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Schematic representation of different direct molecular targets of lithium. These include inositol monophosphatases (IMPAs), Bisphosphate 3′-nucleotidase (BPNT), cyclooxygenase (COX), beta-arrestin 2 (βArr2), and members of the glycogen synthase kinase 3 alpha and beta (GSK3α and β). Since the mechanism by which lithium would inhibit several of these molecules is by competing with magnesium ions (Mg2+) acting as a co-factor we also included the possibility that other molecular targets may be affected through such competition.
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For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. Despite this long history, the molecular mechanisms trough which lithium regulates behavior are still poorly understood. Among several targets, lithium has been shown...
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G protein-coupled receptors (GPCRs) undergo phosphorylation at several intracellular residues by G protein-coupled receptor kinases. The resulting phosphorylation pattern triggers arrestin recruitment and receptor desensitization. The exact sites of phosphorylation and their function remained largely unknown for the human β1-adrenoceptor (ADRB1), a...
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... Li + ions have been suggested to inhibit GSK-3 directly due to the intracellular displacement of Mg 2+ ions, since both have a similar atomic radius [24]. As a result, the β-arrestin/protein phosphatase 2A/Akt complex is no longer stabilized by GSK-3, facilitating the accumulation of free Akt in the cytosol. ...
... As a result, the β-arrestin/protein phosphatase 2A/Akt complex is no longer stabilized by GSK-3, facilitating the accumulation of free Akt in the cytosol. The insulin signaling cascade activates non-complexed Akt to phosphorylate and inactivate the two GSK-3 isoforms at either serine 9 (GSK-3β) or serine 308 (GSK-3α), which further promotes the inhibition of GSK-3 kinase activity [19,[24][25][26]. ...
The amount of dietary sugars and the administration of lithium both impact the lifespan of the fruit fly Drosophila melanogaster. It is noteworthy that lithium is attributed with insulin-like activity as it stimulates protein kinase B/Akt and suppresses the activity of glycogen synthase kinase-3 (GSK-3). However, its interaction with dietary sugar has largely remained unexplored. Therefore, we investigated the effects of lithium supplementation on known lithium-sensitive parameters in fruit flies, such as lifespan, body composition, GSK-3 phosphorylation, and the transcriptome, while varying the dietary sugar concentration. For all these parameters, we observed that the efficacy of lithium was significantly influenced by the sucrose content in the diet. Overall, we found that lithium was most effective in enhancing longevity and altering body composition when added to a low-sucrose diet. Whole-body RNA sequencing revealed a remarkably similar transcriptional response when either increasing dietary sucrose from 1% to 10% or adding 1 mM LiCl to a 1% sucrose diet, characterized by a substantial overlap of nearly 500 differentially expressed genes. Hence, dietary sugar supply is suggested as a key factor in understanding lithium bioactivity, which could hold relevance for its therapeutic applications.
... In addition, AKAP11-PP1 complex can affect HDAC6 stability 85 . Moreover, AKAP11-PKA-regulated GSK3B, one of the molecular targets of lithium, which is the most common medication to prevent recurrences of both manic and depressive episodes in BD patients [18][19][20][21] , has been suggested to be involved in the regulation of HDAC6 activity through phosphorylation events 26 (which was not certified by peer review) is the author/funder. All rights reserved. ...
The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons. In this study, we use genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygous AKAP11 LoF mutations on the gene expression landscape and profile the methylomic and acetylomic modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes functioning as DNA-binding transcription factors, actin and cytoskeleton regulators, and cytokine receptors, as well as genes involved in G-protein-coupled receptors (GPCRs) binding and signaling. A better understanding of the dysregulations resulting from haploinsufficiency in AKAP11 improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.
... 13 Furthermore, lithium chloride is known to inhibit the activity of glycogen synthase kinase 3-β, a master regulator of host chronic intestinal inflammation mediated by tolllike receptors, and has been used as a treatment in a mouse model of IBD. 34,51 However, the effect of lithium on the microbiome has not yet been elucidated. E. coli tolerance to lithium ions is regulated through antiporters, and proline has been shown to induce the uptake of lithium ions by E. coli. ...
