Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Valproate (VPA) and lithium have been used for many years in the treatment of manic depression. However, their mechanisms of action remain poorly understood. Recent studies suggest that lithium and VPA inhibit GSK-3beta, a serine/threonine kinase involved in the insulin and WNT signaling pathways. Inhibition of GSK-3beta by high concentrations of lithium has been shown to mimic WNT-7a signaling by inducing axonal remodeling and clustering of synapsin I in developing neurons. Here we have compared the effect of therapeutic concentrations of lithium and VPA during neuronal maturation. VPA and, to a lesser extent, lithium induce clustering of synapsin I. In addition, lithium and VPA induce similar changes in the morphology of axons by increasing growth cone size, spreading, and branching. More importantly, both mood stabilizers decrease the level of MAP-1B-P, a GSK-3beta-phosphorylated form of MAP-1B in developing neurons, suggesting that therapeutic concentrations of these mood stabilizers inhibit GSK-3beta. In vitro kinase assays show that therapeutic concentrations of VPA do not inhibit GSK-3beta but that therapeutic concentrations of lithium partially inhibit GSK-3beta activity. Our results support the idea that both mood stabilizers inhibit GSK-3beta in developing neurons through different pathways. Lithium directly inhibits GSK-3beta in contrast to VPA, which inhibits GSK-3beta indirectly by an as-yet-unknown pathway. These findings may have important implications for the development of new strategies to treat bipolar disorders.
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PMID:Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons. 1209 58

Valproic acid (VPA, 2-propylpentanoic acid) is an established drug in the long-term therapy of epilepsy. During the past years, it has become evident that VPA is also associated with anti-cancer activity. VPA not only suppresses tumor growth and metastasis, but also induces tumor differentiation in vitro and in vivo. Several modes of action might be relevant for the biological activity of VPA: (1) VPA increases the DNA binding of activating protein-1 (AP-1) transcription factor, and the expression of genes regulated by the extracellular-regulated kinase (ERK)-AP-1 pathway; (2) VPA downregulates protein kinase C (PKC) activity; (3) VPA inhibits glycogen synthase kinase-3beta (GSK-3beta), a negative regulator of the Wnt signaling pathway; (4) VPA activates the peroxisome proliferator-activated receptors PPARgamma and delta; (5) VPA blocks HDAC (histone deacetylase), causing hyperacetylation. The findings elucidate an important role of VPA for cancer therapy. VPA might also be useful as low toxicity agent given over long time periods for chemoprevention and/or for control of residual minimal disease.
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PMID:Anti-tumor mechanisms of valproate: a novel role for an old drug. 1221 May 56

Manic-depression, or bipolar affective disorder, is a prevalent mental disorder with a global impact. Mood stabilizers have acute and long-term effects and at a minimum are prophylactic for manic or depressive poles without detriment to the other. Lithium has significant effects on mania and depression, but may be augmented or substituted by some antiepileptic drugs. The biochemical basis for mood stabilizer therapies or the molecular origins of bipolar disorder is unknown. One approach to this problem is to seek a common target of all mood stabilizers. Lithium directly inhibits two evolutionarily conserved signal transduction pathways. It both suppresses inositol signaling through depletion of intracellular inositol and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase. A number of GSK-3 substrates are involved in neuronal function and organization, and therefore present plausible targets for therapy. Valproic acid (VPA) is an antiepileptic drug with mood-stabilizing properties. It may indirectly reduce GSK-3 activity, and can up-regulate gene expression through inhibition of histone deacetylase. These effects, however, are not conserved between different cell types. VPA also inhibits inositol signaling through an inositol-depletion mechanism. There is no evidence for GSK-3 inhibition by carbamazepine, a second antiepileptic mood stabilizer. In contrast, this drug alters neuronal morphology through an inositol-depletion mechanism as seen with lithium and VPA. Studies on the enzyme prolyl oligopeptidase and the sodium myo-inositol transporter support an inositol-depletion mechanism for mood stabilizer action. Despite these intriguing observations, it remains unclear how changes in inositol signaling underlie the origins of bipolar disorder.
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PMID:Search for a common mechanism of mood stabilizers. 1282 61

Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness.
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PMID:Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. 1526 71

Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3beta gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3beta gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3beta as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3beta heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.
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PMID:Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila. 1595 96

Effective combination antiretroviral therapies (ART) have markedly lengthened survival among HIV infected individuals. In this long-surviving cohort, both psychiatric comorbidities and HIV-associated neurocognitive disorders (HAND) remain common. Even mild neurocognitive impairment can significantly disrupt of activities of daily living and reduce quality of life. Persistence of HAND might reflect incomplete containment of HIV within the central nervous system (CNS) due to the limited penetration of most antiretrovirals (ARVs) across the blood-brain barrier. Recent data support that certain medications used to treat psychiatric comorbidities in HIV-infected individuals may also protect the brain from toxic byproducts of HIV replication and neuroinflammation. Two drug classes in particular, glycogen synthase kinase-3 beta (GSK-3b) inhibitors and serotonin reuptake inhibitors (SRIs), may benefit individuals with HAND. Valproic acid (VPA) and lithium are potentially beneficial GSK-3b inhibitors. While the mechanism of benefit of SRIs in HAND remains unknown, evidence supports some benefit of citalopram and paroxetine. The present brief review focuses on these drugs and assesses their possible adjunct roles in the treatment of HIV-infected individuals.
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PMID:Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders. 1824 65

