Valproic acid regulates catecholaminergic pathways by concentration-dependent threshold effects on TH mRNA synthesis and degradation

D’Souza, Antoni; Onem, Eylem; Patel, Pravin; Gamma, Edmund F. La; Nankova, Bistra B.

doi:10.1016/j.brainres.2008.09.088

Cited by 46 publications

(42 citation statements)

References 61 publications

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“…The neuroprotective effect also correlated with a significant VPA-stimulated increase in the expression of both TH and a-synuclein in the substantia nigra. The VPA effect on positive regulation of TH has been previously observed at the mRNA expression level in the rat locus coeruleus and may be part of a more generalized ability of histone deacetylase inhibitors to regulate expression of TH gene both in vivo and in vitro (Sands et al 2000;DeCastro et al 2005;D'Souza et al 2009). We demonstrate here that also TH protein is upregulated in its expression in the substantia nigra of rats chronically treated with VPA.…”

Section: Discussionmentioning

confidence: 90%

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

et al. 2009

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Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson's disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein alpha-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated alpha-synuclein increased in the same regions. VPA treatment counteracted both these alpha-synuclein alterations. Furthermore, monoubiquitinated alpha-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of alpha-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.

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Section: Discussionmentioning

confidence: 90%

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

et al. 2009

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“…However, newer insights have revealed that HDACI effects on both histone and nonhistone proteins may be more far-reaching than originally thought, modulating cancer cell differentiation, migration and invasion, metastasis, and angiogenesis. Reportedly, HDACIs upregulate a set of metastasis suppressor genes, downregulate a set of metastasis-promoter genes, and repress cancer cell invasion and metastasis in vitro and in vivo (Shen et al, 2005;D'Souza et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Sodium valproate inhibits MDA-MB-231 breast cancer cell migration by upregulating NM23H1 expression

Qian²,

Li³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. Breast cancer is a common cancer in women, with a highly variable course, from inoffensive to lethal. To find a more effective strategy for its treatment, sodium valproate has been tested as an anti-cancer drug; it is the only clinically available histone deacetylase inhibitor. However, data about the effects of sodium valproate on breast cancer are insufficient in both animals and humans; studies have yielded conflicting conclusions. In particular, little is known about the association between expression of the metastasis suppressor Nm23H1 gene and breast cancer. We hypothesized that sodium valproate regulates NM23H1 expression, and affects migration and/or invasion. We found that sodium valproate at concentrations of 0.8-3.2 mM inhibits migration and modulates Nm23H1 gene expression in a concentration-dependent manner. Confluent MDA-MB-231 cells were scratched by a micropipette tip after VPA treatment for 24 h; 24 h later, the scratch was almostly closed in the 0 mM VPA-treated cells, while the 3.2 mM VPA-treated cells migrated the slowest. The cell migration ratio exposed to 0.8, 1.6 and 3.2 mM VPA was about 66.67, 30.67 and 26.67% (P < 0.05). We also found evidence that sodium valproate upregulates NM23H1 expression, which is a clue to its anti-cancer mode of action. The NM23H1 gene expression was relative fold increased determined by Western blotting at 3.2 mM VPA. Collectively, these observations indicate that sodium valproate has potential for use in breast cancer treatment.

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“…We have used this PC12 line to examine the effects of SCFA, principally BA, and their derivatives on gene expression [55], [56], [57], [58]. Of note, our results underscored at least 3 major mechanisms by which BA can regulate TH gene expression: i) modulation of gene transcription by chromatin remodeling, ii) b y activation of transcription factors via different signaling cascades (including Ca2+/cAMP mediated activation of CREB [59]) and involving induction of transcription via an upstream 5′ regulatory element (BRE; GCCTGG at −509 to −504 of the rat TH promoter [60] or iii) by affecting the stability of TH mRNA (e.g.…”

Section: Introductionmentioning

confidence: 99%

Enteric Bacterial Metabolites Propionic and Butyric Acid Modulate Gene Expression, Including CREB-Dependent Catecholaminergic Neurotransmission, in PC12 Cells - Possible Relevance to Autism Spectrum Disorders

et al. 2014

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Alterations in gut microbiome composition have an emerging role in health and disease including brain function and behavior. Short chain fatty acids (SCFA) like propionic (PPA), and butyric acid (BA), which are present in diet and are fermentation products of many gastrointestinal bacteria, are showing increasing importance in host health, but also may be environmental contributors in neurodevelopmental disorders including autism spectrum disorders (ASD). Further to this we have shown SCFA administration to rodents over a variety of routes (intracerebroventricular, subcutaneous, intraperitoneal) or developmental time periods can elicit behavioral, electrophysiological, neuropathological and biochemical effects consistent with findings in ASD patients. SCFA are capable of altering host gene expression, partly due to their histone deacetylase inhibitor activity. We have previously shown BA can regulate tyrosine hydroxylase (TH) mRNA levels in a PC12 cell model. Since monoamine concentration is known to be elevated in the brain and blood of ASD patients and in many ASD animal models, we hypothesized that SCFA may directly influence brain monoaminergic pathways. When PC12 cells were transiently transfected with plasmids having a luciferase reporter gene under the control of the TH promoter, PPA was found to induce reporter gene activity over a wide concentration range. CREB transcription factor(s) was necessary for the transcriptional activation of TH gene by PPA. At lower concentrations PPA also caused accumulation of TH mRNA and protein, indicative of increased cell capacity to produce catecholamines. PPA and BA induced broad alterations in gene expression including neurotransmitter systems, neuronal cell adhesion molecules, inflammation, oxidative stress, lipid metabolism and mitochondrial function, all of which have been implicated in ASD. In conclusion, our data are consistent with a molecular mechanism through which gut related environmental signals such as increased levels of SCFA's can epigenetically modulate cell function further supporting their role as environmental contributors to ASD.

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Valproic acid regulates catecholaminergic pathways by concentration-dependent threshold effects on TH mRNA synthesis and degradation

Cited by 46 publications

References 61 publications

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

Sodium valproate inhibits MDA-MB-231 breast cancer cell migration by upregulating NM23H1 expression

Enteric Bacterial Metabolites Propionic and Butyric Acid Modulate Gene Expression, Including CREB-Dependent Catecholaminergic Neurotransmission, in PC12 Cells - Possible Relevance to Autism Spectrum Disorders

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