Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder?
BACKGROUND
Lithium and certain anticonvulsants, including carbamazepine and valproic acid, are effective antimanic drugs for treating bipolar disorder, but their mechanisms of action remain uncertain.
Feeding rats lithium chloride for 6 weeks, to produce a brain lithium concentration of 0.7mM, reduced arachidonic acid turnover within brain phospholipids by 75%. The effect was highly specific, as turnover rates of docosahexaenoic acid and palmitic acid were unaffected. Arachidonate turnover in rat brain also was reduced by long-term valproic acid administration. Lithium's reduction of arachidonate turnover corresponded to its down-regulating gene expression and enzyme activity of cytosolic phospholipase A(2), an enzyme that selectively liberates arachidonic but not docosahexaenoic acid from phospholipids. Lithium also reduced the brain protein level and activity of cyclooxygenase 2, as well as the brain concentration of prostaglandin E(2), an arachidonate metabolite produced via cyclooxygenase 2.


CONCLUSIONS
These results give rise to the hypothesis that lithium and antimanic anticonvulsants act by targeting parts of the "arachidonic acid cascade," which may be functionally hyperactive in mania. Thus, drugs that target enzymes in the cascade, such as cyclooxygenase 2 inhibitors, might be candidate treatments for mania. Also, in view of competition between arachidonic and docosahexaenoic acids in a number of functional processes, docosahexaenoic acid or its precursors would be expected to be therapeutic. Neither of these predictions is evident from other current hypotheses for the antimanic action of lithium and anticonvulsant drugs.
Rapoport
Stanley I
SI
Brain Physiology and Metabolism Section, Bldg 10, Room 6N202, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. sir@helix.nih.gov
Bosetti
Francesca
F
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016718:Arachidonic Acid / Q000032:analysis / Q000378:metabolism*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D051546:Cyclooxygenase 2; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D008565:Membrane Proteins; D023421:Models, Animal; D019308:Palmitic Acid / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011458:Prostaglandins E / Q000378:metabolism; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D018692:Antimanic Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D010743:Phospholipids; D011458:Prostaglandins E; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D019308:Palmitic Acid; D014635:Valproic Acid; D008094:Lithium; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases