicosanoid concentrations. These results, taken with evidence that carbamazepine and lithium also block k* responses to NMDA in rat brain, suggest that mood stabilizers act in bipolar disorder in part by downregulating glutamatergic signaling involving AA.

Chronic administration of valproic acid inhibits PC3 cell growth by suppressing tumor angiogenesis in vivo

Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. We investigated the mechanisms of chronic valproic acid (VPA) inhibiting PC3 cell growth in the study. We established tumor xenografts of the PC3 cell line and investigated the effect of VPA chronic administration on tumor growth. Apoptosis in tumor tissue was measured using the TUNEL Detection Kit. We detected the effect of VPA chronic administration on histone acetylation; p21CIP1/WAF1 gene expression; vascular endothelial growth factor (VEGF) expression by reverse-transcription Polymerase Chain Reaction (PCR) analysis; immunohistochemistry; and Western Blotting. In mouse models with established subcutaneous prostate (PC3), VPA treatment induced 70% inhibition of tumor growth without overt toxicity. Our result showed that chronic administration of VPA has an effect on tumor growth arrest and the effect was associated with increased histone acetylation, p21CIP1/WAF1 up-regulation, and VEGF down-regulation. We conclude that chronic VPA results in profound decreases in the proliferation of PC3 cells, not only by increasing histone H3 acetylation and up-regulating p21CIP1/WAF1 expression, but also by down-regulating VEGF.

Chronic treatment of rats with sodium valproate downregulates frontal cortex NF‐κB DNA binding activity and COX‐2 mRNA1

Valproic acid (VPA) is used to treat bipolar disorder, but its mechanism of action is not clear. VPA shares many cellular and molecular targets with lithium, including reducing arachidonic acid turnover in rat brain phospholipids and cyclooxygenase-2 (COX-2) protein level and activity in rat brain. We examined the effect of chronic VPA administration (200 mg/kg body weight for 30 days) to produce therapeutically relevant plasma concentrations, on transcription factors (NF-kappaB, AP-1, AP-2, C/EBP, CREB, and ETS) that are known to regulate the COX-2 gene. Chronic VPA significantly increased AP-1 DNA binding activity and decreased NF-kappaB DNA binding activity, p50 subunit protein and mRNA expression of COX-2 in frontal cortex compared with untreated control rats. It did not alter AP-2, C/EBP, ETS or CREB DNA binding activity. VPA downregulates NF-kappaB DNA binding activity, likely by decreasing the p50 protein levels. This effect may explain its downregulation of COX-2 mRNA. The decrease in NF-kappaB activity by chronic VPA may affect other NF-kappaB-regulated genes and may be related to VPA's action in bipolar disorder. Chronic VPA may decrease the reported increased brain NF-kappaB components in bipolar patients.

Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl–CoA by brain microsomal long-chain fatty acyl–CoA synthetases: relevance to bipolar disorder

Several drugs used to treat bipolar disorder (lithium and carbamazepine), when administered chronically to rats, reduce the turnover of arachidonic acid, but not docosahexaenoic acid, in brain phospholipids by decreasing the activity of an arachidonic acid-selective phospholipase A(2). Although chronic valproic acid produces similar effects on brain arachidonic acid and docosahexaenoic acid turnover, it does not alter phospholipase A(2) activity, suggesting that it targets a different enzyme in the turnover pathway. By isolating rat brain microsomal long-chain fatty acyl-CoA synthetases (Acsl), we show in vitro that valproic acid is a non-competitive inhibitor of Acsl, as it reduces the maximal velocity of the reaction without changing the affinity of the substrate for the enzyme. While valproic acid inhibited the synthesis of arachidonoyl-CoA, palmitoyl-CoA, and docosahexaenoyl-CoA, the K (i )for inhibition of arachidonoyl-CoA synthesis (14.1 mM) was approximately one fifth the K (i) for inhibiting palmitoyl-CoA (85.4 mM) and docosahexaenoyl-CoA (78.2 mM) synthesis. As chronic administration of valproic acid in bipolar disorder achieves whole-brain levels of 1.0 to 1.5 mM, inhibition of arachidonoyl-CoA formation can occur at brain concentrations that are therapeutically relevant to this disease. Furthermore, brain microsomal Acsl did not produce valproyl-CoA. This study shows that valproic acid acts as a non-competitive inhibitor of brain microsomal Acsl, and that inhibition is substrate-selective. The study supports the hypothesis that valproic acid acts in bipolar disorder by reducing the brain arachidonic acid cascade, by inhibiting arachidonoyl-CoA formation.

The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems.

Corticotropin-releasing factor (CRF) plays a preeminent role in coordinating the endocrine, autonomic, and behavioral responses to stress. Dysregulation of both hypothalamic and extrahypothalamic CRF systems have been reported in patients with major depression and post-traumatic stress disorder. Moreover, effective treatment of these conditions leads to normalization of these CRF systems. Although there is virtually no data concerning alterations of CRF systems in bipolar disorder (manic depressive illness), previous work indicates that valproic acid, an anticonvulsant also effective in the treatment of acute mania, alters central CRF neuronal systems. In the current studies, we chronically administered valproic acid and lithium, two clinically effective mood stabilizers, in nonstressed rats to extend our previous findings. Chronic valproic acid administration decreased CRF mRNA expression in the paraventricular nucleus of the hypothalamus; lithium administration increased CRF mRNA expression in the central nucleus of the amygdala. Although valproic acid increased CRF(1) receptor mRNA expression in the cortex, CRF(1) receptor binding was decreased in both the basolateral amygdala and cortex, suggesting that chronic valproate treatment may in fact dampen the overall tone in this central stress pathway. Valproate treatment decreased CRF(2A) mRNA expression in both the lateral septum and hypothalamus, although CRF(2A) receptor binding was unchanged. Lithium administration decreased CRF(1) mRNA expression in both the amygdala and frontal cortex, but CRF(1) receptor binding also remained unchanged. These results suggest that the therapeutic actions of these mood stabilizers may, in part, result from their actions on central CRF neuronal systems. The distinct actions of each drug on CRF systems may underlie their synergistic clinical effects.

