n-(4-methoxybenzyl)-n--(5-nitro-1-3-thiazol-2-yl)urea and Bipolar-Disorder

Glycogen synthase kinase-3 is a multi-functional serine-threonine kinase and is involved in diverse physiological processes, including metabolism, cell cycle, and gene expression by regulating a wide variety of known substrates like glycogen synthase, tau-protein and β-catenin. Aberrant GSK-3 has been involved in diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. In this review, we present an overview of the involvement of GSK-3 in various signalling pathways, resulting in a number of adverse pathologies due to its dysregulation. In addition, a detailed description of the small molecule inhibitors of GSK-3 with different mode of action discovered or specifically developed for GSK-3 has been presented. Furthermore, some clues for the future optimization of these promising molecules to develop specific drugs inhibiting GSK-3, for the treatment of associated disease conditions have also been discussed.

Topics: Alzheimer Disease; Animals; Bipolar Disorder; Clinical Trials as Topic; Diabetes Mellitus; Drug Discovery; Glycogen Synthase Kinase 3; Humans; Models, Molecular; Neoplasms; Patents as Topic; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction

The present study evaluated the effects of AR-A014418 on behavioral and oxidative stress parameters of rats submitted to the animal model of mania induced by ouabain (OUA). Wistar rats were submitted to stereotaxic surgery and received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid (aCSF), OUA, or AR-A014418. After 7 days, the animals were submitted to open-field test. After behavioral analysis, the brains were dissected in frontal cortex and hippocampus to the evaluation of oxidative stress. The OUA induced manic-like behavior in rats, which was reversed by AR-A014418 treatment. The ICV administration of OUA increases the levels of superoxide in submitochondrial particles, lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane, protein carbonyl, 3-nitrotyrosine, and activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) in both structures evaluated. In general, the treatment with AR-A014418 reversed these effects of OUA on the submitochondrial particles, LPH, 4-HNE, 8-isoprostane, protein carbonyl, 3-nitrotyrosine levels, and SOD activity. Furthermore, the injection of OUA decreased the catalase activity, and AR-A014418 promoted an increase in activity of this enzyme in the brain structures. These results suggest that GSK-3β inhibition can modulate manic-like behaviors. Also, it can be suggested that inhibition of GSK-3β can be effective against oxidative stress. However, more studies are needed to better elucidate these mechanisms. Graphical Abstract The effects of AR-A014418 on the behavioral and oxidative stress parameters in the animal model of mania induced by ouabain. Superoxide = superoxide production in submitochondrial particles; LPH = lipid hydroperoxide; 4-HNE = 4-hydroxynonenal; SOD = superoxide dismutase; GPx = glutathione peroxidase; GR = glutathione reductase.

Topics: Aldehydes; Animals; Antioxidants; Behavior, Animal; Bipolar Disorder; Catalase; Dinoprost; Disease Models, Animal; Glutathione Peroxidase; Glycogen Synthase Kinase 3 beta; Lipid Peroxidation; Male; Motor Activity; Oxidative Stress; Protein Carbonylation; Rats, Wistar; Submitochondrial Particles; Superoxide Dismutase; Superoxides; Thiazoles; Tyrosine; Urea

The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on the PI3K/Akt signaling pathway in the brains of rats subjected to the ouabain (OUA)-induced animal model of mania. In addition, the effects of AR-A014418, a GSK-3β inhibitor, on manic-like behavior induced by OUA were evaluated. In the first experimental protocol Wistar rats received a single ICV injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li or VPA twice a day. In the second experimental protocol, rats received OUA, aCSF, OUA plus AR-A014418, or aCSF plus AR-A014418. On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, we analyzed the levels of p-PI3K, p-MAPK, p-Akt, and p-GSK-3β in the brain of rats by immunoblot. Li and VPA reversed OUA-related hyperactivity. OUA decreased p-PI3K, p-Akt and p-GSK-3β levels. Li and VPA improved these OUA-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. In addition, AR-A014418 reversed the manic-like behavior induced by OUA. These findings suggest that the manic-like effects of ouabain are associated with the activation of GSK-3β, and that Li and VPA exert protective effects against OUA-induced inhibition of the GSK-3β pathway.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Disease Models, Animal; Frontal Lobe; Glycogen Synthase Kinase 3 beta; Hippocampus; Lithium Compounds; Locomotion; Male; Ouabain; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats, Wistar; Signal Transduction; Thiazoles; Urea; Valproic Acid

There is a growing body of evidence suggesting that animal models can be developed to probe the specific domains of bipolar disorder (BD) using the endophenotype approach. Here we tested clinically active antimanic drugs to validate amphetamine-induced hyperactivity in Black Swiss mice as a putative model of the manic phase of BD. We also co-administered a mood stabilizer and an atypical antipsychotic drug in a manner akin to the clinical treatment regimens. Since lithium has been shown to potentially act through glycogen synthase kinase-3 (GSK3) inhibition, we evaluated the efficacy of selective GSK3 inhibitors in this model. Habituated animals were pretreated with a compound of interest before being challenged with amphetamine (2.0 mg/kg) and returned to activity cages for an additional 1.5 h. We tested lithium, sodium valproate, carbamazepine, olanzapine, ziprasidone as well as co-administered lithium and olanzapine at sub-efficacious doses. The GSK3 inhibitors tested included indirubin, alsterpaullone, TDZD-8, AR-A014418, SB-216763, and SB-627772. All mood stabilizers and antipsychotic drugs reduced hyperactivity without affecting spontaneous locomotion. While subactive doses of lithium and olanzapine were without effect, their co-administration produced robust reductions in hyperactivity. All GSK3 inhibitors were active in the model, producing selective inhibition of rearing hyperactivity. These data support the predictive validity of the model for the acute manic phase of BD and may have utility as an in-vivo model for identifying novel antimanic therapeutics.

Topics: Amphetamine; Animals; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Blood-Brain Barrier; Central Nervous System Stimulants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glycogen Synthase Kinase 3; Humans; Indoles; Male; Maleimides; Mice; Mice, Mutant Strains; Molecular Targeted Therapy; Motor Activity; Reproducibility of Results; Thiadiazoles; Thiazoles; Urea

Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK-3beta, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3beta capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders.

Topics: Affect; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antidepressive Agents; Bipolar Disorder; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Kinesins; Lithium; Male; Mice; Microtubule-Associated Proteins; Models, Biological; Neuronal Plasticity; Receptors, AMPA; Synapses; Thiazoles; Urea