Inflammatory bowel disease (IBD) is a persistent inflammatory condition that affects the gastrointestinal tract and presents significant challenges in its management and treatment. Despite the knowledge that within-host bacterial evolution occurs in the intestine, the disease has rarely been studied from an evolutionary perspective. In this study, we aimed to investigate the evolution of resident bacteria during intestinal inflammation and whether- and how disease-related bacterial genetic changes may present trade-offs with potential therapeutic importance. Here, we perform an in vivo evolution experiment of E. coli in a gnotobiotic mouse model of IBD, followed by multiomic analyses to identify disease-specific genetic and phenotypic changes in bacteria that evolved in an inflamed versus a non-inflamed control environment. Our results demonstrate distinct evolutionary changes in E. coli specific to inflammation, including a single nucleotide variant that independently reached high frequency in all inflamed mice. Using ex vivo fitness assays, we find that these changes are associated with a higher fitness in an inflamed environment compared to isolates derived from non-inflamed mice. Further, using large-scale phenotypic assays, we show that bacterial adaptation to inflammation results in clinically relevant phenotypes, which intriguingly include collateral sensitivity to antibiotics. Bacterial evolution in an inflamed gut yields specific genetic and phenotypic signatures. These results may serve as a basis for developing novel evolution-informed treatment approaches for patients with intestinal inflammation.
... Many molecular targets for Li have been described (Roux & Dosseto, 2017). These include inositol monophosphatase (IMPase) (Harwood, 2005), glycogen synthasekinase-3β (GSK-3β) (Freland & Beaulieu, 2012), sodium myo-inositol co-transporter (Dai et al, 2016), and bisphosphate-39-nucleotidase (BPNT1) (Spiegelberg et al, 2005). The two most well-studied targets of Li are IMPase and GSK-3β. ...
Lithium (Li) is widely used as a mood stabilizer to treat bipolar affective disorder. However, the molecular targets of Li that underpin its therapeutic effect remain unresolved. Inositol monophosphatase (IMPA1) is an enzyme involved in phosphatidylinositol 4,5-bisphosphate (PIP 2 ) resynthesis after PLC signaling. In vitro, Li inhibits IMPA1, but the relevance of this inhibition within neural cells remains unknown. Here, we report that treatment with therapeutic concentrations of Li reduces receptor-activated calcium release from intracellular stores and delays PIP 2 resynthesis. These effects of Li are abrogated in IMPA1 deleted cells. We also observed that in human forebrain cortical neurons, treatment with Li reduced neuronal excitability and calcium signals. After Li treatment of human cortical neurons, transcriptome analyses revealed down-regulation of signaling by glutamate, a key excitatory neurotransmitter in the human brain. Collectively, our findings suggest that inhibition of IMPA1 by Li reduces receptor-activated PLC signaling and neuronal excitability.
... Such inhibition may occur both directly and indirectly. The former implies Li competes with Mg sites due to their similar ionic radius [51,52]; the latter refers to Li-induced increased phosphorylation at Ser9 that inhibits GSK-3β [53,54]. We assessed the activity of GSK-3β by analysing the ratio of Ser9 phosphorylated protein to total protein levels, and our findings indicate no significant difference between the Li and control groups. ...
Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes’ size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity.
... Moreover, lithium-a potent GSK-3 inhibitor-enhanced the antidepressant effects of ketamine in mice. Lithium can also indirectly inhibit GSK-3 by activating the Akt kinase or by disrupting the β-arrestin complex [84,85]. ...
Treatment-resistant depression (TRD) is a subgroup of major depressive disorder in which the use of classical antidepressant treatments fails to achieve satisfactory treatment results. Although there are various definitions and grading models for TRD, common criteria for assessing TRD have still not been established. However, a common feature of any TRD model is the lack of response to at least two attempts at antidepressant pharmacotherapy. The causes of TRD are not known; nevertheless, it is estimated that even 60% of TRD patients are so-called pseudo-TRD patients, in which multiple biological factors, e.g., gender, age, and hormonal disturbances are concomitant with depression and involved in antidepressant drug resistance. Whereas the phenomenon of TRD is a complex disorder difficult to diagnose and successfully treat, the search for new treatment strategies is a significant challenge of modern pharmacology. It seems that despite the complexity of the TRD phenomenon, some useful animal models of TRD meet the construct, the face, and the predictive validity criteria. Based on the literature and our own experiences, we will discuss the utility of animals exposed to the stress paradigm (chronic mild stress, CMS), and the Wistar Kyoto rat strain representing an endogenous model of TRD. In this review, we will focus on reviewing research on existing and novel therapies for TRD, including ketamine, deep brain stimulation (DBS), and psychedelic drugs in the context of preclinical studies in representative animal models of TRD.
