title: A safe lithium mimetic for bipolar disorder.
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.
authors.affiliation: University of Oxford, Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Nisha
authors.initials: N
authors.lastname: Singh
authors.forename: Amy C
authors.initials: AC
authors.lastname: Halliday
authors.forename: Justyn M
authors.initials: JM
authors.lastname: Thomas
authors.forename: Olga V
authors.initials: OV
authors.lastname: Kuznetsova
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Baldwin
authors.forename: Esther C Y
authors.initials: EC
authors.lastname: Woon
authors.forename: Parvinder K
authors.initials: PK
authors.lastname: Aley
authors.forename: Ivi
authors.initials: I
authors.lastname: Antoniadou
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.forename: Sridhar R
authors.initials: SR
authors.lastname: Vasudevan
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
mesh_terms: D000818:Animals; D001393:Azoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007294:Inositol / Q000172:deficiency / Q000494:pharmacology; D054833:Isoindoles; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001393:Azoles; D004791:Enzyme Inhibitors; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D007294:Inositol; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase