lithium-chloride and Neurodegenerative-Diseases

Topics: Animals; Brain; Humans; Iron; Lithium Chloride; Neurodegenerative Diseases; tau Proteins

Bipolar illness is a major psychiatric disorder that affects 1-3% of the worldwide population. Epidemiological studies have demonstrated that this illness is substantially heritable. However, the genetic characteristics remain unknown and a clear personality has not been identified for these patients. The clinical history of lithium began in mid-19th century when it was used to treat gout. In 1940, it was used as a substitute for sodium chloride in hypertensive patients. However, it was then banned, as it had major side effects. In 1949, Cade reported that lithium could be used as an effective treatment for bipolar disorder and subsequent studies confirmed this effect. Over the years, different authors have proposed many biochemical and biological effects of lithium in the brain. In this review, the main mechanisms of lithium action are summarised, including ion dysregulation; effects on neurotransmitter signalling; the interaction of lithium with the adenylyl cyclase system; inositol phosphate and protein kinase C signalling; and possible effects on arachidonic acid metabolism. However, none of the above mechanisms are definitive, and sometimes results have been contradictory. Recent advances in cellular and molecular biology have reported that lithium may represent an effective therapeutic strategy for treating neurodegenerative disorders like Alzheimer's disease, due to its effects on neuroprotective proteins like Bcl-2 and its actions on regulators of apoptosis and cellular resilience, such as GSK-3. However, results are contradictory and more specific studies into the use of lithium in therapeutic approaches for neurodegenerative diseases are required.

Topics: Animals; Antimanic Agents; Bipolar Disorder; History, 20th Century; History, 21st Century; Humans; Lithium Chloride; Neurodegenerative Diseases

For over fifty years lithium has been a fundamental component of therapy for patients with bipolar disorders. Lithium has been considered recently for its potential to alleviate neuronal loss and other neurodegeneration processes. For instance, lithium reduces the severity of some behavioral complications of Alzheimer's disease (AD). And there are growing indications that lithium may be of benefit to the underlying pathology of AD, as well as an array of other common CNS disorders, including stroke, Parkinson's disease, and Huntington's disease. Despite these demonstrated and prospective therapeutic benefits, lithium's mechanism of action remains elusive, and opinions differ regarding the most relevant molecular targets. Lithium inhibits several enzymes; significant among these are inositol monophosphatase (IMPase), glycogen synthase kinase-3 (GSK-3), and the proteasome. Most recent publications discussing the medical application of lithium have converged on GSK-3, so this article reviews data and discussions regarding the roles and interactions of GSK-3 with other proteins and its proposed role in the pathogenesis of Alzheimer's disease.

Topics: Animals; Glycogen Synthase Kinase 3; Humans; Lithium Chloride; Models, Biological; Neurodegenerative Diseases; Neuroprotective Agents

Alzheimer's disease (AD) is one of the most challenging diseases around the world with no effective clinical treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivatives as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and

Topics: Animals; Drug Design; Drug Discovery; Female; Humans; Indoles; Mice; Mitogen-Activated Protein Kinase 10; Models, Molecular; Neurodegenerative Diseases; Neuroprotective Agents; Phosphorylation; Protein Kinase Inhibitors

Status epilepticus (SE) causes irreversible neurodegeneration if not terminated quickly. Perampanel (PER), a potent AMPA receptor antagonist, has previously been shown to terminate seizures in the lithium-pilocarpine SE model. In the present study, we assessed whether PER would also prevent neuronal damage in this model.. SE was induced in rats using lithium chloride and pilocarpine. Initiation of SE was defined as continuous seizures that exhibited as rearing accompanied by bilateral forelimb clonus (Racine score 4). Either PER (0.6, 2, or 6mg/kg) or diazepam (DZP, 10mg/kg) was administered intravenously 30min after SE initiation. Histopathological samples from treated and seizure-naive rats were taken one week after treatment and then stained with an anti-neuronal nuclei (NeuN) antibody. The sections were analyzed by using a pixel-counting algorithm to quantify the amount of staining in the CA1 subregion of the hippocampus, piriform cortex (Pir), and mediodorsal thalamic nucleus (MD).. DZP administration did not suppress seizures or the degeneration of neurons in the examined areas. Seizures were terminated in 100% of rats treated with 6mg/kg PER (n=8) and in 47% (7/15) of rats treated with 2mg/kg PER, and neurons in the analyzed areas of these animals were preserved to the level seen in naive rats. In the eight animals in which 2mg/kg PER did not terminate the seizures, neuronal loss was partially attenuated in CA1 and Pir, and neurons were fully preserved in MD. Treatment with 0.6mg/kg PER did not terminate the seizures or significantly preserve neurons. The anti-seizure effect of PER correlated well with the degree of neuroprotection in each analyzed area.. PER exhibited a strong neuroprotective effect in a drug-refractory SE model, and this effect was correlated with its attenuation of seizure.

