Lithium Articles 4

© 2012

John Cade (1912-1980)

            (Abhishekh and Faizan 2012) Download

It was in his kitchen in Bundoora, Victoria, Australia that John Cade conducted the experiments that would convey his name to posterity. During the course of his experiments he found that guinea pigs ingesting urine concentrates obtained from manic patients showed toxic effects, whereas guinea pigs ingesting urine concentrates from normal individuals did not. He also found that urea ingested alone produced toxicity, but to a lesser degree. He hypothesized that uric acid is a possible contributor to this phenomenon. In order to test his hypothesis he increased the solu- bilityofuricacidbyaddinglithiumcar- bonate to urine. After administering lithium carbonate along with the urea and creatinine, Cade observed a signifi- cant reduction in toxicity (Cade, 1949).

Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage

            (Bachmann, Wang et al. 2009) Download

Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.

Old but still gold: Lithium in stabilizing the mood

            (Balon 2009) Download

Glucocorticoids and lithium reciprocally regulate the proliferation of adult dentate gyrus-derived neural precursor cells through GSK-3beta and beta-catenin/TCF pathway

            (Boku, Nakagawa et al. 2009) Download

Adult hippocampal neurogenesis is decreased in rodent models for stress-related disorders at least partly through an elevated level of glucocorticoids. On the other hand, the mood stabilizer lithium (Li) commonly used for their treatment increases it. This effect is thought to be one of the therapeutic actions of Li, but the molecular mechanism has been poorly understood. Here we established the culture system of adult rat dentate gyrus-derived neural precursor cells (ADPs) and examined the effects of dexamethasone (DEX), an agonist of glucocorticoids receptor, and Li on ADP proliferation. It is possible for ADP to be a type 2a cell, which corresponds to the second stage in a model of four differentiation stages in adult hippocampal neural precursor cells. DEX decreased ADP proliferation, but Li did not have any effect on it. However, Li recovered ADP proliferation decreased by DEX. The recovery effect of Li was abolished by quercetin, an inhibitor of beta-catenin/TCF pathway. The intranuclear translocation of beta-catenin and expression of cyclin D1 are reciprocally regulated by DEX and Li in a way similar to proliferation. In addition, DEX increased the phosphorylation of Tyr(216), which renders glycogen synthase kinase-3beta (GSK-3beta) active on it. These results suggest that GSK-3beta and beta-catenin/TCF pathway might be important in the reciprocal effects between DEX and Li on ADP proliferation and are new targets of therapeutic agents for stress-related disorders.


Neuroprotective action of lithium in disorders of the central nervous system

            (Chiu and Chuang 2011) Download

Substantial in vitro and in vivo evidence of neurotrophic and neuroprotective effects of lithium suggests that it may also have considerable potential for the treatment of neurodegenerative conditions. Lithium's main mechanisms of action appear to stem from its ability to inhibit glycogen synthase kinase-3 activity and also to induce signaling mediated by brain-derived neurotrophic factor. This in turn alters a wide variety of downstream effectors, with the ultimate effect of enhancing pathways to cell survival. In addition, lithium contributes to calcium homeostasis. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, for instance, it suppresses the calcium-dependent activation of pro-apoptotic signaling pathways. By inhibiting the activity of phosphoinositol phosphatases, it decreases levels of inositol 1,4,5-trisphosphate, a process recently identified as a novel mechanism for inducing autophagy. These mechanisms allow therapeutic doses of lithium to protect neuronal cells from diverse insults that would otherwise lead to massive cell death. Lithium, moreover, has been shown to improve behavioral and cognitive deficits in animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, and Huntington's, Alzheimer's, and Parkinson's diseases. Since lithium is already FDA-approved for the treatment of bipolar disorder, our conclusions support the notion that its clinical relevance can be expanded to include the treatment of several neurological and neurodegenerative-related diseases.

Lithium: a key to the genetics of bipolar disorder

            (Cruceanu, Alda et al. 2009) Download

Since the 1950s, lithium salts have been the main line of treatment for bipolar disorder (BD), both as a prophylactic and as an episodic treatment agent. Like many psychiatric conditions, BD is genetically and phenotypically heterogeneous, but evidence suggests that individuals who respond well to lithium treatment have more homogeneous clinical and molecular profiles. Response to lithium seems to cluster in families and can be used as a predictor for recurrence of BD symptoms. While molecular studies have provided important information about possible genes involved in BD predisposition or in lithium response, neither the mechanism of action of this drug nor the genetic profile of bipolar disorder is, as yet, completely understood.


