Impact on the AA cascade.35 Additional downstream in the cascade (Figure 1), COX-2 colocalizes and is functionally coupled with cPLA2 IVA at postsynaptic web sites in brain.36 Each in the 4 mood stabilizers lowered brain COX-2 activity and PGE2 concentration when provided chronically to rats (Table 2). Chronic lithium did not decrease NF-B in the intact rat,37 but does so in neuroblastoma SH-SY5Y cells in vitro.38 Valproate and lamotrigine furthermore reduced COX-2 protein and mRNA as well as the COX-2 transcription factor, NF-B.1a Chronic valproate also decreased brain mRNA levels for 87 genes and improved levels for 34 genes by no less than 40 , indicating that its AA cascade effects are embedded in a number of other brain adjustments.37a Lithium’s selectivity for the COX-2 pathway was illustrated by displaying that it did not modify expression of COX-1, 5-LOX, CYP450, or membrane PGE synthase-2 (mPGES-2) in rat brain.39 At the resting state, it can be believed that PGE2 is created from AA primarily by way of COX-2, TXB2 via COX-1.40 Lithium, lamotrigine or gabapentin didn’t adjust the rat brain TXB2 concentration, while carbamazepine and VPA each decreased TXB2.24c,d,26c,41 Additionally, neither valproate nor carbamazepine altered 5-LOX or its product leukotriene B4 (LTB4), and carbamazepine did not modify CYP450.42 An unexpected and as but incompletely understood observation was that chronic lithium elevated rat brain concentration of antiinflammatory 17-hydroxy-DHA along with other as yet unidentified DHA metabolites.43 This elevation may perhaps contribute to the reported synergy among aspirin and lithium in BD patients, given that 17-hydroxy-DHA is formed from DHA by acetylated COX2 following exposure to aspirin (see under).dx.doi.org/10.1021/cn500058v | ACS Chem. Neurosci. 2014, five, 459-ACS Chemical Neuroscience In contrast to the overlapping actions of the four FDA approved mood stabilizers, the antiepileptic topiramate (2,3:4,5bis-O-(1-methylethylidene)–D-fructopyranose 1-sulfamate), which failed in phase III trials in BD I patients, didn’t adjust any measured rat brain AA cascade marker,45 nor did gabapentin (1-(aminomethyl)cyclohexaneacetic acid), which also lacks efficacy.1-Hydroxy-7-azabenzotriazole Formula 41 Hence, the AA cascade model for lithium’s action has a strong clinical-experimental correlation depending on the rat studies together with the six drugs. two.2. Antidepressants That Switch Bipolar Depression to Mania Improve Rat Brain AA Metabolism. The AA cascade hypothesis has relevance for the effects of specific antidepressants and atypical antipsychotics in BD.1217725-33-1 web 1b,11b As an example, the tricyclic antidepressant imipramine as well as the selective serotonin reuptake inhibitor (SSRI) fluoxetine are reported to enhance “switching” of bipolar depression to mania when applied as monotherapy or with mood stabilizers.PMID:24458656 46 Bupropion, also an antidepressant but a norepinephrine and dopamine reuptake inhibitor and nicotinic antagonist, will not improve switching.46 These clinical distinctions correlated together with the unique effects in the 3 drugs on rat brain AA metabolism. Hence, chronic fluoxetine and imipramine at therapeutically relevant doses increased AA turnover in rat brain phospholipids, also as expression (activity, protein, mRNA, and phosphorylation) of cPLA2 IVA and of its transcription aspect subunit, AP-2,47 whereas chronic bupropion had no comparable impact. These final results imply that the manic or hypomanic phase of BD has a higher brain AA metabolic price than does the depression phase, a hypothesis that can be tested directl.