The Expression of Markers of Acute Kidney Injury Kim1 and NGAL after Administration of High Doses of Lithium Carbonate in Mice with Engrafted Skin Melanoma B16.

The expression of marker proteins of acute kidney injury after administration of high doses of lithium carbonate was assessed to evaluate the possibility of lithium use in neutron capture therapy. In mice with implanted skin melanoma B16, the expression of Kim1 (kidney injury molecule 1) and NGAL (neutrophil gelatinase-associated lipocalin) proteins in the kidneys was evaluated immunohistochemically 15, 30, 90, 180 min, and 7 days after peroral administration of lithium carbonate at single doses of 300 and 400 mg/kg. An increase in the expression of the studied proteins was found in 30 and 90 min after administration of 400 mg/kg lithium carbonate, however, 7 days after the drug administration, the expression returned to the level observed in the control group. It can be suggested that single administration of lithium carbonate in the studied doses effective for lithium neutron capture therapy will not significantly affect the renal function.

Tissue-specific protective properties of lithium: comparison of rat kidney, erythrocytes and brain.

Lithium (Li) represents a first choice mood stabilizer for bipolar disorder (BD). Despite extensive clinical use, questions regarding its mechanism of action and pathological mechanism of renal function impairment by Li remain open. The present study aimed to improve our knowledge in this area paying special attention to the relationship between the length of Li action, lipid peroxidation (LP), and Na+/K+-ATPase properties. The effects of therapeutic Li doses, administered daily to male Wistar rats for 1 (acute), 7 (short term) and 28 days (chronic), were studied. For this purpose, Na+/K+-ATPase activity measurements, [3H]ouabain binding and immunoblot analysis of α-Na+/K+-ATPase were performed. Li-induced LP was evaluated by determining the malondialdehyde concentration by HPLC. Sleep deprivation (SD) was used as an experimental approach to model the manic phase of BD. Results obtained from the kidney were compared to those obtained from erythrocytes and different brain regions in the same tested animals. Whereas treatment with therapeutic Li concentration did not bring any LP damage nor significant changes of Na+/K+-ATPase expression and [3H]ouabain binding in the kidney, it conferred strong protection against this type of damage in the forebrain cortex. Importantly, the observed changes in erythrocytes indicated changes in forebrain cortices. Thus, different resistance to SD-induced changes of LP and Na+/K+-ATPase was detected in the kidney, erythrocytes and the brain of Li-treated rats. Our study revealed the tissue-specific protective properties of Li against LP and Na+/K+-ATPase regulation.

Lithium for Fracture Treatment (LiFT): a double-blind randomised control trial protocol.

INTRODUCTION: Fracture healing can fail in up to 10% of cases despite appropriate treatment. While lithium has been the standard treatment for bipolar disorder, it may also have a significant impact to increase bone healing in patients with long bone fractures. To translate this knowledge into clinical practice, a randomised clinical trial (RCT) is proposed. METHODS AND ANALYSIS: A multicentre double blind, placebo-controlled RCT is proposed to evaluate the efficacy of lithium to increase the rate and predictability of long bone fracture healing in healthy adults compared to lactose placebo treatment. 160 healthy individuals from 18 to 55 years of age presenting with shaft fractures of the femur, tibia/fibula, humerus or clavicle will be eligible. Fractures will be randomised to placebo (lactose) or treatment (300 mg lithium carbonate) group within 2 weeks of the injury. The primary outcome measure will be radiographic union defined as visible callus bridging on three of the four cortices at the fracture site using a validated radiographic union score. Secondary outcome measures will include functional assessment and pain scoring. ETHICS AND DISSEMINATION: Participant confidentiality will be maintained with publication of results. Research Ethics Board Approval: Sunnybrook Research Institute (REB # 356-2016). Health Canada Approval (HC6-24-C201560). Results of the main trial and secondary endpoints will be submitted for publication in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: NCT02999022.

The combination of microfracture with induction of Wnt / ß- Catenin pathway, leads to enhanced cartilage regeneration.

