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  • Effects of lithium and deafferentation on expression of glycogen synthase kinase-3beta, NFkappaB, beta-catenin and pCreb in the chick cochlear nucleus. 18313644

    The avian brainstem serves as a useful model to answer the question of how afferent activity influences the viability of target neurons. Approximately 20-30% of neurons in the avian cochlear nucleus, nucleus magnocellularis (NM) die following deafferentation (i.e., deafness produced by cochlea removal). Interestingly, Bcl-2 mRNA (but not protein) is upregulated in 20-30% of NM neurons following deafferentation. We have recently shown that chronic treatments of lithium upregulates the neuroprotective protein Bcl-2 and increases neuronal survival following deafferentation. The pathways leading to the upregulation of Bcl-2 expression following these two manipulations are unknown. The present experiments examine changes in glycogen synthase kinase-3 beta (Gsk-3beta), and transcription factors nuclear factor kappaB (NFkappaB), beta-catenin, and pCreb following lithium administration and following deafferentation. These molecules are known to be influenced by lithium and to regulate Bcl-2 expression in other model systems. Lithium decreased immunolabeling for Gsk-3beta and increased expression for all three transcription factors. Deafferentation, however, did not alter Gsk-3beta or NFkappaB, resulted in lower beta-catenin expression, but did increase pCreb immunoreactivity. While it is possible that pCreb is a common link in the regulation of Bcl-2 following these two manipulations, the timing and distribution of pCreb labeling suggests that it is not the sole determinant of Bcl-2 upregulation following deafferentation. It is likely that the regulation of Bcl-2 gene expression by lithium and by deafferentation involves different molecular pathways.
    Document Type:
    Reference
    Product Catalog Number:
    06-519
    Product Catalog Name:
    Anti-phospho-CREB (Ser133) Antibody

  • Lithium protects against oxidative stress-mediated cell death in α-synuclein-overexpressing in vitro and in vivo models of Parkinson's disease. 21710541

    Lithium has recently been suggested to have neuroprotective properties in relation to several neurodegenerative diseases. In this study, we examined the potential cytoprotective effect of lithium in preventing oxidative stress-induced protein accumulation and neuronal cell death in the presence of increased α-synuclein levels in vitro and in vivo. Specifically, lithium administration was found to protect against cell death in a hydrogen peroxide-treated, stable α-synuclein-enhanced green fluorescent protein (EGFP)-overexpressing dopaminergic N27 cell line. Lithium feeding (0.255% lithium chloride) of 9-month-old pan-neuronal α-synuclein transgenic mice over a 3-month period was also sufficient to prevent accumulation of oxidized/nitrated α-synuclein as a consequence of chronic paraquat/maneb administration in multiple brain regions, including the glomerular layer, mitral cells, and the granule cell layer of the olfactory bulb (OB), striatum, substantia nigra pars compacta (SNpc) and Purkinje cells of the cerebellum. Lithium not only prevented α-synuclein-mediated protein accumulation/aggregation in these brain regions but also protected neuronal cells including mitral cells and dopaminergic SNpc neurons against oxidative stress-induced neurodegeneration. These results suggest that lithium can prevent both α-synuclein accumulation and neurodegeneration in an animal model of PD, suggesting that this drug, already FDA-approved for use in bipolar disorder, may constitute a novel therapy for another human disease.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Chronic lithium treatment decreases NG2 cell proliferation in rat dentate hilus, amygdala and corpus callosum. 19439244

    An increasing number of investigations suggest volumetric changes and glial pathology in several brain regions of patients with bipolar disorder. Lithium, used in the treatment of this disorder, has been reported to be neuroprotective and increase brain volume. Here we investigate the effect of lithium on the proliferation and survival of glial cells positive for the chondroitin sulphate proteoglycan NG2 (NG2 cells); a continuously dividing cell type implicated in remyelination and suggested to be involved in regulation of neuronal signaling and axonal outgrowth. Adult male rats were treated with lithium for four weeks and injected with the proliferation marker bromodeoxyuridine (BrdU) before or at the end of the treatment period. Immunohistochemical analysis of brain sections was performed to estimate the number of newly born (BrdU-labeled) NG2 cells and oligodendrocytes in hippocampus, basolateral nuclei of amygdala and corpus callosum. Lithium significantly decreased the proliferation of NG2 cells in dentate hilus of hippocampus, amygdala and corpus callosum, but not in the molecular layer or the cornu ammonis (CA) regions of hippocampus. The effect was more pronounced in the corpus callosum. No effect of lithium on the survival of newborn cells or the number of newly generated oligodendrocytes could be detected. Our results demonstrate that in both white and gray matter brain regions implicated in the pathophysiology of bipolar disorder, chronic lithium treatment significantly decreases the proliferation rate of NG2 cells; the major proliferating cell type of the adult brain.
    Document Type:
    Reference
    Product Catalog Number:
    MAB5384

  • Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathology. 20110614

    Neurofibrillary tangles (NFTs) made of phosphorylated tau proteins are a key lesion of Alzheimer's disease and other neurodegenerative diseases, and previous studies have indicated that lithium can decrease tau phosphorylation in tau transgenic models. In this study, we have reassessed the effectiveness of treatment per os with lithium on the prevention, the arrest, or the reversal of NFT development in a tau transgenic line (Tg30tau) developing severe neurofibrillary pathology in the brain and the spinal cord. Wild-type and Tgtau30 mice were treated per os with lithium carbonate or with natrium carbonate by chronic chow feeding for 8 months starting at the age of 3 months (to test for a preventive effect on NFT formation) or by oral gavage for 1 month starting at the age of 9 months (after development of NFTs). In mice treated by oral gavage, a decrease of tau phosphorylation and of Sarkosyl-insoluble aggregated tau was observed in the brain and in the spinal cord. The density of NFTs identified by Gallyas staining in the hippocampus and in the spinal cord was also significantly reduced and was similar to that observed at the beginning of the lithium treatment. In these animals, the level of brain beta-catenin was increased probably as a result of its stabilization by glycogen synthase kinase-3beta inhibition. Despite this inhibitory effect of lithium on NFT development, the motor and working memory deficits were not significantly rescued in these aged animals. Chronic chow feeding with lithium did not alter the development of NFT. Nevertheless, this study indicates that even a relatively short-term per os treatment leading to high blood concentration of lithium is effective in arresting the formation of NFTs in the hippocampus and the spinal cord of a tau transgenic model.
    Document Type:
    Reference
    Product Catalog Number:
    MAB1510

  • Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. 12967765

    The intrigue of lithium, the simplest drug in the modern pharmacopoeia, extends from its complex actions in cells to its therapeutic effects as a mood stabilizer. New surprises from studies of glycogen synthase kinase 3 (GSK-3) show that lithium reduces GSK-3 activity in two ways, both directly and by increasing the inhibitory phosphorylation of GSK-3. These dual effects can act in concert to magnify the influence of lithium on crucial GSK-3-regulated functions (gene expression, cell structure and survival).
    Document Type:
    Reference
    Product Catalog Number:
    05-903
    Product Catalog Name:
    Anti-GSK3α/β Antibody, rabbit monoclonal

  • Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia. 17686496

    Recent studies have demonstrated that lithium has a neuroprotective effect against brain ischemia. Whether this effect is mediated by hippocampal neurogenesis remains unknown. The ERK (extracellular signal-regulated kinase) pathway plays an essential role in regulating neurogenesis. The present study was undertaken to investigate whether lithium regulates hippocampal neurogenesis by the ERK pathway and improves spatial learning and memory deficits in rats after ischemia. Rats were daily injected with lithium (1 mmol/kg) and 2 weeks later subjected to 15-min ischemia induced by four-vessel occlusion method. 5-bromo-2'-deoxyuridine (Brdu; 50mg/kg) was administrated twice daily at postischemic day 6, or for 3 days from postischemic day 6 to 8. We found that lithium increased the ERK1/2 activation after ischemia by western blotting analysis. There was a significant increase in Brdu-positive cells in the hippocampal dentate gyrus after lithium treatment, compared with ischemia group at postischemic days 7 and 21; furthermore, the survival rate of Brdu-positive cells was elevated by lithium. Inhibition of the ERK1/2 activation by U0126 diminished these effects of lithium. The percentages of Brdu-positive cells that expressed a neuronal marker or an astrocytic marker were not significantly influenced by lithium. Moreover, lithium improved the impaired spatial learning and memory ability in Morris water maze, and U0126 attenuated the behavioral improvement by lithium. These results suggest that lithium up-regulates the generation and survival of new-born cells in the hippocampus by the ERK pathway and improves the behavioral disorder in rats after transient global cerebral ischemia.
    Document Type:
    Reference
    Product Catalog Number:
    MAB377B
    Product Catalog Name:
    Anti-NeuN Antibody, clone A60, biotin conjugated

  • Lithium leads to an increased FRQ protein stability and to a partial loss of temperature compensation in the Neurospora circadian clock. 16998153

