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 (Basselin et al. 2008).? ? CARBAMAZEPINE ATTENUATES DOPAMINE D2-LIKE RECEPTOR-INITIATED SIGNALING VIA ARACHIDONIC ACID? Dopamine D2-like receptor mediated signaling involving arachidonic acid (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 (Basselin et al. 2007a).? ? CHRONIC LITHIUM ADMINISTRATION ATTENUATES UPREGULATED BRAIN ARACHIDONIC ACID METABOLISM DURING NEUROINFLAMMATION? Neuroinflammation, caused by cerebroventricular infusion of lipopolysaccharide (LPS), upregulated rat brain arachidonic acid (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 (Basselin et al., 2007b).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000150-01
Application #
7732148
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2008
Total Cost
$269,944
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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