lithium-chloride and Huntington-Disease

Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington's disease (HD), Parkinson's disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown. Using drug screening in C. elegans nematodes with neuronal expression of human exon-1 huntingtin (128Q), we found that 3ß-Methoxy-Pregnenolone (MAP4343), 17ß-oestradiol (17ßE2) and 12 flavonoids including isoquercitrin promote neuronal function in 128Q nematodes. MAP4343, 17ßE2 and isoquercitrin also promote stress resistance in mutant Htt striatal cells derived from knock-in HD mice. Interestingly, daf-16/FOXO is required for MAP4343, 17ßE2 and isoquercitrin to sustain neuronal function in 128Q nematodes. This similarly applies to the GSK3 inhibitor lithium chloride (LiCl) and, as previously described, to resveratrol and the AMPK activator metformin. Daf-16/FOXO and the targets engaged by these compounds define a sub-network enriched for stress-response and neuronally-active pathways. Collectively, these data highlights the dependence on a daf-16/FOXO-interaction network as a common feature of several compound families for prolonging neuronal function in HD.

Topics: Aging; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Drug Evaluation, Preclinical; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation; Gene Knock-In Techniques; Humans; Huntingtin Protein; Huntington Disease; Lithium Chloride; Mice; Neurons; Pregnenolone; Quercetin

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditioning bone marrow-derived mesenchymal stem cells (MSCs) with lithium and VPA prior to intranasal delivery to the brain would enhance their therapeutic efficacy, and thereby facilitate functional recovery in N171-82Q HD transgenic mice. MSCs were treated in the presence or absence of combined lithium and VPA, and were then delivered by brain-targeted single intranasal administration to eight-week old HD mice. Histological analysis confirmed the presence of MSCs in the brain. Open-field test revealed that ambulatory distance and mean velocity were significantly improved in HD mice that received preconditioned MSCs, compared to HD vehicle-control and HD mice transplanted with non-preconditioned MSCs. Greater benefits on motor function were observed in HD mice given preconditioned MSCs, while HD mice treated with non-preconditioned MSCs showed no functional benefits. Moreover, preconditioned MSCs reduced striatal neuronal loss and huntingtin aggregates in HD mice. Gene expression profiling of preconditioned MSCs revealed a robust increase in expression of genes involved in trophic effects, antioxidant, anti-apoptosis, cytokine/chemokine receptor, migration, mitochondrial energy metabolism, and stress response signaling pathways. Consistent with this finding, preconditioned MSCs demonstrated increased survival after transplantation into the brain compared to non-preconditioned cells. Our results suggest that preconditioning stem cells with the mood stabilizers lithium and VPA before transplantation may serve as an effective strategy for enhancing the therapeutic efficacy of stem cell-based therapies.

Topics: Animals; Antimanic Agents; Cytokines; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Drug Administration Schedule; Female; Gene Expression; Huntingtin Protein; Huntington Disease; Lithium Chloride; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Phosphopyruvate Hydratase; Proto-Oncogene Proteins c-kit; Receptors, Cytokine; Up-Regulation; Valproic Acid

The ability to predetermine the fate of transplanted neural progenitor cells (NPCs) and specifically to direct their maturation has the potential to enhance the efficiency of cell-transplantation therapy for neurodegenerative disease. We previously demonstrated that transient exposure of subventricular zone (SVZ)-derived adult NPCs to lithium chloride during in vitro proliferation alters differential fate in vitro and increases the proportion of cells expressing neuronal markers while reducing glial progeny. To extend these findings, we examined whether in vitro priming of adult SVZ-derived NPCs with lithium chloride before transplantation into the quinolinic acid (QA) lesion rat model of Huntington disease altered in vivo neuronal differentiation and sensorimotor function compared with nonprimed NPC transplants.. NPCs were isolated from the SVZ of the adult rat brain and cultured for 2 weeks. Four days before transplantation into the QA-lesioned rat striatum, the cells were labeled with BrdU and primed with lithium chloride. The rats underwent regular evaluation of forelimb use and sensorimotor neglect to establish functional effects of NPC transplantation. Twelve weeks after transplantation, the brains were analyzed with immunohistochemistry to compare the differential fate of primed and nonprimed NPCs.. We observed that in vitro priming of adult NPCs with lithium chloride reduced gliogenesis and enhanced the occurrence of DARPP-32-positive neurons when compared with nonprimed cells 12 weeks after transplantation into the QA-lesioned striatum. Lithium chloride priming also augmented the formation of efferent projections from newly formed neurons in the damaged host striatum to the globus pallidus. This was associated with acceleration of sensorimotor function recovery in rats receiving transplants of lithium chloride-primed adult NPCs compared with nonprimed transplants.. These initial findings indicate that in vitro priming of adult NPCs with lithium chloride may augment transplant efficiency and accelerate sensorimotor function outcome in vivo.