... Thus, Ser9 phosphorylation state determination is not enough and it is essential to evaluate actual GSK3β activity [36]. A few studies demonstrated that the potency of lithium effect may be also linked to the amount of magnesium, showing that Li+ act as uncompetitive inhibitors for the binding of the co-factor magnesium to GSK3 [37,38]. GSK3β plays a pivotal role in AKI by promoting inflammation, oxidative stress and apoptosis which are considered the main mediators of renal dysfunction in glycerol-induced AKI [27,32,39]. ...
Rhabdomyolysis is characterized by muscle damage and leads to acute kidney injury (AKI). Clinical and experimental studies suggest that glycogen synthase kinase 3β (GSK3β) inhibition protects against AKI basically through its critical role in tubular epithelial cell apoptosis, inflammation and fibrosis. Treatment with a single dose of lithium, an inhibitor of GSK3β, accelerated recovery of renal function in cisplatin and ischemic/reperfusion-induced AKI models. We aimed to evaluate the efficacy of a single dose of lithium in the treatment of rhabdomyolysis-induced AKI. Male Wistar rats were allocated to four groups: Sham, received saline 0.9% intraperitoneally (IP); lithium (Li), received a single IP injection of lithium chloride (LiCl) 80 mg/kg body weight (BW); glycerol (Gly), received a single dose of glycerol 50% 5 mL/kg BW intramuscular (IM); glycerol plus lithium (Gly+Li), received a single dose of glycerol 50% IM plus LiCl IP injected 2 hours after glycerol administration. After 24 hours, we performed inulin clearance experiments and collected blood / kidney / muscle samples. Gly rats exhibited renal function impairment accompanied by kidney injury, inflammation and alterations in signaling pathways for apoptosis and redox state balance. Gly+Li rats showed a remarkable improvement in renal function as well as kidney injury score, diminished CPK levels and an overstated decrease of renal and muscle GSK3β protein expression. Furthermore, administration of lithium lowered the amount of macrophage infiltrate, reduced NFκB and caspase renal protein expression and increased the antioxidant component MnSOD. Lithium treatment attenuated renal dysfunction in rhabdomyolysis-associated AKI by improving inulin clearance and reducing CPK levels, inflammation, apoptosis and oxidative stress. These therapeutic effects were due to the inhibition of GSK3β and possibly associated with a decrease in muscle injury.
... It has been theorized that the effects of lithium on the activity of PKC could be related to the treatment of mania [88,94]. In addition, it has been shown that the drug can also decrease the activity of the glycogen synthase kinase-3β [95]. This activity is regulated by direct competition with the binding of Akt and Mg 2+ [96]. ...
Lithium is a source of great scientific interest because although it has such a simple structure, relatively easy-to-analyze chemistry, and well-established physical properties, the plethora of effects on biological systems—which influence numerous cellular and molecular processes through not entirely explained mechanisms of action—generate a mystery that modern science is still trying to decipher. Lithium has multiple effects on neurotransmitter-mediated receptor signaling, ion transport, signaling cascades, hormonal regulation, circadian rhythm, and gene expression. The biochemical mechanisms of lithium action appear to be multifactorial and interrelated with the functioning of several enzymes, hormones, vitamins, and growth and transformation factors. The widespread and chaotic marketing of lithium salts in potions and mineral waters, always at inadequate concentrations for various diseases, has contributed to the general disillusionment with empirical medical hypotheses about the therapeutic role of lithium. Lithium salts were first used therapeutically in 1850 to relieve the symptoms of gout, rheumatism, and kidney stones. In 1949, Cade was credited with discovering the sedative effect of lithium salts in the state of manic agitation, but frequent cases of intoxication accompanied the therapy. In the 1960s, lithium was shown to prevent manic and also depressive recurrences. This prophylactic effect was first demonstrated in an open-label study using the “mirror” method and was later (after 1970) confirmed by several placebo-controlled double-blind studies. Lithium prophylaxis was similarly effective in bipolar and also unipolar patients. In 1967, the therapeutic value of lithemia was determined, included in the range of 0.5–1.5 mEq/l. Recently, new therapeutic perspectives on lithium are connected with improved neurological outcomes after ischemic stroke. The effects of lithium on the development and maintenance of neuroprotection can be divided into two categories: short-term effects and long-term effects. Unfortunately, the existing studies do not fully explain the lithium biological action mechanisms after ischemic stroke.