INTRODUCTION: Microfracture does not lead to complete healing of full-thickness cartilage defects. The aim of this study was to evaluate the effect of modifying Wnt/ß-catenin signaling following microfracture, on the restoration of a full-thickness cartilage defect in a rabbit model. The modification of the canonical Wnt pathway was achieved through per os administration of lithium carbonate, which is an intracellular inhibitor of glycogen synthase kinase 3-ß (Gsk3-ß) and therefore induces Wnt/ß-catenin signaling. MATERIALS AND METHODS: Full-thickness cartilage defects of 4 mm in diameter were created in the patellar groove of the right femurs of 18 male New Zealand white rabbits. The rabbits were divided into three groups of six (n = 6) based on post-surgery treatment differences, as follows: microfracture only (group 1), microfracture plus lithium carbonate 7 mM in the drinking water for 1 week (group 2), microfracture plus lithium carbonate 7 mM in the drinking water for 4 weeks (group 3). All animals were sacrificed 9 weeks after surgery. The outcome was assessed histologically, by using the International Cartilage Repair Society (ICRS) visual histological scale. Immunohistochemistry for type II collagen was also conducted. RESULTS: Statistical analysis of the histological ICRS scores showed that group 3 was significantly superior to group 1 in four out of six ICRS categories, while group 2 was superior to 1 in only two out of six. CONCLUSION: The combination of microfracture and systematic administration of lithium carbonate 7 mM for 4 weeks shows statistically significant superiority in four out of six ICRS categories compared with microfracture only for the treatment of full-thickness cartilage defects in a rabbit experimental model.

Cytological Characteristics of a Heterogeneous Population of Hepatocellular Carcinoma-29 Cells after Injection of Lithium Carbonate in the Experiment.

Five cytological types of hepatocellular carcinoma-29 (G-29) grown in the muscle tissue of the thigh of experimental animals were identified by transmission electron microscopy; 89% of these were poorly differentiated type I-III cells. Lithium in a concentration of 20 mM produced a damaging effect on poorly differentiated G-29 cells: the number of cells with zones of intracellular component destruction and volume density of these zones increased, while volume density of cisterns of endoplasmic reticulum decreased. These results suggest that lithium carbonate can cause destructive changes in the heterogeneous population of G-29 cells during in vivo tumor development.

Impact of Long-Term Lithium Treatment on Renal Function in Patients With Bipolar Disorder Based on Novel Biomarkers.

BACKGROUND: Lithium in the form of lithium carbonate (Li2CO3) has become one of the most effective and widely prescribed drugs for mood stabilization. However, lithium has adverse effects on renal tubular functions, such as decreased concentrating function of the kidneys, and even occasional symptoms of nephrogenous diabetes insipidus occur with additional evidence of glomerular disruption in lithium-treated patients. METHODS: We assessed the kidney function of patients with bipolar disorder who are under long-term lithium treatment using novel markers of kidney damage such as plasma neutrophil gelatinase-associated lipocalin, cystatin C, albuminuria, estimated glomerular filtration rate, Chronic Kidney Disease-Epidemiology Investigation using creatinine and cystatin C, and serum and urinary osmolality, and compared the results with those of age-matched patients with bipolar disorder not treated with lithium. The study enrolled 120 patients with bipolar disorder, consisting of 80 (30 male and 50 female patients) who have been receiving lithium for 0.5 to 20 (mean, 7) years and 40 (10 male and 30 female patients) who had never been exposed to lithium treatment. RESULTS: Patients treated with lithium had significantly decreased urine osmolality (mean ± SD, 405 ± 164 vs 667 ± 174 mmol/kg) and urine-to-serum osmolality ratio (1.35 ± 0.61 vs 2.25 ± 0.96). No significant difference was found in creatinine, estimated glomerular filtration rate values calculated using the Chronic Kidney Disease-Epidemiology Investigation using creatinine and cystatin C, neutrophil gelatinase-associated lipocalin, cystatin C, and albuminuria between both groups. We found no significant difference in renal biomarkers between patients treated with lithium for 6 to 24 months and those treated for 25 to 240 months. CONCLUSIONS: We found significantly decreased kidney concentrating ability in the long-term lithium-treated patients compared with the control group. Other renal function markers did not indicate any significant signs of renal dysfunction.

Dose optimization of lithium to increase the uptake and retention of I-131 in rat thyroid.

