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H GUNOSEWOYO, I. N. GAISINA, T HANANIA, L THIEDE, A FEDOLAK, D BRUNNER, A MIDZAK, V PAPADOPOULOS, A. P. KOZIKOWSKI

Bipolar disorder is a severely debilitating mental illness, affecting almost 6 million people of 18 years and older per year in the United States. Lithium has been widely used as an acute and prophylactic treatment regimen for bipolar disorder indication since the discovery of its antimanic effects by John Cade in 1949. The currently known direct targets of lithium include glycogen synthase kinase-3 (GSK-3), phosphoglucomutase, inositol monophosphatase, other inositol polyphosphatases, and monophosphoesterases. Of particular interest, recent findings in the literature support the notion that GSK-3 plays an important role in the pathophysiology and treatment of bipolar disorder. Various pharmacological and molecular biology approaches have shown that GSK-3 is closely regulated by serotonin, dopamine, and serotonin-modulating drugs such as antidepressants and atypical antipsychotics. We have identified a potent GSK-3 inhibitor ING-135, which has been previously shown to possess antimanic-like effects by attenuating hyperactivity induced by a combination of amphetamine and chlordiazepoxide in mice.1 This lead compound demonstrated an excellent selectivity profile for GSK-3 (IC50 = 21 nM at GSK-3)when tested comprehensively against a panel of 320 kinases and approximately 50 common neuroreceptors and enzymes utilizing the Psychoactive Drug Screening Program, UNC. Preliminary ADMET studies including brain PK showed rapid equilibration between the plasma and the brain. Chronic administration of this compound at 50 mg/kg in wild-type C57BL6/J mice was followed by a series of behavioral tests looking at the exploratory behavior and antidepressant-like effects, with lithium as a comparator. While the antimanic-like effects of ING-135-administered mice were further confirmed by the decreased exploratory behavior in open field test, there was no apparent antidepressant-like activity. More recently, some of our GSK-3 inhibitors also demonstrated both acute and chronic stimulation of steroidogenesis by association with the translocator protein (TSPO), and induction of mitochondrial cholesterol delivery, presumably through the kinase signaling pathway. Taken together, the present collection of chemistry, biochemical, pharmacological and behavioral data with our lead GSK-3 inhibitor ING-135 have demonstrated its antimanic-like properties in vivo which is likely to be mediated through selective GSK-3 inhibition.