Topics: Animals; Anticonvulsants; Antigens, Nuclear; Brain; Cell Death; Diazepam; Dose-Response Relationship, Drug; Immunohistochemistry; Lithium Chloride; Male; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Nitriles; Pilocarpine; Pyridones; Rats, Sprague-Dawley; Status Epilepticus

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucelotide repeat that encodes an abnormal polyglutamine (PolyQ) tract in the disease protein, ataxin-3. The formation of neuronal intranuclear inclusions in the specific brain regions is one of the pathological hallmarks of SCA3. Acceleration of the degradation of the mutant protein aggregates is proven to produce beneficial effects in SCA3 and other PolyQ diseases. Lithium is known to be neuroprotective in various models of neurodegenerative disease and can reduce the mutant protein aggregates by inducing autophagy. In this study, we explored the therapeutic potential of lithium in a SCA3 Drosophila model. We showed that chronic treatment with lithium chloride at specific doses notably prevented eye depigmentation, alleviated locomotor disability, and extended the median life spans of SCA3 transgenic Drosophila. By means of genetic approaches, we showed that co-expressing the mutant S9E, which mimicked the phosphorylated S9 state of Shaggy as done by lithium, also partly decreased toxicity of gmr-SCA3tr-Q78. Taken together, our findings suggest that lithium is a promising therapeutic agent for the treatment of SCA3 and other PolyQ diseases.

Topics: Age Factors; Animals; Animals, Genetically Modified; Ataxin-3; Disease Models, Animal; Dose-Response Relationship, Drug; Drosophila; Enzyme Activation; Eye; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lithium Chloride; Microscopy, Electron, Scanning; Motor Activity; Movement Disorders; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroprotective Agents; Nuclear Proteins; Peptides; Repressor Proteins

Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers a great potential for severe CNS unmet diseases, being one of the inhibitors on clinical trials for different tauopathies. Following our hypothesis based on the enhanced reactivity of residue Cys199 in the binding site of GSK-3, we examine here the suitability of phenylhalomethylketones as irreversible inhibitors. Our data confirm that the halomethylketone unit is essential for the inhibitory activity. Moreover, addition of the halomethylketone moiety to reversible inhibitors turned them into irreversible inhibitors with IC(50) values in the nanomolar range. Overall, the results point out that these compounds might be useful pharmacological tools to explore physiological and pathological processes related to signaling pathways regulated by GSK-3 opening new avenues for the discovery of novel GSK-3 inhibitors.

Topics: Adenosine Triphosphate; Animals; Binding Sites; Cattle; Central Nervous System Agents; Cerebellum; Drug Design; Glycogen Synthase Kinase 3; Humans; In Vitro Techniques; Ketones; Mice; Models, Molecular; Neurodegenerative Diseases; Neurons; Phosphorylation; Protein Binding; Rats; Receptors, Neurotransmitter; Stereoisomerism; Structure-Activity Relationship; tau Proteins