GABA levels within the medial preoptic area: effects of chronic administration of sodium valproic acid.

Sodium valproic acid (VPA) is a widely prescribed anticonvulsant medication that has been shown to interfere with pubertal maturation of the reproductive system, and induce endocrine abnormalities in adults, within a subset of the clinical population. While VPA's mechanism of action is still poorly understood, it may exert its anti-reproductive effects by enhancing GABAergic inhibition of the GnRH neuronal population within the medial preoptic area (mPOA). The purpose of this study was to determine if chronic administration of VPA alters GABA levels within the mPOA region. In Experiment 1, the mPOA, caudate, and arcuate nucleus regions were harvested from VPA-treated and control mice. Analysis of whole tissue content of GABA revealed that levels were lower in the caudate and arcuate nucleus regions of VPA-treated animals, whereas there were no group differences for the mPOA region. Collapsing across drug group, there was also a trend for males having overall higher levels of GABA as compared to females. In Experiments 2 and 3, mice were implanted with microdialysis probes within the mPOA region and sampled for extracellular GABA levels. Females (Exp. 3) were sampled either on diestrous, proestrous, or estrous. Results from males (Exp. 2) revealed that VPA enhanced extracellular GABA levels in the mPOA region compared with controls. However, GABA levels for both groups remained stable across the sampling period. Conversely, in Exp. 3, females showed cyclical release of GABA across the sampling period. For control females, GABA levels increased during the afternoon on all cycle days, but the rise on proestrus was smaller than on other cycle days. VPA-treated animals showed an overall reduction in GABA levels compared with controls. Furthermore, while GABA increased over sampling time on estrus and diestrus days of the cycle, there was not a significant rise in GABA on proestrus. These data indicate: (1) regional specificity in VPA effects upon GABA levels, (2) a sex difference in the effects of VPA on GABA levels within the mPOA, and (3) GABA levels increase on the afternoon of all days of the estrous cycle with VPA attenuating the rise seen on the afternoon of proestrus. These results provide evidence that VPA effects upon the reproductive axis may involve changes in GABA release, and that males and females show different patterns of neurochemical response to the drug.

Chronic administration of valproic acid induces a decrease in rat striatal glutamate and taurine levels

The effect of acute and chronic (10 days) administration of 200 mg/kg (i.p.) of valproic acid (VPA) on endogenous levels of aspartate, glutamate, alanine, glycine and taurine in the cerebral frontal cortex and corpus striatum of rats was studied. Quantification of the amino acid levels was performed by HPLC.Valproic acid (VPA) did not either induce changes on these neurotransmitters contents in corpus striatum after acute treatment. After chronic administration we found a decrease on the endogenous levels of glutamic acid (24%, p < 0.05) which was related to an increase (250%, p < 0.02) of the in vitro KCl evoked release of glutamate. We found decrements in taurine endogenous levels (22%, p < 0.05) which was not associated with an increase of its release.In cerebral frontal cortex there was not found any change neither under the acute nor under the chronic condition.Thus, it may be conclude that chronic treatment with VPA produces decreases on the endogenous levels of glutamate and taurine. However the relevance of this effect concerning it therapeutic action remains unclear.

Chronic administration of sodium valproic acid slows pubertal maturation in inbred DBA/2J mice: skeletal, histological, and endocrinological evidence.

Sodium valproic acid (VPA) has been reported to occasionally delay pubertal maturation in children. In the current study, we sought to establish a valid animal model with which to further investigate the neuroendocrinological sequelae of VPA administration. Male and female DBA/2J mice were weaned at 2 weeks of age and administered either VPA (17-20 mg/kg/day) or control solution via drinking water. Animals were weighed and sacrificed via decapitation at 4, 6, or 8 weeks of age. Testes and ovaries were prepared for histological analyses. In addition, the length of the left humerus bone from each animal was obtained as an index of skeletal growth, and trunk blood was assayed for circulating follicle-stimulating hormone (FSH) and prolactin (PRL). For males, testicular weights of the animals receiving VPA were significantly lower than those of control animals at all three sampling ages. No between-group differences were found for body weight at any sampling age, and yet the rate of skeletal maturation (as indexed by humerus length) was decreased significantly for the VPA-treated males at all three sampling periods. Additionally, while hormone levels did not consistently differ, histological analyses of the gonadal tissue demonstrated significantly decreased rats of spermatogenesis at all sampling points for VPA-treated animals. For females, chronic VPA administration led to a significant reduction in uterine weight at the 4 and 6 week sampling periods, and yet by 8 weeks of age the uterine weights for the two groups did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)