During cell aging, proteins accumulate damages, which affect their structure and activity. The protein l-isoaspartyl methyltransferase (PIMT) is involved in the repair of proteins containing abnormal L-isoaspartyl residues. Although its mechanism of action is well defined, little is known about the pathways involved in the regulation of PIMT expression. In this study, we demonstrated that glycogen synthase kinase-3 (GSK-3) and beta-catenin are involved in the regulation of PIMT expression. Treatment of astrocytoma cells (U-87) with direct pharmacological GSK-3 inhibitors such as lithium, SB-216763 and SB-415286 stimulated PIMT expression ( approximately twofold). As expected, GSK-3 inhibition led to an increase of phosphorylated GSK-3beta (Ser9) and to beta-catenin accumulation. PIMT induction by lithium was dependent on increased protein synthesis. In addition, RT-PCR analysis showed higher level of PIMT mRNA following GSK-3 inhibition, which was abolished by the transcriptional inhibitor actinomycin D. These results demonstrated regulation of PIMT expression by lithium at both the transcriptional and the translational levels. Additionally, inhibition by siRNA of GSK-3 and beta-catenin modulated the expression of the PIMT in accordance with GSK-3 pharmacological inhibition. Valproic acid, an antiepileptic drug with mood-stabilizing properties, up-regulated phospho-GSK-3beta (Ser9), beta-catenin and PIMT levels similarly to lithium. This study reports that PIMT expression is up-regulated by GSK-3 inhibition and beta-catenin stabilization upon treatments with lithium and valproic acid. These findings suggest a possible therapeutic role for PIMT in certain brain diseases including epilepsy.
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PMID:Up-regulation of protein L-isoaspartyl methyltransferase expression by lithium is mediated by glycogen synthase kinase-3 inactivation and beta-catenin stabilization. 1858 78

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid beta-protein (Abeta), the central component of neuritic plaques, is derived from beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Abeta production by inhibiting GSK-3beta-mediated gamma-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.
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PMID:Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. 1895 71

Proteins are susceptible to various non-enzymatic post-translational modifications occurring during aging and in certain pathological states. The protein L-isoaspartyl methyltransferase (PIMT) is an enzyme that recognizes and repairs the abnormal L-isoaspartyl residues in proteins. Recently, we reported that PIMT expression was stimulated by the anti-epileptic drug valproic acid and that this was mediated through the glycogen synthase kinase-3 (GSK-3)/beta-catenin pathway. In this study, to gain further insights into which of the signaling pathways activated by valproic acid regulate PIMT abundance, astrocytoma U-87 MG and neuroblastoma SH-SY5Y cells were treated with this drug to investigate the possible involvement of the extracellular-regulated kinase (ERK) pathway in PIMT induction. Valproic acid increased ERK1/2 phosphorylation on Thr202/Tyr204 and Thr185/Tyr187, respectively. Pharmacological inhibitors against the kinases Src, c-Raf, MEK1/2 and ERK1/2 abolished the ERK1/2 phosphorylation stimulated by valproic acid, thus preventing PIMT induction by the drug. Furthermore, MEK1/2 inhibition with U0126 blocked the higher phosphorylation of RSK-1 on Thr359/Ser363 and of GSK-3beta on Ser9 as well as the increased expression of RSK-1, beta-catenin and PIMT upon treatment with valproic acid. RSK-1 knockdown by interfering RNA abrogated the increased expression of RSK-1, beta-catenin and PIMT as well as the induced phosphorylation of RSK-1 and GSK-3beta due to valproic acid. Thus, our findings demonstrated that PIMT up-regulation by valproic acid required the activation of the ERK signaling pathway including RSK-1 the latter being responsible for inactivating GSK-3 and subsequently leading to beta-catenin stabilization.
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PMID:Valproic acid enhances protein L-isoaspartyl methyltransferase expression by stimulating extracellular signal-regulated kinase signaling pathway. 1937 92

A malfunction of retinoid X receptor-alpha (RXRalpha) due to phosphorylation is associated with the development of hepatocellular carcinoma (HCC) and acyclic retinoid (ACR), which targets RXRalpha, can prevent the development of second primary HCC. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induces apoptosis and cell cycle arrest in cancer cells. VPA can also enhance the sensitivity of cancer cells to retinoids. The present study examined the possible combined effects of ACR plus VPA in HepG2 human HCC cell line. The combination of 5muM ACR and 1mM VPA, about the IC(25) value for both compounds, synergistically inhibited the growth of HepG2 cells without affecting the growth of Hc normal human hepatocytes. The combined treatment with ACR plus VPA also acted synergistically to induce apoptosis and G(0)-G(1) cell cycle arrest in HepG2 cells. This combination further exerted a synergistic inhibition of the phosphorylation of RXRalpha, ERK, Akt and GSK-3beta proteins and caused an accumulation of acetylated histones H3 and H4 proteins. VPA enhanced the ability of ACR to raise the cellular levels of RARbeta and p21(CIP1). The combination of these agents markedly increased both the RARE and RXRE promoter activities in HepG2 cells. These results suggest that ACR and VPA cooperatively increase the expression of RARbeta and p21(CIP1), while inhibiting the phosphorylation of RXRalpha, and these effects were associated with induction of apoptosis and the inhibition of cell growth in HepG2 cells. This combination might therefore be an effective regimen for the chemoprevention and chemotherapy of HCC.
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PMID:Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells. 1952 Apr 94


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