We investigated the neuroprotective effects of lithium in an experimental neurodegeneration model gated to kainate (KA) receptor activation.. The hippocampus from KA-treated mice and hippocampal cell cultures were used to evaluate the pathways regulated by chronic lithium pretreatment in both in vivo and in vitro models.. Treatment with KA, as measured by fragmentation of alpha-spectrin and biochemically, induced the activation of calpain resulting in p35 cleavage to p25, indicating activation of cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase-3ss (GSK-3ss) and an increase in tau protein phosphorylation. Treatment with lithium reduced calpain activation and reduced the effects of cdk5 and GSK-3ss on tau. KA treatment of cultures resulted in neuronal demise. According to nuclear condensed cell counts, the addition of lithium to neuronal cell cultures (0.5-1 mM) a few days before KA treatment had neuroprotective and also antiapoptotic effects. The action of lithium on calpain/cdk5 and GSK-3ss pathways produced similar results in vivo. As calpain is activated by an increase in intracellular calcium, we showed that lithium reduced calcium concentrations in basal and KA-treated hippocampal cells, which was accompanied by an increase in NCX3, a Na+/Ca2+ exchanger pump.. A robust neuroprotective effect of lithium in the excitotoxic process induced by KA in mouse hippocampus was demonstrated via modulation of calcium entry and the subsequent inhibition of the calpain pathway. These mechanisms may act in an additive way with other mechanisms previously described for lithium, suggesting that it may be useful as a possible therapeutic strategy for Alzheimer's disease.

Topics: Animals; Calcium; Calpain; Cell Survival; Cells, Cultured; Cyclin-Dependent Kinase 5; Disease Models, Animal; Glycogen Synthase Kinases; Hippocampus; Kainic Acid; Lithium Chloride; Male; Mice; Mice, Inbred Strains; Neurodegenerative Diseases; Neuroprotective Agents; Phosphorylation; tau Proteins

Although significant progress in understanding brain function has been made in the last 15 years, the unmet medical need for effective therapeutic treatment of devastating neurodegenerative disorders is still enormous and represents a formidable challenge at the beginning of the 21st century. With the recent accumulation of evidence that the Wnt signaling pathway might be impaired in such diseases, a new avenue for potential therapeutic intervention has been opened which comprises many putative drug targets.

Topics: Animals; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Homeostasis; Humans; Indoles; Lithium Chloride; Maleimides; Models, Biological; Nervous System; Neurodegenerative Diseases; Pyridines; Pyrimidines; Signal Transduction; Thiazoles; Urea; Wnt Proteins

In most neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and Alzheimer disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated astrocytes and microglia and their cytotoxic agents play a crucial pathological role. Current treatments for these diseases are not effective. In the present study we investigate the effect of thiadiazolidinone derivatives, which have been recently suggested to play a role in neurodegenerative disorders. We have found that thiadiazolidinones are potent neuroprotector compounds. Thiadiazolidinones inhibited inflammatory activation of cultured brain astrocytes and microglia by diminishing lipopolysaccharide-induced interleukin 6, tumor necrosis factor alpha, inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor-alpha and nitric oxide production and, concomitantly, protected cortical neurons from cell death induced by the cell-free supernatant from activated microglia. The neuroprotective effects of thiadiazolidinones are completely inhibited by the peroxisome proliferator-activated receptor gamma antagonist GW9662. In contrast the glycogen synthase kinase 3beta inhibitor LiCl did not show any effect. These findings suggest that thiadiazolidinones potently attenuate lipopolysaccharide-induced neuroinflammation and reduces neuronal death by a mechanism dependent of peroxisome proliferator-activated receptor gamma activation.

Topics: Alitretinoin; Anilides; Animals; Anti-Inflammatory Agents; Apoptosis; Astrocytes; Brain; Cell Death; Cell Line; Cell-Free System; Cells, Cultured; Cyclooxygenase 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutamic Acid; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Immunohistochemistry; In Vitro Techniques; Inflammation; Interleukin-6; Lipopolysaccharides; Lithium Chloride; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Models, Chemical; Neurodegenerative Diseases; Neuroglia; Neurons; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; PPAR gamma; Prostaglandin-Endoperoxide Synthases; Rats; Staurosporine; Thiazolidinediones; Time Factors; Transfection; Tretinoin; Tumor Necrosis Factor-alpha

Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.

Topics: Animals; Disease Progression; Enzyme Inhibitors; Epitopes; Glycogen Synthase Kinase 3; Humans; Image Processing, Computer-Assisted; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Lithium; Lithium Chloride; Mice; Mice, Transgenic; Neurodegenerative Diseases; Neurons; Phosphorylation; tau Proteins; Tauopathies