Gabapentin's minimal action on markers of rat brain arachidonic acid metabolism agrees with its inefficacy against bipolar disorder

Reese, Edmund A.; Cheon, Yewon; Ramadan, Epolia; Kim, Hyung‐Wook; Chang, Lisa; Rao, Jagadeesh S.; Rapoport, Stanley I.; Taha, Ameer Y.

doi:10.1016/j.plefa.2012.06.003

Cited by 7 publications

(5 citation statements)

References 53 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These differences distinguish between anticonvulsant activity and anti-BD activity of these drugs, and suggest that they have different mechanisms of action in each of the two disorders. Similarly, the clinically useful anticonvulsants, topiramate and gabapentin, do not measurably affect rat brain AA metabolism [63–66]. …”

Section: Discussionmentioning

confidence: 99%

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

Modi

Basselin

Taha

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

Self Cite

View full text Add to dashboard Cite

Background Mood stabilizers used for treating bipolar disorder (BD) selectively downregulate arachidonic acid (AA) turnover (deacylation-reacylation) in brain phospholipids, when given chronically to rats. In vitro studies suggest that one of these, valproic acid (VPA), which is teratogenic, reduces AA turnover by inhibiting the brain acyl-CoA synthetase (Acsl)-4 mediated acylation of AA to AA-CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl-4 catalyzed acylation, and thus have potential anti-BD action. Methods Rat Acsl4-flag protein was expressed in E. coli, and the ability of three VPA analogues, propylisopropylacetic acid (PIA), propylisopropylacetamide (PID) and N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (MTMCD), and of sodium butyrate, to inhibit conversion of AA to AA-CoA by Acsl4 was quantified using Michaelis-Menten kinetics. Results Acsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a Ki of 11.4 mM compared to a published Ki of 25 mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect. Conclusions PIA's ability to inhibit conversion of AA to AA-CoA by Acsl4 in vitro suggests that, like VPA, PIA may reduce AA turnover in brain phospholipids in unanesthetized rats, and if so, may be effective as a non-teratogenic mood stabilizer in BD patients.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Modi

Basselin

Taha

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

Self Cite

View full text Add to dashboard Cite

show abstract

“…At the resting state, it is thought that PGE 2 is produced from AA primarily via COX-2, TXB 2 via COX-1 . Lithium, lamotrigine or gabapentin did not change the rat brain TXB 2 concentration, while carbamazepine and VPA each reduced TXB 2 . ,,, Additionally, neither valproate nor carbamazepine altered 5-LOX or its product leukotriene B 4 (LTB 4 ), and carbamazepine did not change CYP450 …”

Section: Effects Of Drugs Used In Bipolar Disorder On Arachidonic Aci...mentioning

confidence: 99%

“…44 In contrast to the overlapping actions of the four FDA approved mood stabilizers, the antiepileptic topiramate (2,3:4,5bis-O-(1-methylethylidene)-β-D-fructopyranose 1-sulfamate), which failed in phase III trials in BD I patients, did not change any measured rat brain AA cascade marker, 45 nor did gabapentin (1-(aminomethyl)cyclohexaneacetic acid), which also lacks efficacy. 41 Thus, the AA cascade model for lithium's action has a strong clinical-experimental correlation based on the rat studies with the six drugs.…”

Section: Effects Of Drugs Used In Bipolar Disordermentioning

confidence: 99%

Lithium and the Other Mood Stabilizers Effective in Bipolar Disorder Target the Rat Brain Arachidonic Acid Cascade

Rapoport

2014

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

This Review evaluates the arachidonic acid (AA, 20:4n-6) cascade hypothesis for the actions of lithium and other FDA-approved mood stabilizers in bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered lithium, carbamazepine, valproate, or lamotrigine each downregulated brain AA metabolism, and it is consistent with reported upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain phospholipids, cyclooxygenase-2 expression, and prostaglandin E2 concentration. Lithium and carbamazepine also reduced expression of cytosolic phospholipase A2 (cPLA2) IVA, which releases AA from membrane phospholipids, whereas valproate uncompetitively inhibited in vitro acyl-CoA synthetase-4, which recycles AA into phospholipid. Topiramate and gabapentin, proven ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical antipsychotics olanzapine and clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic NMDA and dopaminergic D2 receptor activation, while lithium enhanced the signal during cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the antidepressants fluoxetine and imipramine, which tend to switch BD depression to mania, each increased AA turnover and cPLA2 IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD mania than depression. The AA hypothesis for mood stabilizer action is consistent with reports that low-dose aspirin reduced morbidity in patients taking lithium, and that high n-3 and/or low n-6 polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD and migraine patients.

show abstract

“…54 Other anti-epileptic drugs with clinically-proven anti-manic efficacy (carbamazepine, valproate, lamotrigine) also downregulated the rat brain AA metabolic cascade, 55–57 while topiramate or gabapentin, anti-epileptic medications that have failed phase 3 trials, did not. 4,58–60 Synthesizing these data has led to the hypothesis that therapeutic downregulation of the AA cascade can be tied specifically to effective treatment of BD. Intervention could involve drugs (see above) as well and changing the PUFA content of the diet (see below).…”

Section: Anti-manic Medications Alter Aa Metabolismmentioning

confidence: 99%

Reconsidering Dietary Polyunsaturated Fatty Acids in Bipolar Disorder: A Translational Picture

Saunders

Ramsden

Sherazy

et al. 2016

J. Clin. Psychiatry

Self Cite

View full text Add to dashboard Cite

Inflammation is an important mediator of pathophysiology in bipolar disorder (BD). The omega (n)-3 and omega (n)-6 polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes, and have been linked through epidemiological and clinical studies to BD and its response to treatment. We review the proposed role of PUFA metabolism in neuroinflammation, modulation of brain PUFA metabolism by antimanic medications in rodent models, and anti-inflammatory pharmacotherapy in BD and in major depressive disorder (MDD). Though the convergence of findings between pre-clinical and post-mortem clinical data is compelling, we investigate why human trials of PUFA as treatment are mixed. We view the biomarker and treatment study findings in light of the evidence for the hypothesis that arachidonic acid (AA) hypermetabolism contributes to BD pathophysiology, and propose that a combined high n-3 plus low n-6 diet should be tested as an adjunct to current medication in future trials.

show abstract

Gabapentin's minimal action on markers of rat brain arachidonic acid metabolism agrees with its inefficacy against bipolar disorder

Cited by 7 publications

References 53 publications

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

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

Lithium and the Other Mood Stabilizers Effective in Bipolar Disorder Target the Rat Brain Arachidonic Acid Cascade

Reconsidering Dietary Polyunsaturated Fatty Acids in Bipolar Disorder: A Translational Picture

Contact Info

Product

Resources

About