I. MOOD STABILIZERS LITHIUM AND THE OTHER MOOD STABILIZERS EFFECTIVE IN BIPOLAR DISORDER TARGET THE RAT BRAIN ARACHIDONIC ACID CASCADE. A critical review evaluated the arachidonic acid (AA, 20:4n-6) cascade hypothesis for 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 is consistent with 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, which are 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 switch BD depression to mania, 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 our 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. (3) II. TESTING NONTERATOGENIC SUBSTITUTES FOR VALPROATE IN TREATING BIPOLAR DISORDER VALNOCTAMIDE, A NON-TERATOGENIC AMIDE DERIVATIVE OF VALPROIC ACID, INHIBITS ARACHIDONIC ACID ACTIVATION IN VITRO BY RECOMBINANT ACYL-COA SYNTHETASE-4. Valproic acid (VPA), a mood stabilizer used in bipolar disorder (BD), uncompetitively inhibits acylation of arachidonic acid (AA) by recombinant AA-selective acyl-CoA synthetase 4 (Acsl4) at an enzyme inhibition constant (Ki ) of 25 mM. Inhibition may account for VPA's therapeutic effect against BD. However, VPA is teratogenic. We tested whether valnoctamide (VCD), a non-teratogenic amide derivative of a VPA chiral isomer, which had antimanic potency in a phase III BD trial, also inhibits recombinant Acsl4. Rat Acsl4-flag protein was expressed in Escherichia coli. Using Michaelis-Menten kinetics, we showed that activation of AA to AA-CoA by Acsl4 was inhibited uncompetitively by VCD, with a Ki of 6.38 mM. at a lower Ki than VPA, VCD and other non-teratogenic Acsl4 inhibitors might be considered further for treating BD. (1) DOES CHRONIC VALNOCTAMIDE INHIBIT ARACHIDONIC ACID TURNOVER IN BRAIN OF UNANESTHETIZED RAT? As a follow up, we are testing whether valnoctamide (VCD), which inhibits Acsl4 in vitro, also reduces AA turnover in unanesthetized rats, as does valproate and lithium. If so, we would apply for a use patent for it as a non-teratogenic analog of valproate for less toxic treatment of bipolar disorder. III. DRUG EFFECTS ON BRAIN ARACHIDONATE METABOLISM TRANSIENT POSTNATAL FLUOXETINE DECREASES BRAIN ARACHIDONIC ACID METABOLISM AND CYTOCHROME P450 4A IN ADULT MICE. Fetal and perinatal exposure to selective serotonin (5-HT) reuptake inhibitors (SSRIs) have been reported to alter childhood behavior, while transient postnatal exposure in rodents alters behavior and decreases brain 5-HT in adulthood. In this study, we tested whether transient postnatal exposure to fluoxetine also alters brain arachidonic acid (AA) metabolism in adult mice. Brain AA incorporation coefficients k* and rates Jin were imaged following intravenous 1-14CAA infusion of unanesthetized adult mice that had been injected daily with fluoxetine (10mg/kg i.p.) or saline during postnatal days P4-P21. Brain AA metabolic enzymes and other relevant markers also were measured. On neuroimaging, k* and Jin were decreased widely in early fluoxetine- compared to saline-treated adult mice. AA-selective cPLA2 activity was unchanged, while Ca(2+)-independent iPLA2 activity was increased. Importantly, there was a significant 74% reduced protein level of cytochrome P450 (CYP) 4A, which can convert AA to bioactive 20-hydroxyeicosatetraenoic acid (HETE). These changes might contribute to the reported altered behavior following early SSRIs in rodents or humans. (3). TRANSIENT POSTNATAL FLUOXETINE REDUCES CYTOCHROME P450 4A METABOLITES IN ADULT MICE. As a follow up study, we are using ELISA to examine arachidonic acid (AA) metabolites in brains of adult mice treated postnatally at P4-P21 with fluoxetine. We are finding reduced concentrations of cytochrome P450 4A metabolites, as predicted by that study, namely bioactive 20-hydroxyeicosatetraenoic acid (HETE) and 15-epi-(lipoxin) LXA4. Behavioral effects in adulthood of early fluoxetine exposure may be mediated in part by disturbed metabolism of AA through the cytochrome P450 pathway. Research is in progress. LOW-DOSE ASPIRIN DAMPENDS INFLAMMATION-INDUCED INCREMENTS IN BRAIN ARACHIDONIC ACID METABOLITES IN OLD HIV-1 TRANSGENIC RAT. Even HIV-1 patients treated with antiretroviral therapy are at risk of developing HIV-1-associated neurocognitive disorder (HAND). Older HIV-1 transgenic rats that develop behavioral changes and show neuroinflammation, neuronal loss, and increased brain arachidonic acid (AA) metabolism, are a model for HAND. We are showing that chronic low-dose aspirin (equivalent to a human low dose) reduces upregulated brain AA metabolism in HIV-1 transgenic rats. Wildtype and HIV-1 transgenic rats, aged 7-9 months, were treated for an additional 42 days with 10 mg/kg/day (equivalent to human low-dose) aspirin in drinking water, then were subjected to head-focused microwave fixation. ELISA measurements showed that brain 15-epi-lipoxin A4 and 8-isoprostane concentrations were significantly higher in the HIV-1 transgenic than wildtype rats. These differences were insignificant following aspirin. Aspirin also reduced brain prostaglandin E2 and leukotriene B4 concentrations in HIV-1 Tg but not wildtype rats. Thromboxane B2, 15-HETE, lipoxin A4 and resolvin D1 concentrations were unrelated to genotype or treatment. Treatment with low-dose aspirin reduces AA-metabolite markers of inflammation and oxidative stress in HIV-1 Tg brain, and might be considered in clinical trials in HIV-1 patients with HAND. Work submitted for publication.

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Kim, Helena K; Isaacs-Trepanier, Cameron; Elmi, Nika et al. (2016) Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment. J Psychiatr Res 76:59-65
Blanchard, Helene C; Taha, Ameer Y; Rapoport, Stanley I et al. (2015) Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders. Prostaglandins Leukot Essent Fatty Acids 96:25-30
Blanchard, Helene; Chang, Lisa; Rezvani, Amir H et al. (2015) Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression. Neurochem Res 40:2293-303
Yuan, Zhi-Xin; Rapoport, Stanley I (2015) Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice. Prostaglandins Leukot Essent Fatty Acids 101:9-14
Rapoport, Stanley I (2014) Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. ACS Chem Neurosci 5:459-67
Modi, Hiren R; Basselin, Mireille; Rapoport, Stanley I (2014) Valnoctamide, a non-teratogenic amide derivative of valproic acid, inhibits arachidonic acid activation in vitro by recombinant acyl-CoA synthetase-4. Bipolar Disord 16:875-80
Ramadan, Epolia; Blanchard, Helene; Cheon, Yewon et al. (2014) Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice. Prostaglandins Leukot Essent Fatty Acids 90:191-7
Modi, Hiren R; Taha, Ameer Y; Kim, Hyung-Wook et al. (2013) Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability. J Neurochem 124:376-87
Modi, Hiren R; Basselin, Mireille; Taha, Ameer Y et al. (2013) 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. Biochim Biophys Acta 1831:880-6
Ramadan, Epolia; Basselin, Mireille; Rao, Jagadeesh S et al. (2012) Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder. Int J Neuropsychopharmacol 15:931-43

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