Lithium and hematology: established and proposed uses

            (Focosi, Azzara et al. 2009) Download

Lithium (as lithium carbonate) is an inexpensive drug, widely used in psychiatry for over 50 years in treatment of mood instability (bipolar disorder) and as an adjunct to antidepressants. Hematological effects of neutrophilia and increased circulating CD34+ cells of marrow origin have long been known. Lithium was at the center of hematological investigations in the 1980s, but no definitive use in hematology has yet emerged. We review evidence that lithium increases G-CSF and augments G-CSF effects. We suggest possible therapeutic uses of lithium in neutropenia. In bone marrow transplantation, preharvest lithium-assisted hematopoietic stem cell mobilization may be useful as well.

Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study

            (Hajek, Bauer et al. 2012) Download

BACKGROUND: Neuroprotective effects of lithium (Li) have been well documented in tissue cultures and animal models, whereas human data continue to be limited. Previous studies investigating the association between Li treatment and brain N-acetylaspartate (NAA), a putative neuronal marker, showed mixed results because of methodological heterogeneity. METHODS: To investigate the effects of Li on prefrontal cortex NAA levels, we compared patients with bipolar disorder from specialized Li clinics in Berlin and Halifax with at least 2 years of ongoing Li treatment (Li group), patients with lifetime Li exposure of less than 3 months more than 2 years ago (non-Li group) and healthy controls. Participants in both patient groups had at least 10 years of illness and 5 episodes. We measured left prefrontal NAA levels using 1.5-T magnetic resonance spectroscopy. RESULTS: We enrolled 27 participants in the Li, 16 in the non-Li and 21 in the healthy control groups. The non-Li group had lower prefrontal NAA levels than the Li group (t41 = -3.44, corrected p < 0.01) or control participants (t35 = -2.91, corrected p < 0.05), who did not differ from the Li group (t46 = -0.14, p = 0.89). The same pattern of prefrontal NAA differences was replicated in both sites. In addition, there was a negative correlation between prefrontal NAA and duration of illness in the non-Li group (r = -0.60, p = 0.019) but not in the Li group (r = 0.07, p = 0.74). LIMITATIONS: Study limitations include the crosssectional design and exposure to other medications. CONCLUSION: Whereas patients with bipolar disorder, substantial illness burden and limited lifetime Li exposure had significantly lower prefrontal NAA levels than controls, Li-treated patients with similar illness burden showed prefrontal NAA levels comparable to those of healthy controls. These findings provide indirect support for neuroprotective effects of Li and for negative effects of illness burden on prefrontal NAA levels in patients with bipolar disorder.


Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis

            (Hajek, Kopecek et al. 2012) Download

Background: Smaller hippocampal volumes relative to controls are among the most replicated neuroimaging findings in individuals with unipolar but not bipolar depression. Preserved hippocampal volumes in most studies of participants with bipolar disorder may reflect potential neuroprotective effects of lithium (Li). Methods: To investigate hippocampal volumes in patients with bipolar disorder while controlling for Li exposure, we performed a meta-analysis of neuroimaging studies that subdivided patients based on the presence or absence of current Li treatment. To achieve the best coverage of literature, we categorized studies based on whether all or a majority, or whether no or a minority of patients were treated with Li. Hippocampal volumes were compared by combining standardized differences between means (Cohen d) from individual studies using random-effects models. Results: Overall, we analyzed data from 101 patients with bipolar disorder in the Li group, 245 patients in the non-Li group and 456 control participants from 16 studies. Both the left and right hippocampal volumes were significantly larger in the Li group than in controls (Cohen d = 0.53, 95% confidence interval [CI] 0.18 to 0.88; Cohen d = 0.51, 95% CI 0.21 to 0.81, respectively) or the non-Li group (Cohen d = 0.93, 95% CI 0.56 to 1.31; Cohen d = 1.07, 95% CI 0.70 to 1.45, respect ively), which had smaller left and right hippocampal volumes than the control group (Cohen d = -0.36, 95% CI -0.55 to -0.17; Cohen d = -0.38, 95% CI -0.63 to -0.13, respectively). There was no evidence of publication bias. Limitations: Missing information about the illness burden or lifetime expos ure to Li and polypharmacy in some studies may have contributed to statistical heterogeneity in some analyses. Conclusion: When expos ure to Li was minimized, patients with bipolar disorder showed smaller hippocampal volumes than controls or Li-treated patients. Our findings provide indirect support for the negative effects of bipolar disorder on hippocampal volumes and are consist ent with the putative neuroprotective effects of Li. The preserved hippocampal volumes among patients with bipolar disorder in most individual studies and all previous meta-analyses may have been related to the inclusion of Li-treated participants.