Topics: Adjuvants, Immunologic; Adult Stem Cells; Animals; Brain; Cell Movement; Cell Survival; Cell- and Tissue-Based Therapy; Cells, Cultured; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Huntington Disease; Lithium Chloride; Male; Neural Stem Cells; Neurogenesis; Rats; Rats, Wistar; SOXB1 Transcription Factors

Lithium reduced striatal neurodegeneration induced in rats by 3-nitropropionic acid inhibiting calpain activation. Lithium prevented an increase in cdk5 activity, as shown by the levels of the co-activator p35. Myocite enhancer factor 2 (MEF2), a downstream substrate for cdk5 with pro-survival activity, showed increased phosphorylation. In primary cultures of neurons treated with 3-NP, lithium also reduced protease activity mediated by calpain, cdk5 activation and cellular death. These observations indicate that lithium has a neuroprotective effect. Lithium treatment also reduced the intracellular increase in calcium induced by 3-NP. The finding that lithium mediates the modulation of the calpain/cdk5 pathway further supports its use in the treatment of neurodegenerative diseases.

Topics: Animals; Calcium; Calpain; Cell Survival; Cells, Cultured; Cyclin-Dependent Kinase 5; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Embryo, Mammalian; Gene Expression Regulation; Hippocampus; Huntington Disease; Lithium Chloride; Male; Mice; Neurons; Neuroprotective Agents; Nitro Compounds; Propionates; Rats; Rats, Sprague-Dawley; Signal Transduction; Succinate Dehydrogenase

The prolonged time course of Huntington's disease (HD) neurodegeneration increases both the time and cost of testing potential therapeutic compounds in mammalian models. An alternative is to initially assess the efficacy of compounds in invertebrate models, reducing time of testing from months to days.. We screened candidate therapeutic compounds that were identified previously in cell culture/animal studies in a C. elegans HD model and found that two FDA approved drugs, lithium chloride and mithramycin, independently and in combination suppressed HD neurotoxicity. Aging is a critical contributor to late onset neurodegenerative diseases. Using a genetic strategy and a novel assay, we demonstrate that lithium chloride and mithramycin remain neuroprotective independent of activity of the forkhead transcription factor DAF-16, which mediates the effects of the insulin-like signaling pathway on aging.. These results suggest that pathways involved in polyglutamine-induced degeneration are distinct from specific aging pathways. The assays presented here will be useful for rapid and inexpensive testing of other potential HD drugs and elucidating pathways of drug action. Additionally, the neuroprotection conferred by lithium chloride and mithramycin suggests that these drugs may be useful for polyglutamine disease therapy.

Topics: Aging; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Disease Models, Animal; Drug Combinations; Forkhead Transcription Factors; Huntington Disease; Lithium Chloride; Longevity; Neuroprotective Agents; Peptides; Plicamycin; Transcription Factors

Expression of the Huntington's disease (HD) mutation in mice (R6/2 line) causes a progressive neurological phenotype that includes deterioration of motor function resembling that seen in HD. The current study sought to determine whether or not chronic treatment of R6/2 mice with lithium chloride would have an effect on the progression of the phenotype, in light of lithium's reported neuroprotective and anti-depressive properties. Treatment began either before or after the onset of symptoms. Chronic treatment with lithium caused a significant improvement in rotarod performance when treatment was started post- but not pre-symptomatically. There was no overall effect on survival in either group, but further analysis revealed that in the post-symptomatic group, mice could be assigned to one of two distinct groups, depending on the effects of lithium. One subgroup of mice lost weight faster, died earlier and showed rotarod performance similar to the vehicle-treated controls. The other subgroup lost weight at a normal rate, died at a similar age, but showed greatly improved motor performance compared to controls. The improvement in rotarod performance suggests that lithium may improve motor symptoms as well as depression in some HD patients.

