Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition

Jeong, Mi Ra; Hashimoto, Ryota; Senatorov, Vladimir V.; Fujimaki, Koichiro; Ren, Ming; Lee, Min Soo; Chuang, De‐Maw

doi:10.1016/s0014-5793(03)00350-8

Cited by 115 publications

(75 citation statements)

References 20 publications

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“…3) the effect of second-generation tVPA drugs on the stimulation of total hemoglobin production in individuals with ␤-thalassemia and sickle cell diseases; 4) the role of VPA and second-generation VPA drugs in mediating the neuroprotective action of cortical neurons from spontaneous cell deaths; 64 5) research into the basic neurological mechanisms of brain physiology and novel pharmacotherapies for the treatment of pain and bipolar disorder by VPA analogues and derivatives.…”

Section: Future Directionsmentioning

confidence: 99%

Valproic Acid: Second Generation

2007

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Summary:The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become secondgeneration VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.

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Section: Future Directionsmentioning

confidence: 99%

Valproic Acid: Second Generation

2007

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“…The classical group of HDIs include short chain fatty acids (such as 4-phenylbutyrate and valproic acid), hydroxamic acids (such as suberoylanilide hydroxamic acid or SAHA, pyroxamide, trichostatin A or TSA, oxamflatin and CHAPs), cyclic tetrapeptides (such as trapoxin, apicidin and depsipeptide-also known as FK-228 or FR 901228), benzamides (such as MS-275) and a variety of other chemical compounds (6)(7)(8)(9). HDIs have been identified in natural sources, and synthetic inhibitors are also available (Table I).…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

Kouraklis¹,

Theocharis²

2006

Oncol Rep

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Abstract. Accumulating evidence suggests that the acetylation and deacetylation of histones play significant roles in transcriptional regulation of eukaryotic cells. The balance between acetylation and deacetylation is an important factor in regulating gene expression and is thus linked to the control of cell fate. The histone deacetylase inhibitors (HDIs) including the hydroxamic acids, such as suberoylanilide hydroxamic acid and pyroxamide, the benzamides MS-275 and CI-994 and the butyrate derivative 4-PBA are a new class of anti-neoplastic agents currently being evaluated in clinical trials. Moreover, new synthetic HDIs have been used recently in phase I and II clinical trials. Over the next few years experts believe that as first generation HDIs produce clinical benefits and second generation inhibitors are rationally designed with improved specificity, this class of drugs will emerge as a new way of cancer treatment. The first clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to become possible. The use of HDIs, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising for cancer patients. Further evaluation is needed to establish the clinical activity of combination therapy using HDIs with cytotoxic drugs or differentiation induced agents.

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“…2 Valproic acid as well as lithium have shown protective effects on neural tissue in vivo and in vitro. [3][4][5][6] Both medications have also been found to regulate biochemical processes involved in cellular protection. 7,8 Furthermore, in vivo magnetic resonance spectroscopy (MRS) of the brain has provided evidence for a neurotrophic/neuroprotective effect of lithium in patients.…”

Section: Introductionmentioning

confidence: 99%

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

et al. 2008

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Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, 1 H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use 1 H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and c-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

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Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition

Cited by 115 publications

References 20 publications

Valproic Acid: Second Generation

Valproic Acid: Second Generation

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

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