n-(4-methoxybenzyl)-n--(5-nitro-1-3-thiazol-2-yl)urea and 4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione

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

Immune mediators and leukocyte engagement of brain microvascular endothelial cells (BMVECs) contribute to blood-brain barrier impairment during neuroinflammation. Glycogen synthase kinase 3beta (GSK3beta) was recently identified as a potent regulator of immune responses in in vitro systems and animal models. However, the role of GSK3beta in regulation of immune endothelial functions remains undetermined. Here we evaluated the effect of GSK3beta inhibition on the regulation of inflammatory responses in BMVECs. A focused PCR gene array of 84 genes was performed to identify the cytokine and chemokine gene expression profile in tumor necrosis factor (TNF) alpha-stimulated BMVECs after GSK3beta inactivation by specific inhibitors. Fifteen of 39 genes induced by TNFalpha stimulation were down-regulated after GSK3beta inhibition. Genes known to contribute to neuroinflammation that were most negatively affected by GSK3beta inactivation included IP-10/CXCL10, MCP-1/CCL2, IL-8/CXCL8, RANTES/CCL5, and Groalpha/CXCL1. GSK3beta suppression resulted in diminished secretion of these proinflammatory mediators by inflamed BMVECs detected by ELISA. GSK3beta inhibition in BMVECs reduced adhesion molecule expression as well as monocyte adhesion to and migration across cytokine stimulated BMVEC monolayers. Interactions of monocytes with TNFalpha-activated BMVECs led to barrier disruption, and GSK3beta suppression in the endothelium restored barrier integrity. GSK3beta inhibition in vivo substantially decreased leukocyte adhesion to brain endothelium under inflammatory conditions. In summary, inhibition of GSK3beta emerges as an important target for stabilization of the blood-brain barrier in neuroinflammation.

Topics: AIDS Dementia Complex; Animals; Blood-Brain Barrier; Brain; Case-Control Studies; Cell Adhesion; Cells, Cultured; Drug Evaluation, Preclinical; Encephalitis; Endothelial Cells; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Monocytes; Protein Kinase Inhibitors; Thiadiazoles; Thiazoles; Urea