How can the mood stabilizer VPA limit both mania and depression?
The mood stabilizing drugs commonly used to treat bipolar disorder--lithium, valproic acid (VPA), and carbamazepine (CBZ)--limit the frequency of swings to either manic or depressive states. We previously showed that these drugs all have a common action on cultured neurons, which can be reversed by the addition of either inositol or specific inhibitors of the enzyme prolyl oligopeptidase (PO). Inhibition of PO activity is reported to enhance phosphoinositide (PIns) signaling consistent with the suggestion that mood stabilizers inhibit PIns signaling. We now report that VPA directly inhibits recombinant PO activity, which would have the opposite effect on PIns signaling. This unexpected result suggests a model that could explain the dual action of VPA in stabilizing mood: we propose that euthymic mood is dependent on stable PIns signaling and that VPA may limit mood swings to mania by decreasing PIns signaling, and that it may limit mood swings to depression by inhibiting PO and thus increasing PIns signaling.
Cheng
Lili
L
MRC Laboratory for Molecular Cell Biology and Department of Biology, UCL, Gower Street London, WC1E 6BT, UK.
Lumb
Michael
M
Polgár
László
L
Mudge
Anne W
AW
D000818:Animals; D000831:Animals, Newborn; D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D000085822:Prolyl Oligopeptidases; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D018692:Antimanic Agents; D010716:Phosphatidylinositols; D011993:Recombinant Fusion Proteins; D014635:Valproic Acid; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases