A safe lithium mimetic for bipolar disorder

Nat Commun. 2013;4:1332. doi: 10.1038/ncomms2320.

Abstract

Lithium is the most effective mood stabilizer for the treatment of bipolar disorder, but it is toxic at only twice the therapeutic dosage and has many undesirable side effects. It is likely that a small molecule could be found with lithium-like efficacy but without toxicity through target-based drug discovery; however, therapeutic target of lithium remains equivocal. Inositol monophosphatase is a possible target but no bioavailable inhibitors exist. Here we report that the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behaviour, which are reversed with inositol, consistent with a mechanism involving inhibition of inositol recycling. Ebselen is part of the National Institutes of Health Clinical Collection, a chemical library of bioavailable drugs considered clinically safe but without proven use. Therefore, ebselen represents a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azoles / chemistry
  • Azoles / pharmacology
  • Azoles / therapeutic use
  • Behavior, Animal / drug effects
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / enzymology
  • Bipolar Disorder / pathology
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / enzymology
  • Blood-Brain Barrier / pathology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Inositol / deficiency
  • Inositol / pharmacology
  • Lithium / pharmacology
  • Lithium / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Mimicry*
  • Organoselenium Compounds / chemistry
  • Organoselenium Compounds / pharmacology
  • Organoselenium Compounds / therapeutic use
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / metabolism

Substances

  • Azoles
  • Enzyme Inhibitors
  • Organoselenium Compounds
  • ebselen
  • Inositol
  • Lithium
  • Phosphoric Monoester Hydrolases
  • myo-inositol-1 (or 4)-monophosphatase