Lithium side-effects and predictors of hypothyroidism in patients with bipolar disorder: sex differences

            (Henry 2002) Download

OBJECTIVE: To determine the prevalence of the side effects of lithium therapy and possible predictors of hypothyroidism in women and men with bipolar disorder. METHOD: Twenty-two men and 38 women with bipolar disorder and taking lithium for at least 1 year, were interviewed about lithium side effects using a list of the most commonly reported symptoms. RESULTS: The complaint most frequently reported was polyuria-polydipsia syndrome, which affected 36 (60%) of 60 patients. More men than women reported tremor (54% v. 26%, p < 0.05), but weight gain during the first year of treatment was more frequent in women than men (47% v. 18%, p < 0.05), as was the development of clinical hypothyroidism (37% v. 9%, p < 0.05). Weight gain during the first year of treatment (and not sex) was the only significant predictor of hypothyroidism. CONCLUSION: Weight gain during the first year of lithium treatment, in the absence of biological evidence of subclinical hypothyroidism, was the most predictive and, possibly, the first sign of hypothyroidism.

Lithium--early development, toxicity, and renal function

         (Johnson 1998) Download

The report of the effectiveness of lithium in the treatment of mania by John Cade was followed by a number of studies confirming his observations and developing guidelines for safe and effective use. Premature rejection of lithium on safety grounds denied many patients the benefit of treatment and may have cost more lives than it saved. A similar safety alarm was triggered by reports of kidney damage in the late 1970s. Subsequent reports have questioned the significance of anatomical findings, and functional impairment and relationship to lithium treatment. Recent findings support the conclusion that progressive impairment of glomerular and tubular function in patients during lithium maintenance is the exception rather than the rule and is related more to lithium intoxication, maintenance plasma lithium levels, concurrent medications, somatic illness, and age than on time on lithium. Guidelines for lithium use and monitoring of renal function are outlined.


The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis

            (Machado-Vieira, Manji et al. 2009) Download

Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention. Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium's neurotrophic effects since Cade's original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium's neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium's neurotrophic effects in BD are an example of an old molecule acting as a new proof-of-concept agent. Continued work to decipher lithium's molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses.

Lithium treatment effects on Myo-inositol in adolescents with bipolar depression

         (Patel, DelBello et al. 2006) Download

BACKGROUND: The neurochemical effects of lithium in adolescents with bipolar disorder largely are unknown. This study used proton magnetic resonance spectroscopy (1H MRS) to identify the in vivo effects of lithium on myo-inositol (mI) concentrations in adolescent bipolar depression. METHODS: Twenty-eight adolescents (12-18 years old) with bipolar I disorder, current episode depressed, received open-label lithium 30 mg/kg, adjusted to achieve serum levels of 1.0-1.2 mEq/L. The mI concentrations in the medial as well as the left and right lateral prefrontal cortices were measured at baseline, day 7, and day 42 of treatment. Changes in mI concentrations over time were analyzed. RESULTS: Significant main effects of time were observed for mI concentrations in the medial (p = .03) and right lateral (p = .05) prefrontal cortices. Baseline concentrations of mI were not significantly different from day 7 or day 42 concentrations. However, mI concentrations on day 42 were significantly higher than those on day 7 (p = .02) in both regions. CONCLUSIONS: This study demonstrates that prefrontal mI concentrations do not significantly change from baseline after acute and chronic lithium treatment in adolescents with bipolar depression. Further investigation of the effect of lithium on mI is warranted to better understand possible mechanisms by which lithium exerts antidepressant activity.