Topics: Aging; Animals; Antimanic Agents; Behavior, Animal; Body Weight; Disease Models, Animal; Drug Administration Routes; Female; Huntington Disease; Lithium Chloride; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Mutation; Norbornanes; Phenotype; Psychomotor Performance; Rotation; Survival; Time Factors

Huntington's disease is one of nine known neurodegenerative disorders caused by an expanded polyglutamine (poly(Q)) tract in the disease protein. These diseases are associated with intraneuronal protein aggregates. Heat-inducible chaperones like HSP70 and HSP27 suppress poly(Q) aggregation and/or toxicity/cell death. Heat shock transcription factors, including HSF-1, regulate HSP70 and HSP27 expression. HSF-1 activity is reduced by glycogen synthase kinase-3 (GSK-3) and enhanced by GSK-3 inhibitors, like lithium. Thus, we hypothesized that lithium treatment may partially rescue death in Huntington's disease cell models. LiCl reduced poly(Q) toxicity in neuronal and nonneuronal cell lines, but this was not associated with elevation of HSP70 or HSP27. The protective effect of lithium involved GSK-3beta inhibition, since poly(Q) toxicity was also reduced by SB216763, a GSK-3beta inhibitor, and by overexpression of a dominant-negative GSK-3beta mutant. LiCl and SB216763 increased beta-catenin-dependent T-cell factor-mediated transcription. Since beta-catenin overexpression protected cells from poly(Q) toxicity, we tested whether this pathway was impaired by a poly(Q) expansion mutation. Cells expressing expanded repeats had reduced beta-catenin levels associated with a parallel decrease in T-cell factor-mediated transcription, compared with cells expressing wild type constructs. Since LiCl can protect against polyglutamine toxicity in cell lines, it is an excellent candidate for further in vivo therapeutic trials.

Topics: Animals; beta Catenin; Cell Aggregation; Cell Death; COS Cells; Cytoskeletal Proteins; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Huntington Disease; Indoles; Lithium Chloride; Maleimides; Molecular Chaperones; Mutation; Neoplasm Proteins; Peptides; Proto-Oncogene Proteins c-bcl-2; Trans-Activators; Transcription, Genetic; Tumor Cells, Cultured

Huntington's disease is a progressive, inherited neurodegenerative disorder characterized by the loss of subsets of neurons primarily in the striatum. In this study, we assessed the neuroprotective effect of lithium against striatal lesion formation in a rat model of Huntington's disease in which quinolinic acid was unilaterally infused into the striatum. For this purpose, we used a dopamine receptor autoradiography and glutamic acid decarboxylase mRNA in situ hybridization analysis, methods previously shown to be adequate for quantitative analysis of the excitotoxin-induced striatal lesion size. Here we demonstrated that subcutaneous injections of LiCl for 16 days prior to quinolinic acid infusion considerably reduced the size of quinolinic acid-induced striatal lesion. Furthermore, these lithium pre-treatments also decreased the number of striatal neurons labeled with the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. Immunohistochemistry and western blotting demonstrated that lithium-elicited neuroprotection was associated with an increase in Bcl-2 protein levels. Our results raise the possibility that lithium may be considered as a neuroprotective agent in treatment of neurodegenerative diseases such as Huntington's disease.

Topics: Animals; Antimanic Agents; Benzazepines; Cell Death; Cyclin D1; Disease Models, Animal; Dopamine Antagonists; Glutamate Decarboxylase; Huntington Disease; Immunohistochemistry; In Situ Nick-End Labeling; Isoenzymes; Lithium; Lithium Chloride; Male; Neostriatum; Neurons; Neuroprotective Agents; Neurotoxins; Quinolinic Acid; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; RNA, Messenger