The present study was undertaken to optimize the dose of lithium, with an aim to increase the retention of I-131 in the thyroid follicles while maintaining the euthyroid state. 24 female Wistar rats weighing 110 ± 20 g were segregated into four groups. Animals in group I were fed standard laboratory feed and water throughout the period of experimentation. Animals in group II, III and IV were additionally fed with lithium in the form of lithium carbonate orally, at a dose of 10 mg/kg body weight, 20 mg/kg body weight, 30 mg/kg body weight respectively. The dose of lithium was started 1 week prior to radioiodine administration and continued thereafter for another 8 days. After 7 days of lithium treatment, 0.48 MBq of carrier-free I-131 was injected intraperitoneally into each rat, of the four groups. I-131 thyroidal uptake and biokinetics, as well as serum TSH, T3, T4 levels were estimated in all the treatment groups. A significant increase in the thyroid and whole body counts was observed after 4 and 24 h of I-131 aministration in lithium treated rats, compared to control animals. An increase in thyroidal effective t1/2 and serum TSH levels, along with decrease in the levels of serum T3 and T4 was observed with a dose of 20 mg/kg or higher. In Conclusion, a Lithium dose of 10 mg/kg body weight in rats could increase the uptake of I-131 in the thyroid, without disturbing the control circulating levels of thyroid hormones.

Lithium entrapped chitosan nanoparticles to reduce toxicity and increase cellular uptake of lithium.

Lithium carbonate is an effective drug against bipolar disorders. Direct use of lithium carbonate has been reported to result in lithium toxication and pulmonary complications. With chitosan micro and nanoparticles gaining attention for their protein absorption, drug targeting and improved dissolution rate of sparingly water-soluble drugs, this work has focused on chitosan loaded Li as a possible alternative to Li alone for cellular uptake. Well standardized ionic gelation technique employed in this study resulted in Li loaded chitosan nanoparticles with hydrodynamic diameter below 300 nm and zeta potential of + 30 mV and oval morphology. Through various techniques electrostatic interaction as well as Claritin dependent endocytic pathway is suggested as facilitating 1.3 times increase in cell proliferation in lithium carbonate loaded chitosan nanoparticles treated PC12 cells. A controlled Li release to the extent of less than 50% in 48 h from the nanoparticle was observed. This observation has very high significance as it ensures that the lithium toxicity can be avoided. These results indicated that chitosan is a promising carrier for lithium carbonate and may improve its therapeutic efficacy and also overcome toxicity during its use in the treatment of neuropsychiatric disorders.

[Lithium toxicity after bariatric surgery]. / Intoxication au lithium après chirurgie bariatrique.

Since many years a correlation between neuropsychiatric disorders and eating disorders resulting in obesity is well established. According to different studies, 1.2 - 4 % of patients scheduled for bariatric surgery are taking lithium as a mood stabilizer treatment for bipolar disorder. We are presenting a case of lithium toxicity after vertical sleeve gastrectomy surgery in a 40 years-old female. The patient developed severe neurological and renal signs needing an intensive care unit admission and continuous veno-venous hemodiafiltration. A literature review provides insights into physiological and pharmacokinetics changes that could contribute to lithium poisoning after bariatric surgery. This article illustrates the need for closer monitoring of lithium serum levels following bariatric surgery and presents guidance in managing lithium therapy during perioperative period based on experts' opinion.

Une corrélation entre troubles neuropsychiatriques et troubles alimentaires est maintenant établie depuis plusieurs années. Selon les études, 1,2 à 4% des patients éligibles pour une chirurgie bariatrique ont un traitement chronique comprenant du lithium (1-3). Nous rapportons le cas d'une patiente de 40 ans qui développe une intoxication au lithium dans le décours d'une «sleeve¼ - gastrectomie avec des signes neurologiques et rénaux sévères nécessitant sa prise en charge aux soins intensifs avec hémodiafiltration continue veino-veineuse. Nous détaillons les modifications physiologiques et pharmacocinétiques susceptibles d'induire un surdosage en lithium après une telle chirurgie. Nous revoyons enfin les recommandations concernant la prise en charge de l'intoxication au lithium ainsi que les mesures préventives péri-opératoires afin d'éviter une telle situation.

Short term treatment with lithium carbonate as adjunct to radioiodine treatment for long-lasting Graves' hyperthyroidism.

