VALPROIC ACID REDUCES BRAIN NMDA SIGNALING VIA ARACHIDONIC ACID Brain glutamatergic function is elevated in bipolar disorder, and elevated glutamatergic function is associated with excitotoxicity and neuroinflammation in rat brain. Chronic administration to rats of the anti-bipolar agent, valproic acid, prevented increased brain signaling involving arachidonic acid (AA), caused by acute injection of the glutamate receptor antagonist, N-methyl-D-aspartate (NMDA). These results, plus evidence that chronic carbamazepine and lithium also blocked AA responses to NMDA in rat brain, suggest that mood stabilizers downregulate AA metabolism in bipolar disorder in part by blocking NMDA-receptor mediated activation of cytosolic phospholipase A2 and release of AA (Ref. 1). CARBAMAZEPINE ATTENUATES DOPAMINE D2-LIKE RECEPTOR-INITIATED SIGNALING VIA ARACHIDONIC ACID Dopamine D2-like receptor mediated signaling involving AA was downregulated in rats treated chronically with carbamazepine, a mood stabilizer approved for bipolar disorder. The findings are consistent with mood stabilizers acting in bipolar disorder by downregulating brain AA metabolism and interfering with dopamine neurotransmission (Ref. 2). CHRONIC LITHIUM ADMINISTRATION ATTENUATES UPREGULATED BRAIN ARACHIDONIC ACID METABOLISM DURING NEUROINFLAMMATION Neuroinflammation, caused by cerebroventricular infusion of lipopolysaccharide (LPS), upregulated rat brain AA metabolic markers, including AA incorporation into brain on neuroimaging, brain cytoplasmic phospholipase A2 activity, and prostaglandin E2 and thromboxane B2 concentrations. Pretreatment with lithium, a mood stabilizer, prevented this upregulation. To the extent that increased brain AA metabolism associated with neuroinflammation has neuropathological consequences, lithium might be considered for treating Alzheimer disease and other human diseases associated with neuroinflammation. ASPIRIN MAY BE USEFUL IN BIPOLAR DISORDER We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, also would ameliorate BD symptoms. Medication histories on subjects who had been prescribed lithium were collected from the Netherlands PHARMO Record Linkage System. Data were stratified according to drug classes that inhibit PLA2 and/or COX enzymes, and duration of use. Incidence density (ID) of medication events (dose increase or substance change) was used as a proxy for clinical worsening. ID ratios in patients with the inhibitors plus lithium were compared to ratios in patients using lithium alone. Low-dose acetylsalicylic acid (aspirin) significantly reduced the ID ratio of medication events, independent of use duration. The ID ratios of NSAIDs and glucocorticoids did not differ significantly from 1.0 if prescribed for ≥180 or ≥90 days, but exceeded 1.0 with shorter use. Selective COX-2 inhibitors had no significant effect and multiagent administration increased the ID ratio above 1.0. Low-dose aspirin produced a statistically significant duration-independent reduction in the relative risk of clinical deterioration in subjects on lithium, whereas other NSAIDs and glucocorticoids did not. These tentative findings could be tested on larger databases containing detailed information about diagnosis and disease course, as well as by controlled clinical trials (Ref. 3).
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