    In many organisms, the presence of lithium leads to an increase of the circadian period length. In Neurospora crassa, it was earlier found that lithium results in a decrease of overall growth and increased circadian periods. In this article, the authors show that lithium leads to a reduction of FRQ degradation with elevated FRQ levels and to a partial loss of temperature compensation. At a concentration of 13 mM lithium, FRQ degradation is reduced by about 60% while, surprisingly, the activity of the 20S proteasome remains unaffected. Experiments and model calculations have shown that the stability of FRQ is dependent on its phosphorylation state and that increased FRQ protein stabilities lead to increased circadian periods, consistent with the observed increase of the period when lithium is present. Because in Neurospora the proteasome activity is unaffected by lithium concentrations that lead to significant FRQ stabilization, it appears that lithium acts as an inhibitor of kinases that affect phosphorylation of FRQ and other proteins. A competition between Li(+) and Mg(2+) ions for Mg(2+)-binding sites may be a mechanism to how certain kinases are inhibited by Li(+). A possible kinase in this respect is GSK-3, which in other organisms is known to be inhibited by lithium. The partial loss of temperature compensation in the presence of lithium can be understood as an increase in the overall activation energy of FRQ degradation. This increase in activation energy may be related to a reduction in FRQ phosphorylation so that more kinase activity, that is, higher temperature and longer times, is required to achieve the necessary amount of FRQ phosphorylation leading to turnover. Using a modified Goodwin oscillator as a semiquantitative model for the Neurospora clock, the effects of lithium can be described by adding lithium inhibitory terms of FRQ degradation to the model.
    Document Type:
    Reference
    Product Catalog Number:
    APT280
    Product Catalog Name:
    20S Proteasome Activity Assay

  • Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cells. 21727907

    Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by defined factors. The low efficiency of reprogramming and genomic integration of oncogenes and viral vectors limited the potential application of iPSCs. Here we report that Lithium (Li), a drug used to treat mood disorders, greatly enhances iPSC generation from both mouse embryonic fibroblast and human umbilical vein endothelial cells. Li facilitates iPSC generation with one (Oct4) or two factors (OS or OK). The effect of Li on promoting reprogramming only partially depends on its major target GSK3β. Unlike other GSK3β inhibitors, Li not only increases the expression of Nanog, but also enhances the transcriptional activity of Nanog. We also found that Li exerts its effect by promoting epigenetic modifications via downregulation of LSD1, a H3K4-specific histone demethylase. Knocking down LSD1 partially mimics Li's effect in enhancing reprogramming. Our results not only provide a straightforward method to improve the iPSC generation efficiency, but also identified a histone demethylase as a critical modulator for somatic cell reprogramming.
    Document Type:
    Reference
    Product Catalog Number:
    AB5731
    Product Catalog Name:
    Anti-Nanog Antibody, NT

  • Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain. 22800605

    Lithium was recently shown to inhibit apoptosis and promote survival of neural progenitor cells after hypoxia-ischemia in the immature rat brain. Our aim was to evaluate the effects of lithium on cell death and proliferation in the hippocampus after irradiation (IR) to the immature brain. Male mice were injected with 2mmol/kg lithium chloride i.p. on postnatal day 9 (P9) and additional lithium injections, 1mmol/kg, were administered at 24h intervals for up to 7days. BrdU was injected 4h after lithium injections on P9 and P10. The left hemisphere received a single dose of 8Gy (MV photons) on P11. The animals were euthanized 6h or 7weeks after IR. The number of BrdU-labeled cells in the subgranular zone (SGZ) of the granule cell layer (GCL) 6h after IR was 24% higher in the lithium-treated mice. The number of proliferating, phospho-histone H3-positive cells in the SGZ 7weeks after IR was 59% higher in the lithium group, so the effect was long-lasting. The number of apoptotic cells in the SGZ 6h after IR was lower in the lithium group, as judged by 3 different parameters, pyknosis, staining for active caspase-3 and TUNEL. Newly formed cells (BrdU-labeled 1 or 2days before IR) showed the greatest degree of protection, as judged by 50% fewer TUNEL-positive cells, whereas non-BrdU-labeled cells showed 38% fewer TUNEL-positive cells 6h after IR. Consequently, the growth retardation of the GCL was less pronounced in the lithium group. The number and size of microglia in the DG were also lower in the lithium group, indicating reduced inflammation. Learning was facilitated after lithium treatment, as judged by improved context-dependent fear conditioning, and improved place learning, as judged by assessment in the IntelliCage platform. In summary, lithium administration could decrease IR-induced neural progenitor cell apoptosis in the GCL of the hippocampus and ameliorate learning impairments. It remains to be shown if lithium can be used to prevent the debilitating cognitive late effects seen in children treated with cranial radiotherapy.
    Document Type:
    Reference
    Product Catalog Number:
    ABN14
    Product Catalog Name:
    Anti-Brain lipid binding protein Antibody

  • WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. 25539912

    TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (pless than 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (pless than 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (pless than 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (pless than 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
    Document Type:
    Reference
    Product Catalog Number:
    05-636
    Product Catalog Name:
    Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301