ATYPICAL ANTIPSYCHOTICS OLANZAPINE DECREASES BRAIN ARACHIDONIC ACID METABOLISM BY REDUCING ITS PLASMA AVAILABILITY. Olanzapine, an atypical antipsychotic drug, is F approved for treating bipolar disorder (BD), and psychosis in Alzheimer disease patients and schizophrenia, but its therapeutic mechanism of action is not agreed on. We hypothesized that, like mood stabilizers, chronic olanzapine would decrease brain arachidonic acid (AA) metabolism in rats. We administered olanzapine to male rats once daily for 21 days, and determined its effect or that of vehicle (saline) on the brain AA metabolism using our kinetic model. A washout group received 21 days of olanzapine, followed by vehicle on day 22. After the last injection, 1-14CAA was infused intravenously, and arterial plasma was sampled and the brain analyzed. Olanzapine decreased unesterified fatty acid concentrations in plasma after 21 days, but this effect was absent after washout. Olanzapine also decreased incorporation rates of AA into brain choline glycerophospholipids (ChoGpl), phosphatidylinositol and neutral lipids, but not after washout. Thus, olanzapine, like approved mood stabilizers, reduced rat brain AA metabolism, which may contribute to f its therapeutic action, as AA metabolic markers are upregulated in bipolar disorder brain (Cheon et al., In press). ANTIDEPRESSANTS CHRONIC IMIPRAMINE BUT NOT BUPROPION INCREASES ARACHIDONIC ACID SIGNALING IN RAT BRAIN: RELATION TO 'SWITCHING'IN BIPOLAR DISORDER Agents effective against bipolar mania decrease turnover of arachidonic acid (AA) in phospholipids and expression of AA-selective cytosolic phospholipase A2 (cPLA2) in rat brain. In contrast, fluoxetine, an antidepressant that can switch bipolar depression to mania, increases cPLA2 expression and AA turnover in rat brain. We hypothesized that other antidepressants that increase switching also increase cPLA2 and AA turnover. To test this, male rats were administered imipramine and bupropion, with reported high and low switching rates, respectively, or saline (control) for 21 days. Brain expression of PLA2 enzymes and AA turnover rates were measured. Compared with saline, chronic imipramine but not bupropion increased cPLA2 mRNA activity, protein and phosphorylation, expression of the cPLA2 transcription factor, activator protein-2alpha ,and AA turnover in phospholipids. These results, taken with data on chronic fluoxetine, suggest that antidepressants that increase switching tendency of bipolar depressed patients to mania do so by increasing AA recycling and metabolism in brain. Bipolar mania thus may involve upregulated brain AA metabolism (Lee et al., 2010). MOOD STABILIZERS LAMOTRIGINE BLOCKS NMDA RECEPTOR-INITIATED ARACHIDONIC ACID SIGNALING IN RAT BRAIN: IMPLICATIONS FOR ITS EFFICACY IN BIPOLAR DISORDER. N-methyl-d-aspartate receptors (NMDARs) allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release AA from membrane phospholipid. We hypothesized that lamotrigine (LTG), like other approved mood stabilizers, would reduce NMDAR-mediated AA signaling in the brain, thought to be upregulated in bipolar disorder (BD). NMDA or saline was administered acutely to unanesthetized rats that had been treated p.o. daily for 42 days with vehicle or a therapeutically relevant dose of LTG. Regional brain AA incorporation coefficients k* and rates Jin, AA signals, were measured using quantitative autoradiography after intravenous 1-14CAA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, NMDA compared to saline increased k* and Jin in widespread brain regions, prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA-binding activity of the COX-2 transcription factor, NF-kappaB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signaling involving AA. Since AA cascade and of NMDAR signaling markers are upregulated in the BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signaling and the AA cascade (Ramadan et al., 2011). CHRONIC VALPROATE TREATMENT BLOCKS D2-LIKE RECEPTOR-MEDIATED BRAIN SIGNALING VIA ARACHIDONIC ACID IN RATS. Lithium and carbamazepine, approved for BD, attenuate brain dopaminergic D2-like receptor signaling involving arachidonic acid (AA) in unanesthetized rats. We hypothesized that valproate (VPA), with mood-stabilizing properties, would also reduce this signaling. An acute dose of quinpirole or saline was administered to unanesthetized rats that had been treated with a therapeutically relevant dose of VPA or vehicle. Regional brain AA incorporation coefficients, k*, and rates, Jin, markers of AA signaling, were measured by quantitative autoradiography after intravenous 1-14CAA infusion, as were prostaglandin (PG)E2 and thromboxane (TX)B2 concentrations. Quinpirole compared to saline significantly increased k* in brain regions with D2 receptors, and the concentration PGE2 in chronic vehicle-treated rats. VPA treatment reduced concentrations of plasma unesterified AA and whole brain PGE2 and TXB2, and blocked the quinpirole-induced increments in k* and PGE2. These results further support our hypothesis that similar to lithium and carbamazepine, VPA downregulates brain dopaminergic D2-like receptor-signaling involving AA (Ramadan et al., In press). VALPROATE UNCOMPETITIVELY INHIBITS ARACHIDONIC ACID ACYLATION BY RAT ACYL-COA SYNTHETASE 4 The ability of valproate (VPA) to reduce arachidonic acid (AA) turnover in brain phospholipids of unanesthetized rats was ascribed to its inhibition of acyl-CoA synthetase (Acsl)-mediated activation of AA to AA-CoA. We identified a unique rat Acsl isoenzyme that could be inhibited by VPA in vitro as the likely target, Acsl4, using different enzyme flag expressed in E. coli. VPA inhibition of activation of long-chain fatty acids to acyl-CoA was estimated using Michaelis-Menten kinetics, and shown to be uncompetitive for AA and docosahexaenoic (DHA). Acsl4-mediated conversion of AA to AA-CoA showed substrate inhibition and high catalytic efficiency. These findings, likely account for VPA's selective reduction of AA turnover in rat brain phospholipids, and contribute to VPA's efficacy against bipolar disorder (Shimshoni et al., 2011). ASPIRIN ASPIRIN ENHANCES LITHIUM S EFFICACY IN BIPOLAR DISORDER Using a pharmacological database, we showed that aspirin enhanced anti-bipolar disorder effects of lithium treatment, consistent with common ability of aspirin and lithium to downregulate brain arachidonic acid (AA) metabolism and increase docosahexaenoic acid metabolism in rats. We showed by pharmacoepidemiological analysis that low dose aspirin significantly reduced the number of medical events (dose increase or addition of antipsychotic agent) in patients treated with lithium, whereas other nonsteroidal antiinflammatory drugs and glucocorticoids did not. These findings support our proposal of upregulated brain AA metabolism in bipolar disorder, and suggest that lithium plus aspirin might be considered for this disease as well as neuroinflammatory diseases such as Alzheimer disease (Stolk et al., 2010).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000150-04
Application #
8335772
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$494,309
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
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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
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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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