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

Rabbit heart has a single, non-specific, fatty acyl-CoA synthetase (HP1) which is dependent on Mg2+, apart from the requirement for MgATP2-. Two long-chain fatty acyl-CoA synthetase activities (LP1 and LP2) can be resolved by hydroxyapatite chromatography of liver preparations; the Mg2+ requirement for these enzymes is undefined. These experiments were done to define the Mg2+ requirements of the liver enzymes and to compare them with the heart enzyme. For all three sources of enzyme and for arachidonic, oleic and palmitic acid substrates, the overall velocity of the reaction increased as [Mg2+] increased. Depending on the substrate and the source of enzyme, the increase in overall velocity could be attributed to changes in affinity or maximal velocity or both. The substrate preference of the HP1 enzyme for arachidonic acid (AA) was fifth or sixth of eight substrates regardless of the concentration of Mg2+. In contrast, increasing [Mg2+] shifted the relative substrate preference of both liver enzymes for AA. At low [Mg2+], AA was ranked seventh or eighth (least preferred) of eight substrates, whereas at high [Mg2+], AA was ranked as fifth or sixth. Hill plots of competition studies were consistent with Mg2+-induced positive co-operativity in LP1, but not in HP1 or LP2. Although enzymes from the three sources exhibit substantial kinetic differences, it is uncertain whether they are three different enzymes.

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Effects of Long-Chain Fatty Acyl-CoA Synthetase 1 on Diglyceride Synthesis and Arachidonic Acid Metabolism in Sheep Adipocytes

International Journal of Molecular Sciences ◽

10.3390/ijms21062044 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2044

Author(s):

Yang Cao ◽

Sutian Wang ◽

Shunqi Liu ◽

Yanli Wang ◽

Haiguo Jin ◽

...

Keyword(s):

Arachidonic Acid ◽

Acid Metabolism ◽

Fatty Acyl ◽

Arachidonic Acid Metabolism ◽

Rna Seq ◽

Triglyceride Content ◽

Metabolome Profiling ◽

Essential Enzyme ◽

Cox2 Expression ◽

Long Chain

Long-chain fatty acyl-CoA synthetase (ACSLs) is an essential enzyme for the synthesis of fatty acyl-CoA. ACSL1 plays a key role in the synthesis of triglycerides, phospholipids, and cholesterol esters. Background: In the current study, triglyceride content did not increase after overexpression of the ACSL1 gene. Methods: RNA-seq and lipid metabolome profiling were performed to determine why triglyceride levels did not change with ACSL1 overexpression. Results: Fatty acyl-CoA produced by ACSL1 was determined to be involved in the diglyceride synthesis pathway, and diglyceride content significantly increased when ACSL1 was overexpressed. Moreover, the arachidonic acid (AA) content in sheep adipocytes significantly increased, and the level of cyclooxygenase 2 (COX2) expression, the downstream metabolic gene, was significantly downregulated. Knocking down the ACSL1 gene was associated with an increase in COX2 mRNA expression, as well as an increase in prostaglandin content, which is the downstream metabolite of AA. Conclusions: The overexpression of the ACSL1 gene promotes the production of AA via downregulation of COX2 gene expression.

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Is the brain arachidonic acid cascade a common target of drugs used to manage bipolar disorder?

Biochemical Society Transactions ◽

10.1042/bst0371104 ◽

2009 ◽

Vol 37 (5) ◽

pp. 1104-1109 ◽

Cited By ~ 14

Author(s):

Richard P. Bazinet

Keyword(s):

Bipolar Disorder ◽

Valproic Acid ◽

Arachidonic Acid ◽

Rat Brain ◽

Bipolar Depression ◽

Chronic Administration ◽

Mood Stabilizers ◽

Arachidonic Acid Cascade ◽

Brain Phospholipids ◽

The Brain

Although lithium has been used therapeutically to treat patients with bipolar disorder for over 50 years, its mechanism of action, as well as that of other drugs used to treat bipolar disorder, is not agreed upon. In the present paper, I review studies in unanaesthetized rats using a neuropharmacological approach, combined with kinetic, biochemical and molecular biology techniques, demonstrating that chronic administration of three commonly used mood stabilizers (lithium, valproic acid and carbamazepine), at therapeutically relevant doses, selectively target the brain arachidonic acid cascade. Upon chronic administration, lithium and carbamazepine decrease the binding activity of activator protein-2 and, in turn, the transcription, translation and activity of its arachidonic acid-selective calcium-dependent phospholipase A2 gene product, whereas chronic valproic acid non-competitively inhibits long-chain acyl-CoA synthetase. The net overlapping effects of the three mood stabilizers are decreased turnover of arachidonic acid, but not of docosahexaenoic acid, in rat brain phospholipids, as well as decreased brain cyclo-oxygenase-2 and prostaglandin E2. As an extension of this theory, drugs that are thought to induce switching to mania, especially when administered during bipolar depression (fluoxetine and imipramine), up-regulate enzymes of the arachidonic acid cascade and turnover of arachidonic acid in rat brain phospholipids. Future basic and clinical studies on the arachidonic acid hypothesis of bipolar disorder are warranted.

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Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: A potential drug for bipolar disorder

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2013.01.008 ◽

2013 ◽

Vol 1831 (4) ◽

pp. 880-886 ◽

Cited By ~ 4

Author(s):

Hiren R. Modi ◽

Mireille Basselin ◽

Ameer Y. Taha ◽

Lei O. Li ◽

Rosalind A. Coleman ◽

...

Keyword(s):

Bipolar Disorder ◽

Valproic Acid ◽

Arachidonic Acid ◽

Potential Drug

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Delirium Secondary to Lamotrigine Toxicity

Current Drug Safety ◽

10.2174/1574886315666200225111057 ◽

2020 ◽

Vol 15 (2) ◽

pp. 156-159 ◽

Cited By ~ 1

Author(s):

Deborah L. Sanchez ◽

Adam J. Fusick ◽

Steven R. Gunther ◽

Michael J. Hernandez ◽

Gregory A. Sullivan ◽

...

Keyword(s):

Bipolar Disorder ◽

Valproic Acid ◽

Mental Status ◽

The United States ◽

Clinical Correlation ◽

Medication Regimen ◽

Medication Effects ◽

United States Food ◽

States Food ◽

Rule Out

Background: Lamotrigine is a phenyltriazine medication that has been approved by the United States Food and Drug Administration as monotherapy and as an adjunctive agent for the treatment of seizure disorder. It was later approved by the FDA for the treatment of bipolar disorder. Lamotrigine is generally well tolerated by patients, but some serious symptoms can occur during treatment. These severe side effects include rashes and multi-organ failure. Lamotrigine has also been associated with the development of mental status changes, frequently when used concurrently with other medications that may impact the metabolism of lamotrigine. Objective: To present the case of a 65-year-old man being treated with lamotrigine and valproic acid who developed mental status changes after the addition of sertraline to his medication regimen, and to compare this case to existing cases reported in the literature. Discussion: Our case adds to the existing literature by demonstrating that patients may experience adverse medication effects despite lamotrigine levels that are normally considered to be in the therapeutic range, highlighting the importance of clinical correlation when obtaining medication levels. Conclusion: Clinicians should use caution interpreting lamotrigine levels when working up delirium, as normal levels may not rule out the development of lamotrigine toxicity.

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