lithium-chloride and pyrazolanthrone

Lithium (Li) is one of the currently prescribed drugs for bipolar disorders (BPDs) and has many neuro-regulatory and immune-modulating properties. Because many neuro-pathological diseases including BPDs have been associated with some level of inflammation, Li's effect on inflammation may have some crucial consequences. Even though Li has been shown to have pro- and anti-inflammatory activities in different cell models, mechanisms involved in these effects are not well understood. Moreover, Li's effect on inflammation in the presence of activators of Toll-like receptors (TLRs), especially TLR-2 (that activates MyD88-dependent pathway) and TLR-3 (that activates TRIF-dependent pathway) is not known. Here we tested the role of Li in the presence and absence of TLR2, and TLR3 on MAPK and NFκB pathways and the consequent production of tumor necrosis factor-α (TNFα) in Raw264.7 macrophages. Our results indicate that Li enhances TNFα production both in the absence and presence of TLR stimulation. Interestingly, Li differentially modulates MAPK and NFκB pathways in the absence and presence of TLR2/3 ligands. Our results further indicate that the effect of Li on TNFα occurs at the post-transcriptional level. Together, these studies demonstrate that Li induces TNFα production in macrophages and that it modulates signaling at different levels depending on the presence or absence of TLR2/3 stimulation.

Topics: Animals; Anthracenes; Cell Line; Inflammation; Lithium Chloride; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; NF-kappa B; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 3; Tumor Necrosis Factor-alpha

The fruit fly, Drosophila melanogaster, is a commonly used model organism for neurodegenerative diseases. Its major advantages include a short lifespan and its susceptibility to manipulation using sophisticated genetic techniques. Here, we report the systematic comparison of fly models of two polyglutamine (polyQ) diseases. We induced expression of the normal and mutant forms of full-length Ataxin-1 and Huntingtin exon 1 in cholinergic, dopaminergic, and motor neurons, and glial cells using cell type-specific drivers. We systematically analyzed their effects based on multiple phenotypes: eclosion rate, lifespan, motor performance, and circadian rhythms of spontaneous activity. This systematic assay system enabled us to quantitatively evaluate and compare the functional disabilities of different genotypes. The results suggest different effects of Ataxin-1 and Huntingtin on specific types of neural cells during development and in adulthood. In addition, we confirmed the therapeutic effects of LiCl and butyrate using representative models. These results support the usefulness of this assay system for screening candidate chemical compounds that modify the pathologies of polyQ diseases.

Topics: Animals; Animals, Genetically Modified; Anthracenes; Ataxin-1; Behavior, Animal; Butyrates; Drosophila melanogaster; Drosophila Proteins; Gene Expression Regulation; Huntingtin Protein; JNK Mitogen-Activated Protein Kinases; Lithium Chloride; Longevity; Microtubule-Associated Proteins; Models, Animal; Motor Activity; Neuroprotective Agents

The death of endothelial cells may play a critical role in the development of various vascular diseases, including atherosclerosis. While free fatty acids (FFAs) may stimulate endothelial apoptosis, the molecular and cellular mechanisms of this effect have not been studied intensively. To elucidate the mechanisms involved in FFA-induced endothelial cell apoptosis, we investigated the effect of different pharmacological inhibitors on palmitate-induced apoptosis in human umbilical vein endothelial cells (HUVECs). Interestingly, lithium, a glycogen synthase kinase-3 (GSK-3) inhibitor, showed a strong protective effect.. To examine the involvement of GSK-3beta in palmitate-induced HUVEC apoptosis, its dephosphorylation at Ser9 and enzymatic activation in response to palmitate treatment were monitored by immunoblotting and in vitro kinase assays, respectively. GSK-3beta was dephosphorylated and its enzymatic activity increased in palmitate-treated HUVECs. In addition, pretreatment with other GSK-3beta inhibitors, e.g. SB216763 or TDZD-8, as well as adenoviral transduction with a catalytically inactive GSK-3beta had significant protective effects against palmitate-induced HUVEC apoptosis.. These results demonstrate that the GSK-3beta signalling pathway is involved in palmitate-induced HUVEC apoptosis.

Topics: Adenoviridae; Anthracenes; Apoptosis; Caspase 3; Cell Cycle; Cells, Cultured; Cytosol; Endothelial Cells; Endothelium, Vascular; Enzyme Activation; Fumonisins; Genetic Vectors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Imidazoles; Indoles; Lithium Chloride; Maleimides; Mitochondria; Palmitates; Phosphorylation; Phosphoserine; Poly(ADP-ribose) Polymerases; Protein Processing, Post-Translational; Pyridines; Thiadiazoles; Transduction, Genetic; Umbilical Veins