Cytoprotective effect of lithium against spontaneous and induced apoptosis of lymphoid cell line MOLT-4

            (Pietruczuk, Jozwik et al. 2009) Download

Lithium (Li) is still useful in the treatment of bipolar disorder. Cellular mechanisms of Li action are not fully understood and include some cytoprotective properties. Data concerning Li effect on the apoptotic mechanisms in cells other than neurons are fragmentary and contradictory. We have investigated anti-apoptotic activity of Li in a lymphoid derived MOLT-4 cell line. Spontaneous and camptothecin-induced apoptosis was analyzed in cells treated with 0-20 mM Li carbonate. Early apoptosis was identified as significant mitochondrial depolarization (JC-1 staining). Later stages of apoptosis were estimated with annexin V binding and by the proportion of cells containing sub-G1 amounts of DNA (PI staining). We have observed a biphasic effect of Li on the proportion of spontaneously apoptotic cells;namely, low (therapeutic) concentrations of Li had a significant effect stabilizing the mitochondrial membrane polarization, while 10 and 20mM Li increased apoptosis. The latter could be seen both as mitochondrial depolarization as well as an increased proportion of sub-G1 cells, accompanied by reduced proportion of S phase cells. Li at concentrations above 2 mM had a significant, dose-dependent, anti-apoptotic effect on the cells undergoing camptothecin induced apoptosis. In conclusion, demonstrated cytoprotective effect of Li is at least partially related to stabilization of mitochondrial membrane potential and to the reduction of DNA damaging effects in proliferating cells; both may form part of the mechanism through which Li is useful in therapy of bipolar disorder, but may have more general consequences.

Lithium not only stabilizes mood, it is also neuroprotective

            (Praharaj 2011) Download


Lithium promotes neural precursor cell proliferation: evidence for the involvement of the non-canonical GSK-3beta-NF-AT signaling

            (Qu, Sun et al. 2011) Download

Lithium, a drug that has long been used to treat bipolar disorder and some other human pathogenesis, has recently been shown to stimulate neural precursor growth. However, the involved mechanism is not clear. Here, we show that lithium induces proliferation but not survival of neural precursor cells. Mechanistic studies suggest that the effect of lithium mainly involved activation of the transcription factor NF-AT and specific induction of a subset of proliferation-related genes. While NF-AT inactivation by specific inhibition of its upstream activator calcineurin antagonized the effect of lithium on the proliferation of neural precursor cells, specific inhibition of the NF-AT inhibitor GSK-3beta, similar to lithium treatment, promoted neural precursor cell proliferation. One important function of lithium appeared to increase inhibitory phosphorylation of GSK-3beta, leading to GSK-3beta suppression and subsequent NF-AT activation. Moreover, lithium-induced proliferation of neural precursor cells was independent of its role in inositol depletion. These findings not only provide mechanistic insights into the clinical effects of lithium, but also suggest an alternative therapeutic strategy for bipolar disorder and other neural diseases by targeting the non-canonical GSK-3beta-NF-AT signaling.

Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects

            (Quiroz, Machado-Vieira et al. 2010) Download

The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders.


Lithium desensitizes brain mitochondria to calcium, antagonizes permeability transition, and diminishes cytochrome C release

            (Shalbuyeva, Brustovetsky et al. 2007) Download

Among the numerous effects of lithium on intracellular targets, its possible action on mitochondria remains poorly explored. In the experiments with suspension of isolated brain mitochondria, replacement of KCl by LiCl suppressed mitochondrial swelling, depolarization, and a release of cytochrome c induced by a single Ca2+ bolus. Li+ robustly protected individual brain mitochondria loaded with rhodamine 123 against Ca2+-induced depolarization. In the experiments with slow calcium infusion, replacement of KCl by LiCl in the incubation medium increased resilience of synaptic and nonsynaptic brain mitochondria as well as resilience of liver and heart mitochondria to the deleterious effect of Ca2+. In LiCl medium, mitochondria accumulated larger amounts of Ca2+ before they lost the ability to sequester Ca2+. However, lithium appeared to be ineffective if mitochondria were challenged by Sr2+ instead of Ca2+. Cyclosporin A, sanglifehrin A, and Mg2+, inhibitors of the mitochondrial permeability transition (mPT), increased mitochondrial Ca2+ capacity in KCl medium but failed to do so in LiCl medium. This suggests that the mPT might be a common target for Li+ and mPT inhibitors. In addition, lithium protected mitochondria against high Ca2+ in the presence of ATP, where cyclosporin A was reported to be ineffective. SB216763 and SB415286, inhibitors of glycogen synthase kinase-3beta, which is implicated in regulating reactive oxygen species-induced mPT in cardiac mitochondria, did not increase Ca2+ capacity of brain mitochondria. Altogether, these findings suggest that Li+ desensitizes mitochondria to elevated Ca2+ and diminishes cytochrome c release from brain mitochondria by antagonizing the Ca2+-induced mPT.