OBJECTIVE: Lithium carbonate is primarily used for the treatment of patients with bipolar affective disorders. Initial treatment of Graves' hyperthyroidism (GHT) with antithyroid drugs (ATD) has limitations at over 50% of treated patients because of significant side effects and relatively high relapses of the disease after drugs withdrawal. Till now, the influence of LiCO3on RIT outcome was mainly studied in patients with recent onset of GHT, and results were contradicted. Meta-analysis of case-control studies showed higher rated hypothyroidism in patients with mood disorders treated with LiCO3(121/869) than in controls (10/578). Although in a small number of patients (n=28) with long-lasting GHT, preliminary results of ours showed that ¹³¹I treatment with LiCO3for 7 days significantly improved the efficacy of RIT versus the non-LiCO3treated patients (P<0.001). Lithium treated patients were cured faster (12 of 13 patients were cured after one month) than those treated only with ¹³¹I (8 patients were cured after one and 11/15 patients after 12 months). Fewer patients treated with ¹³¹I and LiCO3had persistent hyperthyroidism than those treated with ¹³¹I alone. There were no toxic effects of LiCO3during 7 days treatment. CONCLUSION: These observations indicate of that short-term treatment with LiCO3in GHT patients as adjunct to ¹³¹I-NaI improves the efficacy of RIT, prevents transient exacerbation of hyperthyroidism, early induction of hypothyroidism and does not worsen ophthalmopathy.

Treatment and outcomes of an Australian cohort of outpatients with bipolar I or schizoaffective disorder over twenty-four months: implications for clinical practice.

BACKGROUND: The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, prospective, non-interventional, observational study designed to explore the clinical and functional outcomes associated with 'real-world' treatment of participants with bipolar I or schizoaffective disorder. All participants received treatment as usual. There was no study medication. METHODS: Participants prescribed either conventional mood stabilizers (CMS; n = 155) alone, or olanzapine with, or without, CMS (olanzapine ± CMS; n = 84) were assessed every 3 months using several measures, including the Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale, Clinical Global Impressions Scale - Bipolar Version, and the EuroQol Instrument. This paper reports 24-month longitudinal clinical, pharmacological, functional, and socioeconomic data. RESULTS: On average, participants were 42 (range 18 to 79) years of age, 58%; were female, and 73%; had a diagnosis of bipolar I. Polypharmacy was the usual approach to pharmacological treatment; participants took a median of 5 different psychotropic medications over the course of the study, and spent a median proportion of time of 100%; of the study on mood stabilizers, 90%; on antipsychotics, 9%; on antidepressants, and 5%; on benzodiazepines/hypnotics. By 24 months, the majority of participants had achieved both symptomatic and syndromal remission of both mania and depression. Symptomatic relapse rates were similar for both the CMS alone (65%;) and the olanzapine ± CMS (61%;) cohorts. CONCLUSIONS: Participants with bipolar I or schizoaffective disorder in this study were receiving complex medication treatments that were often discordant with recommendations made in contemporary major treatment guidelines. The majority of study participants demonstrated some clinical and functional improvements, but not all achieved remission of symptoms or syndrome.

Cholinergic stimulation of adrenal medulla is essential for the granulicytopoietic response to lithium.

Granulocytopoietic response to lithium carbonate (Li+) in rat was eliminated completely by N-cholinergic blocking agent, and independently by alpha-1-adrenergic antagonist. A link between these two contradictory events is explained by release of acetylcholine from the cholinergic preganglionic nerve endings in adrenal medulla triggered by Li+, and subsequent discharge of catecholamines (CA) from medullar chromaffin cells, which on their part activate adrenergic receptors of alpha-1 class on hematopoietic progenitor cells. Respectively, granulocytopoietic response to Li+ is blocked by cholinergic N-blocking agent at the level of adrenal medulla, and by the alpha-adrenergic blocking agent at the level of the hematopoietic cells proper. The stimulatory action of Li+ on granulocytopoietic cells is indirect, while is mediated by CA release from adrenal chromaffine cells. At the initial stages of leukocyte restitution in the acute myelotoxic leucopenia relative increase in "large" lymphocyte fraction (Lge) preceding the increment in granulocyte counts is evident. In this fraction of lymphocytes peripheral blood progenitor cells (PBPC) are expected.

The use of lithium carbonate to prevent lomustine-induced myelosuppression in dogs: a pilot study.

