Sodium valproate at therapeutic concentrations changes Ca2+response accompanied with its weak inhibition of protein kinase C in human astrocytoma cells

Kurita, Masatake; Nishino, Satoshi; Ohtomo, Koji; Rai, Mayumi; Shirakawa, Hisayoshi; Mashiko, Hirobumi; Niwa, Shin‐Ichi; Nakahata, Norimichi

doi:10.1016/j.pnpbp.2006.11.019

Cited by 10 publications

(5 citation statements)

References 20 publications

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“…It is known that VPA enhances GABA activity within the brain by inhibiting its degradation, stimulating its synthesis and release, and directly enhancing its postsynaptic effects [78]. VPA also acts as an inhibitor on the protein kinase C, decreasing the release of neurotransmitters [70,79,80].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Histone Deacetylase Inhibition on the Levels of Cerebral Cytokines in an Animal Model of Mania Induced by Dextroamphetamine

et al. 2017

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Studies have suggested the involvement of inflammatory processes in the physiopathology of bipolar disorder. Preclinical evidences have shown that histone deacetylase inhibitors may act as mood-stabilizing agents and protect the brain in models of mania and depression. The aim of the present study was to evaluate the effects of sodium butyrate (SB) and valproate (VPA) on behavioral changes, histone deacetylase activity, and the levels of cytokines in an animal model of mania induced by dextroamphetamine (d-AMPH). Wistar rats were first given d-AMPH or saline (Sal) for a period of 14 days, and then, between the 8th and 14th days, the rats were treated with SB, VPA, or Sal. The activity of histone deacetylase and the levels of cytokines (interleukin (IL) IL-4, IL-6, and IL-10 and tumor necrosis factor-alpha (TNF-α)) were evaluated in the frontal cortex and striatum of the rats. The administration of d-AMPH increased the activity of histone deacetylase in the frontal cortex. Administration of SB or VPA decreased the levels of histone deacetylase activity in the frontal cortex and striatum of rats. SB per se increased the levels of cytokines in both of the brain structures evaluated. AMPH increased the levels of cytokines in both of the brain structures evaluated, and VPA reversed this alteration. The effects of SB on d-AMPH-induced cytokine alterations were dependent on the brain structure and the cytokine evaluated. Despite VPA and SB having a similar mechanism of action, both being histone deacetylase inhibitors, they showed different effects on the levels of cytokines. The present study reinforces the need for more research into histone deacetylase inhibitors being used as a possible target for new medications in the treatment of bipolar disorder.

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Section: Discussionmentioning

confidence: 99%

The Effects of Histone Deacetylase Inhibition on the Levels of Cerebral Cytokines in an Animal Model of Mania Induced by Dextroamphetamine

et al. 2017

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“…All other compounds tested had minimal effect despite using concentrations that were more than 20 times their reported PKC selective IC 50 values. The non-selective PKC inhibitor, valproic acid, was not inhibitory and perhaps (retrospectively) should have been tested at higher concentrations than we used here (80 μM and 350 μM) since relatively recent work showed only 40% inhibition of PKC in human astrocytoma cells at 600 μM valproic acid concentration (Kurita et al 2007). Regardless, three other non-selective PKC inhibitors were also found to have significant inhibitory effects without any overt signs of toxicity.…”

Section: Discussionmentioning

confidence: 92%

Role for protein kinase C delta in the functional activity of human UGT1A6: implications for drug–drug interactions between PKC inhibitors and UGT1A6

Volak¹,

Court²

2010

Xenobiotica

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1. Many UDP-glucuronosyltransferases (UGTs) require phosphorylation by protein kinase C (PKC) for glucuronidation activity. Inhibition of UGT phosphorylation by PKC inhibitor drugs may represent a novel mechanism for drug-drug interactions. 2. The potential for PKC-mediated inhibition of human UGT1A6, an isoform involved in the glucuronidation of drugs such as acetaminophen and endogenous substrates including serotonin, was evaluated using various cell model systems. 3. Of 10 different PKC inhibitors screened for effects on acetaminophen glucuronidation by human LS180 colon cells, only rottlerin (PKC-δ selective inhibitor; IC50 = 9.0 ± 1.2 μM) and the non-selective PKC inhibitors (calphostin-C, curcumin and hypericin), decreased glucuronidation by more than 50%. 4. Using UGT1A6-infected Sf9 insect cells, calphostin-C and hypericin showed three-times more potent inhibition of serotonin glucuronidation in treated whole cells versus cell lysates. However, both curcumin and rottlerin showed significant direct inhibition and so (indirect) PKC effects could not be differentiated in this model system. 5. Of 9 PKC isoforms co-expressed with UGT1A6 in human embryonic kidney 293T cells only PKC δ increased protein-normalized UGT1A6-mediated serotonin glucuronidation significantly (by 63±4%). 6. These results identify an important role for PKC δ in UGT1A6 mediated glucuronidation and suggest that PKC δ inhibitors could interfere with glucuronidation of UGT1A6 substrates.

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“…The rat brain findings differ from our findings in astrocytoma cells in terms of Li effects. In our experimental model [16]- [18], measurements were taken without neurotrophic factors acting on the astrocytes by not adding FCS to the cultured cells in order to eliminate their effects on BDNF measurements. Measurements beyond Day 7 were not possible because of dwindling cell numbers, because the cultured cells are unable to survive long without FCS.…”

Section: Discussionmentioning

confidence: 99%

Effects of Lithium and Valproic Acid on the Production of Brain-Derived Neurotrophic Factor in Astrocytoma

Ohtomo¹,

Nishino²,

Kurita³

et al. 2014

OJPsych

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No systematic investigation considering BDNF and its receptor TrkB has been conducted on the effects of mood-stabilizing drugs. We therefore decided to quantify BDNF production and the expression of TrkB-T1 receptor and PLCγ in astrocytoma. 1321N human astrocytoma cells were grown to a sufficient quantity in 5% fetal calf serum (FCS). The mood-stabilizing drugs Li and VPA were added to the therapeutic concentrations of 1 mM and 600 μM, respectively. The production of BDNF was determined by an enzyme-linked immunosorbent assay. The expressions of TrkB-T1 and PLCγ were determined by Western blot. The production of BDNF was significantly higher on Day 7 in the VPA samples (P < 0.05) and was significantly suppressed beginning on Day 1 in the Li samples (P < 0.05). TrkB-T1 expression, in contrast to BDNF production, was significantly higher in the VPA samples (P < 0.05) but did not change in the Li samples. PLCγ expression did not change. Li and VPA seem differently affect BDNF production and TrkB-T1 (BDNF receptor) expression.

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Sodium valproate at therapeutic concentrations changes Ca2+response accompanied with its weak inhibition of protein kinase C in human astrocytoma cells

Cited by 10 publications

References 20 publications

The Effects of Histone Deacetylase Inhibition on the Levels of Cerebral Cytokines in an Animal Model of Mania Induced by Dextroamphetamine

The Effects of Histone Deacetylase Inhibition on the Levels of Cerebral Cytokines in an Animal Model of Mania Induced by Dextroamphetamine

Role for protein kinase C delta in the functional activity of human UGT1A6: implications for drug–drug interactions between PKC inhibitors and UGT1A6

Effects of Lithium and Valproic Acid on the Production of Brain-Derived Neurotrophic Factor in Astrocytoma

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