The treatment of manic psychoses by the administration of lithium salts

            (Schou, Juel-Nielsen et al. 1954) Download

Is phosphoadenosine phosphate phosphatase a target of lithium's therapeutic effect?

            (Shaltiel, Deutsch et al. 2009) Download

Lithium, which is approved for treating patients with bipolar disorder, is reported to inhibit 3'(2')-phosphoadenosine-5'-phosphate (PAP) phosphatase activity. In yeast, deletion of PAP phosphatase results in elevated PAP levels and in inhibition of sulfation and of growth. The effect of lithium on PAP phosphatase is remarkable for the low Ki (approximately 0.2 mM), suggesting that this system would be almost completely shut down in vivo with therapeutic levels of 1 mM lithium, thereby elevating PAP levels. To test the hypothesis that lithium inhibition of PAP phosphatase is pharmacologically relevant to bipolar disorder, we fed rats LiCl for 6 weeks, and assayed brain PAP levels after subjecting the brain to high-energy microwaving. We also measured PAP phosphatase mRNA and protein levels in frozen brain tissue of lithium-treated mice. Brain adenosine phosphates were extracted by trichloroacetic acid and assayed by HPLC with a gradient system of two phases. PAP phosphatase mRNA was measured by RT-PCR, and PAP phosphatase protein was measured by Western blotting. Brain PAP levels were below detection limit of 2 nmol/g wet weight, even following lithium treatment. Lithium treatment also did not significantly change brain PAP phosphatase mRNA or protein levels. These results question the relevance of PAP phosphatase to the therapeutic mechanism of lithium. A statistically significant 25% reduced brain ADP/ATP ratio was found following lithium treatment in line with lithium's suggested neuroprotective effects.

3'-5' phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo

            (Toledano, Ogryzko et al. 2012) Download

pAp (3'-5' phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP-ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the Km and the Vmax of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl)ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity.

Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3beta, beta-catenin, and neurotrophin cascades

            (Wada 2009) Download

Mood disorders are not merely attributed to the functional defect of neurotransmission, but also are due to the structural impairment of neuroplasticity. Chronic stress decreases neurotrophin levels, precipitating or exacerbating depression; conversely, antidepressants increase expression of various neurotrophins (e.g., brain-derived neurotrophic factor and vascular endothelial growth factor), thereby blocking or reversing structural and functional pathologies via promoting neurogenesis. Since the worldwide approval of lithium therapy in 1970, lithium has been used for its anti-manic, antidepressant, and anti-suicidal effects, yet the therapeutic mechanisms at the cellular level remain not-fully defined. During the last five years, multiple lines of evidence have shown that the mood stabilization and neurogenesis by lithium are due to the lithium-induced inhibition of glycogen synthase kinase-3beta (GSK-3beta), allowing accumulation of beta-catenin and beta-catenin-dependent gene transcriptional events. Altered levels of GSK-3beta and beta-catenin are associated with various neuropsychiatric and neurodegenerative diseases, while various classical neuropsychiatric drugs inhibit GSK-3beta and up-regulate beta-catenin expression. In addition, evidence has emerged that insulin-like growth factor-I enhances antidepression, anti-anxiety, memory, neurogenesis, and angiogenesis; antidepressants up-regulate expression of insulin-like growth factor-I, while insulin-like growth factor-I up-regulates brain-derived neurotrophic factor expression and its receptor TrkB level, as well as brain-derived neurotrophic factor-induced synaptic protein levels. More importantly, physical exercise and healthy diet raise transport of peripheral circulating insulin-like growth factor I into the brain, reinforcing the expression of neurotrophins (e.g., brain-derived neurotrophic factor) and the strength of cell survival signalings (e.g., phosphoinositide 3-kinase / Akt / GSK-3beta pathway). This review will focus on the rapidly advancing new trends in the last five years about lithium, GSK-3beta/beta-catenin, and neurotrophin cascades.

