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Identification of a glycogen synthase kinase-3? inhibitor that attenuates hyperactivity in CLOCK mutant mice.

ABSTRACT: Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5?million people in the United States. Current treatment regimes include the so-called "mood-stabilizing drugs", such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3? (GSK-3?) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3?. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC?? values in the range of 4 to 680?nM against human GSK-3?. One of these compounds exhibits reasonable kinase selectivity and promising preliminary absorption, distribution, metabolism, and excretion (ADME) data. The administration of this compound at doses of 10 to 25?mg?kg?¹ resulted in the attenuation of hyperactivity in amphetamine/chlordiazepoxide-induced manic-like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400?mg?kg?¹) and the antipsychotic haloperidol (1?mg?kg?¹). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the CLOCK gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK-3? in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3? as a relevant therapeutic target in the identification of new therapies for bipolar patients.

SUBMITTER: Kozikowski AP

PROVIDER: S-EPMC3428230 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Identification of a glycogen synthase kinase-3β inhibitor that attenuates hyperactivity in CLOCK mutant mice.

Kozikowski Alan P AP Gunosewoyo Hendra H Guo Songpo S Gaisina Irina N IN Walter Richard L RL Ketcherside Ariel A McClung Colleen A CA Mesecar Andrew D AD Caldarone Barbara B

ChemMedChem 20110705 9

Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called "mood-stabilizing drugs", such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3β (GSK-3β) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3β. We designed a series of second generation benz ...[more]

PMID: 21732538

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Project description:Type 1 diabetic Akita mice develop severe cardiac parasympathetic dysfunction that we have previously demonstrated is due at least in part to an abnormality in the response of the end organ to parasympathetic stimulation. Specifically, we had shown that hypoinsulinemia in the diabetic heart results in attenuation of the G-protein coupled inward rectifying K channel (GIRK) which mediates the negative chronotropic response to parasympathetic stimulation due at least in part to decreased expression of the GIRK1 and GIRK4 subunits of the channel. We further demonstrated that the expression of GIRK1 and GIRK4 is under the control of the Sterol Regulatory element Binding Protein (SREBP-1), which is also decreased in response to hypoinsulinemia. Finally, given that hyperactivity of Glycogen Synthase Kinase (GSK)3β, had been demonstrated in the diabetic heart, we demonstrated that treatment of Akita mice with Li+, an inhibitor of GSK3β, increased parasympathetic responsiveness and SREBP-1 levels consistent with the conclusion that GSK3β might regulate IKACh via an effect on SREBP-1. However, inhibitor studies were complicated by lack of specificity for GSK3β. Here we generated an Akita mouse with cardiac specific inducible knockout of GSK3β. Using this mouse, we demonstrate that attenuation of GSK3β expression is associated with an increase in parasympathetic responsiveness measured as an increase in the heart rate response to atropine from 17.3 ± 3.5% (n = 8) prior to 41.2 ± 5.4% (n = 8, P = 0.017), an increase in the duration of carbamylcholine mediated bradycardia from 8.43 ± 1.60 min (n = 7) to 12.71 ± 2.26 min (n = 7, P = 0.028) and an increase in HRV as measured by an increase in the high frequency fraction from 40.78 ± 3.86% to 65.04 ± 5.64 (n = 10, P = 0.005). Furthermore, patch clamp measurements demonstrated a 3-fold increase in acetylcholine stimulated peak IKACh in atrial myocytes from GSK3β deficiency mice compared with control. Finally, western blot analysis of atrial extracts from knockout mice demonstrated increased levels of SREBP-1, GIRK1 and GIRK4 compared with control. Taken together with our prior observations, these data establish a role of increased GSK3β activity in the pathogenesis of parasympathetic dysfunction in type 1 diabetes via the regulation of IKACh and GIRK1/4 expression.

Dataset Information

Identification of a glycogen synthase kinase-3? inhibitor that attenuates hyperactivity in CLOCK mutant mice.

Publications

Identification of a glycogen synthase kinase-3β inhibitor that attenuates hyperactivity in CLOCK mutant mice.

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