... The phosphorylation at T58 of c-Myc is mediated by the processive kinase GSK3β [5,6]. Lithium, a medication for bipolar disorder, is a direct and indirect inhibitor of GSK-3 [30]. Lithium chloride (LiCl) had similar cytotoxic effects, and a relatively safe dosage below 20 mM retained 80% of activities in OECM-1 and SG cells ( Figure 5A,B). ...
... GSK-3 activity suppresses cell proliferation and survival. Lithium, a medication for bipolar disorder, is a direct and indirect inhibitor of GSK-3 [30]. Many studies have shown that the phosphorylation at T58 of c-Myc is mediated by the processive kinase GSK3β [33][34][35]. ...
MYC has a short half-life that is tightly regulated through phosphorylation and proteasomal degradation. Many studies have claimed that treatment with disulfiram (DSF) with or without copper ions can cause cancer cell death in a reactive oxygen species (ROS)-dependent manner in cancer cells. Our previous study showed that the levels of c-Myc protein and the phosphorylation of threonine 58 (T58) and serine 62 (S62) increased in DSF-Cu-complex-treated oral epidermoid carcinoma Meng-1 (OECM-1) cells. These abovementioned patterns were suppressed by pretreatment with an ROS scavenger, N-acetyl cysteine. The overexpression of c-Myc failed to induce hypoxia-inducible factor 1α protein expression, which was stabilized by the DSF-Cu complex. In this study, we further examined the regulatory mechanism behind the induction of the c-Myc of the DSF-Cu complex in an OECM-1 cell compared with a Smulow–Glickman (SG) human normal gingival epithelial cell. Our data showed that the downregulation of c-Myc truncated nick and p62 and the induction of the ratio of H3P/H3 and p-ERK/ERK might not be involved in the increase in the amount of c-Myc via the DSF/copper complexes in OECM-1 cells. Combined with the inhibitors for various signaling pathways and cycloheximde treatment, the increase in the amount of c-Myc with the DSF/copper complexes might be mediated through the increase in the stabilities of c-Myc (T58) and c-Myc (S62) proteins in OECM-1 cells. In SG cells, only the c-Myc (T58) protein was stabilized by the DSF-Cu (I and II) complexes. Hence, our findings could provide novel regulatory insights into the phosphorylation-dependent stability of c-Myc in DSF/copper-complex-treated oral squamous cell carcinoma.
... The later reports highlight the fact that GSK3β manipulation must be highly controlled and probably with only moderate levels of modulation. In this line, one of the most studied GSK3β inhibitors and already used in humans for the treatment of bipolar disorder, lithium, also acts indirectly by enhancing the serine phosphorylation of GSK3β (Freland and Beaulieu, 2012). Lithium treatment alleviates memory deficits in mice expressing both APP and PS1 (Zhang et al., 2011). ...
Glycogen synthase kinase 3β (GSK3β) is a core protein, with a relevant role in many neurodegenerative disorders including Alzheimer’s disease. The enzyme has been largely studied as a potential therapeutic target for several neurological diseases. Unfortunately, preclinical and clinical studies with several GSK3β inhibitors have failed due to many reasons such as excessive toxicity or lack of effects in human subjects. We previously reported that meridianins are potent GSK3β inhibitors without altering neuronal viability. In the present work, we examine whether meridianins are capable to inhibit neural GSK3β in vivo and if such inhibition induces improvements in the 5xFAD mouse model of Alzheimer’s Disease. Direct administration of meridianins in the third ventricle of 5xFAD mice induced robust improvements of recognition memory and cognitive flexibility as well as a rescue of the synaptic loss and an amelioration of neuroinflammatory processes. In summary, our study points out meridianins as a potential compound to treat neurodegenerative disorders associated with an hyperactivation of GSK3β such as Alzheimer’s disease.