Low-dose lithium uptake promotes longevity in humans and metazoans

            (Zarse, Terao et al. 2011) Download

PURPOSE: Lithium is a nutritionally essential trace element predominantly contained in vegetables, plant-derived foods, and drinking water. Environmental lithium exposure and concurrent nutritional intake vary considerably in different regions. We here have analyzed the possibility that low-dose lithium exposure may affect mortality in both metazoans and mammals. METHODS: Based on a large Japanese observational cohort, we have used weighted regression analysis to identify putative effects of tap water-derived lithium uptake on overall mortality. Independently, we have exposed Caenorhabditis elegans, a small roundworm commonly used for anti-aging studies, to comparable concentrations of lithium, and have quantified mortality during this intervention. RESULTS: In humans, we find here an inverse correlation between drinking water lithium concentrations and all-cause mortality in 18 neighboring Japanese municipalities with a total of 1,206,174 individuals (beta = -0.661, p = 0.003). Consistently, we find that exposure to a comparably low concentration of lithium chloride extends life span of C. elegans (p = 0.047). CONCLUSIONS: Taken together, these findings indicate that long-term low-dose exposure to lithium may exert anti-aging capabilities and unambiguously decreases mortality in evolutionary distinct species.


Lithium suppresses astrogliogenesis by neural stem and progenitor cells by inhibiting STAT3 pathway independently of glycogen synthase kinase 3 beta

            (Zhu, Kremer et al. 2011) Download

Transplanted neural stem and progenitor cells (NSCs) produce mostly astrocytes in injured spinal cords. Lithium stimulates neurogenesis by inhibiting GSK3b (glycogen synthetase kinase 3-beta) and increasing WNT/beta catenin. Lithium suppresses astrogliogenesis but the mechanisms were unclear. We cultured NSCs from subventricular zone of neonatal rats and showed that lithium reduced NSC production of astrocytes as well as proliferation of glia restricted progenitor (GRP) cells. Lithium strongly inhibited STAT3 (signal transducer and activator of transcription 3) activation, a messenger system known to promote astrogliogenesis and cancer. Lithium abolished STAT3 activation and astrogliogenesis induced by a STAT3 agonist AICAR (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside), suggesting that lithium suppresses astrogliogenesis by inhibiting STAT3. GSK3beta inhibition either by a specific GSK3beta inhibitor SB216763 or overexpression of GID5-6 (GSK3beta Interaction Domain aa380 to 404) did not suppress astrogliogenesis and GRP proliferation. GSK3beta inhibition also did not suppress STAT3 activation. Together, these results indicate that lithium inhibits astrogliogenesis through non-GSK3beta-mediated inhibition of STAT. Lithium may increase efficacy of NSC transplants by increasing neurogenesis and reducing astrogliogenesis. Our results also may explain the strong safety record of lithium treatment of manic depression. Millions of people take high-dose (>1 gram/day) lithium carbonate for a lifetime. GSK3b inhibition increases WNT/beta catenin, associated with colon and other cancers. STAT3 inhibition may reduce risk for cancer.


References

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Bachmann, R. F., Y. Wang, et al. (2009). "Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage." Int J Neuropsychopharmacol 12(6): 805-22.

Balon, R. (2009). "Old but still gold: Lithium in stabilizing the mood." Indian J Psychiatry 51(2): 157-8.

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Toledano, E., V. Ogryzko, et al. (2012). "3'-5' phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo." Biochem J 443(2): 485-90.

Wada, A. (2009). "Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3beta, beta-catenin, and neurotrophin cascades." J Pharmacol Sci 110(1): 14-28.

Zarse, K., T. Terao, et al. (2011). "Low-dose lithium uptake promotes longevity in humans and metazoans." Eur J Nutr.

Zhu, Z., P. Kremer, et al. (2011). "Lithium suppresses astrogliogenesis by neural stem and progenitor cells by inhibiting STAT3 pathway independently of glycogen synthase kinase 3 beta." PLoS One 6(9): e23341.