This was a preliminary investigation of the use of lithium to prevent lomustine-induced myelosuppression. Four 10 to 11 kg beagles received lomustine 20 to 30 mg, PO, q3wk, with cephalexin prophylaxis. Two dogs also received lithium, 150 to 300 mg, PO, q12h. Lithium blood concentrations fluctuated in and out of therapeutic interval. Lithium was discontinued in one dog in week 13, and in the other dog in week 38, due to toxicoses. All dogs developed grade 1 to 4 neutropenia after each lomustine treatment. In dogs receiving lomustine only, platelet concentrations decreased from 274 and 293 × 10(9)/L in week 1, to 178 and 218 × 10(9)/L in weeks 38 and 13, respectively. In dogs receiving lomustine and lithium, platelet concentrations decreased from 351 and 288 × 10(9)/L in week 1, to 214 and 212 × 10(9)/L, in weeks 36 and 13, respectively. Lithium did not prevent lomustine-induced myelosuppression and had important side-effects.

[Catatonic dilemma in a schizoaffective patient with combined lithium-risperidone administration]. / Katatones Dilemma unter Kombinationsbehandlung mit Lithium und Risperidon.

OBJECTIVE: The case of a schizoaffective patient suffering from a malignant catatonic syndrome following combined lithium-risperidone therapy is explored. METHOD: A case report and relevant deliberations regarding pathophysiology of the catatonic dilemma are discussed. CONCLUSIONS: There are two critical transitions in the development of a malignant catatonic syndrome. Dopaminergic system and psychopharmacological factors are supposed to play a key role. However, other neurotransmitter systems and the individual predisposition must be considered.

Effects of 4-week treatment with lithium and olanzapine on levels of brain-derived neurotrophic factor, B-cell CLL/lymphoma 2 and phosphorylated cyclic adenosine monophosphate response element-binding protein in the sub-regions of the hippocampus.

A large body of evidence indicates that lithium, the prototype mood stabilizer in the treatment of bipolar disorder, has diverse neuroprotective and neurotrophic actions, and the actions are associated with its efficacy in treating bipolar disorder. It has been suggested that up-regulation of neurotrophic and neuroprotective factors including brain-derived neurotrophic factor (BDNF) and B-cell CLL/lymphoma 2 (Bcl-2) may underlie these neuroplastic actions of the drug. Olanzapine, an atypical anti-psychotic drug, has been shown to be an effective mood stabilizer. Olanzapine also has neurotrophic and neuroprotective actions, and these actions may underlie the efficacy of the drug for bipolar disorder and schizophrenia. However, the molecular mechanism by which the drug produces the neuroplastic actions is poorly understood. To understand a common molecular mechanism underlying the neuroplastic actions of lithium and olanzapine, we assessed the effect of 4-week lithium and olanzapine treatment on the levels of BDNF, Bcl-2 and cyclic adenosine monophosphate response element-binding protein (CREB), a transcription factor involved in expression of BDNF and Bcl-2, in the dentate gyrus and hippocampal area CA1. Our results show that 4-week treatment with both olanzapine and lithium increases the levels of Bcl-2 and CREB in the dentate gyrus and hippocampal area CA1. Four-week lithium treatment up-regulates BDNF in the dentate gyrus, and 4-week olanzapine treatment marginally did so. Neither drug altered BDNF levels in area CA1. These results suggest that the up-regulation of Bcl-2 and CREB may underlie the neuroplastic actions of olanzapine and lithium.

Protective role of lithium in ameliorating the aluminium-induced oxidative stress and histological changes in rat brain.

This study was carried out to investigate the effects of lithium (Li) supplementation on aluminium (Al) induced changes in antioxidant defence system and histoarchitecture of cerebrum and cerebellum in rats. Al was administered in the form of aluminium chloride (100 mg/kg b.wt./day, orally) and Li was given in the form of Li carbonate through diet (1.1 g/kg diet, daily) for a period of 2 months. Al treatment significantly enhanced the levels of lipid peroxidation and reactive oxygen species in both the cerebrum and cerebellum, which however were decreased following Li supplementation. The enzyme activities of catalase, superoxide dismutase (SOD) and glutathione reductase (GR) were significantly increased in both the regions following Al treatment. Li administration to Al-fed rats decreased the SOD, catalase and GR enzyme activities in both the regions; however, in cerebellum the enzyme activities were decreased in comparison to normal controls also. Further, the specific activity of glutathione-s-transferase and the levels of total and oxidized glutathione were significantly decreased in cerebrum and cerebellum following Al treatment, which however showed elevation upon Li supplementation. The levels of reduced glutathione were significantly decreased in cerebrum but increased in cerebellum following Al treatment, which however were normalized upon Li supplementation but in cerebellum only. Apart from the biochemical changes, disorganization in the layers of cerebrum and vacuolar spaces were also observed following Al treatment indicating the structural damage. Similarly, the loss of purkinje cells was also evident in cerebellum. Li supplementation resulted in an appreciable improvement in the histoarchitecture of both the regions. Therefore, the study shows that Li has a potential to exhibit neuroprotective role in conditions of Al-induced oxidative stress and be explored further to be treated as a promising drug against neurotoxicity.

Effects of mood stabilizers on the inhibition of adenylate cyclase via dopamine D(2)-like receptors.

OBJECTIVE: The mood stabilizing drugs lithium, carbamazepine and valproate modulate brain adenosine monophosphate (cAMP) levels, which are assumed to be elevated in bipolar disorder patients. The aim of this work was to investigate how these three mood stabilizing agents affect the regulation of cAMP levels by dopamine D(2)-like receptors in vitro in rat cortical neurons in culture and in vivo in the rat prefrontal cortex. METHODS: The production of cAMP was measured in the cultured cortical neurons or in microdialysis samples collected from the prefrontal cortex of freely moving rats using the [8-(3)H] and [(125)I] radioimmunoassay kits. RESULTS: In vitro and in vivo data showed that the treatment with the mood stabilizing drugs had no effect on basal cAMP levels in vitro, but had differential effects in vivo. Direct stimulation of adenylate cyclase (AC) with forskolin increased cAMP levels both in vitro and in vivo, and this effect was significantly inhibited by all three mood stabilizers. Activation of dopamine D(2)-like receptors with quinpirole partially inhibited forskolin-induced increase in cAMP in untreated cultures, but no effect was observed in cortical neuron cultures treated with the mood stabilizing drugs. Similar results were obtained by chronic treatment with lithium and valproate in the prefrontal cortex in vivo. However, surprisingly, in carbamazepine-treated rats the activation of dopamine D(2)-like receptors enhanced the responsiveness of AC to subsequent activation by forskolin, possibly as a consequence of chronic inhibition of the activity of the enzyme. CONCLUSIONS: It was shown that each of these drugs affects basal- and forskolin-evoked cAMP levels in a distinct way, resulting in differential responses to dopamine D(2)-like receptors activation.

Lithium normalizes elevated intracellular sodium.

BACKGROUND: Both mania and bipolar depression are characterized by elevations of intracellular sodium concentrations. This observation has been purported to be central to the pathophysiology of abnormal moods in bipolar illness. Reduction of sodium influx is a proposed shared mechanism of action of effective mood stabilizers, but direct documentation of this effect for lithium has never been demonstrated. METHODS: Flame spectroscopic determinations of intracellular sodium concentration were performed in the human glioma cell line, LN292, after treatment with the sodium pump inhibitor, ouabain, and co-treatment with ouabain and lithium. RESULTS: Ouabain 0.1 microM doubles the intracellular sodium concentration after 3 days. Pretreatment with lithium 1 mM for 1 week normalizes intracellular sodium. CONCLUSION: This is the first demonstration that lithium can normalize abnormally elevated intracellular sodium levels. This may be an important mechanism of lithium action.

Concurrent administration of Neu2000 and lithium produces marked improvement of motor neuron survival, motor function, and mortality in a mouse model of amyotrophic lateral sclerosis.

The Fas pathway and oxidative stress mediate neuronal death in stroke and may contribute to neurodegenerative disease. We tested the hypothesis that these two factors synergistically produce spinal motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Levels of reactive oxygen species were increased in motor neurons from ALS mice compared with wild-type mice at age 10 weeks, before symptom onset. The proapoptotic proteins Fas, Fas-associated death domain, caspase 8, and caspase 3 were also elevated. Oral administration of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000), a potent antioxidant, blocked the increase in reactive oxygen species but only slightly reduced activation of proapoptotic proteins. Administration of lithium carbonate (Li(+)), a mood stabilizer that prevents apoptosis, blocked the apoptosis machinery without preventing oxidative stress. Neu2000 or Li(+) alone significantly enhanced survival time and motor function and together had an additive effect. These findings provide evidence that jointly targeting oxidative stress and Fas-mediated apoptosis can prevent neuronal loss and motor dysfunction in ALS.