Supercharging cancer-fighting T cells with lithium carbonate.

Lactate influences the behavior of various immune cell types. In a recent Nature Immunology study, Ma et al. revealed that lithium carbonate induces monocarboxylate transporter 1 translocation to mitochondria, enhancing cytoplasmic lactate transport into the mitochondria and increasing lactate mitochondrial metabolism, thereby promoting T cell effector function.

Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.

The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.

Effects of olanzapine and lithium carbonate antipsychotic agents on dopamine oxidation.

Olanzapine (OLZ) and lithium carbonate (Li2CO3) are the main drugs for treating mental disorders related to dopamine (DA). A highly conductive carbon paper sensing electrode is used to investigate the effects of OLZ and Li2CO3 on DA oxidation due to its amplification of oxidation peak currents. Different chemical properties of drugs have different effects on DA oxidation. The presence of OLZ fouling on the electrode surface due to the irreversible adsorption weakens the sensing activity and thus reduces the DA oxidation peak current. However, the fixed DA oxidation peak potential at 0.22 V indicates no interaction between them. The hydrolysis effect of Li2CO3 increases the solution pH from 7.47 to 9.73, which promotes the deprotonation of DA, leading to a 156 mV negative shift of the DA oxidation peak potential. Additionally, a 94% decrease of the DA peak current may be related to the generation of polydopamine in alkaline media.

Lithium carbonate accelerates the healing of apical periodontitis.

Apical periodontitis is a disease caused by bacterial invasions through the root canals. Our previous study reported that lithium chloride (LiCl) had a healing effect on apical periodontitis. The aim of this report is to investigate the healing properties and mechanism of lithium ion (Li+) for apical periodontitis using rat root canal treatment model. 10-week-old male Wistar rat's mandibular first molars with experimentally induced apical periodontitis underwent root canal treatment and were applied lithium carbonate (Li2CO3) containing intracanal medicament. Base material of the medicament was used as a control. Subject teeth were scanned by micro-CT every week and the periapical lesion volume was evaluated. The lesion volume of Li2CO3 group was significantly smaller than that of the control group. Histological analysis showed that in Li2CO3 group, M2 macrophages and regulatory T cells were induced in the periapical lesion. In situ hybridization experiments revealed a greater expression of Col1a1 in Li2CO3 group compared with the control group. At 24 h after application of intracanal medicament, Axin2-positive cells were distributed in Li2CO3 group. In conclusion, Li2CO3 stimulates Wnt/ß-catenin signaling pathway and accelerate the healing process of apical periodontitis, modulating the immune system and the bone metabolism.

Lithium carbonate alleviates colon inflammation through modulating gut microbiota and Treg cells in a GPR43-dependent manner.

BACKGROUND: Recent evidence suggests that neuropsychiatric stabilizers have a place in resolving gastrointestinal disorders. Lithium carbonate (LC) is one of the most commonly used drugs for bipolar disorder clinically. Here, we estimate the therapeutic function of LC against colitis and investigate the mechanism of intestinal flora and metabolism modulation. METHODS: A colitis model was constructed by continuously administering 2.5% dextran sodium sulfate (DSS) solution daily for 7 days. Analysis of gut microbiota was carried out by 16S rRNA gene high-throughput sequencing. Spectrum antibiotic cocktail (ABX) and faecal microbiota transplantation (FMT) were employed to evaluate the protective effect of intestinal flora. Colonic Treg cells and related immune responses were detected by flow cytometry. RESULTS: LC treatment significantly alleviated colon inflammation by regulating gut microbial diversity and altering flora composition. Notably, LC treatment upregulated short-chain fatty acid (SCFA)-producing bacteria, especially Akkermansia muciniphila (A. muciniphila), and transformed metabolite SCFA profiles. LC activated anti-inflammatory Treg cell responses in colonic lamina propria (LP) in a G-protein coupled receptor 43 (GPR43)-dependent mechanism. ABX, FMT and single bacteria gavage experiments were conducted to confirm the above mechanism. CONCLUSIONS: As an intestinal microbiome and metabolite modulator, LC alleviates colon inflammation in a GPR43-dependent manner through activating Treg cell responses. Therefore, the therapeutic strategy of the microbiome-metabolite-immune axis, as observed in the A. muciniphila-SCFA-Treg cell axis in our study, might provide a new direction for the treatment of IBD.

Green tea extract modulates lithium-induced thyroid follicular cell damage in rats.

BACKGROUND: The aim of the current work was to clarify the modulation role of green tea extract (GTE) over structural and functional affection of the thyroid gland after long term use of lithium carbonate (LC). The suggested underlying mechanisms participating in thyroid affection were researched. MATERIALS AND METHODS: Twenty-four Sprague-Dawley adult albino rats were included in the work. They were divided into three groups (control, LC, and concomitant LC + GTE). The work was sustained for 8 weeks. Biochemical assays were performed (thyroid hormone profile, interleukin 6 [Il-6]). Histological, histochemical (Periodic Acid Schiff [PAS]) and immunohistochemical (caspase-3, tumour necrosis factor alpha [TNF-α], proliferating cell nuclear antigen [PCNA]) evaluations were done. Oxidative/antioxidative markers (malondialdehyde [MDA]/gluthathione [GSH], superoxide dismutase [SOD]) and Western blot evaluation of the Bcl2 family were done. RESULTS: Lithium carbonate induced hypothyroidism (decreased T3, T4/increased thyroid-stimulating hormone [TSH]). The follicles were distended, others were involuted. Some follicles were disorganised, others showed detached follicular cells. Apoptotic follicular cells were shown (BAX and caspase-3 increased, Bcl2 decreased, BAX/Bcl2 ratio increased). The collagen fibres' content and proinflammatory markers (TNF-α and IL-6) increased. The proliferative nuclear activity was supported by increased expression of PCNA. Oxidative stress was established (increased MDA/decreased GSH, SOD). With the use of GTE, the thyroid hormone levels increased, while the TSH level decreased. Apoptosis was improved as BAX decreased, Bcl2 increased, and BAX/Bcl2 ratio was normal. The collagen fibres' content and proinflammatory markers (TNF-α and IL-6) decreased. The expression of PCNA and caspase-3 were comparable to the control group. The oxidative markers were improved (decreased MDA/increased GSH, SOD). CONCLUSIONS: In conclusion, prolonged use of LC results in hypothyroidism, which is accompanied by structural thyroid damage. LC induced thyroid damage through oxidative stress that prompted sterile inflammation and apoptosis. With the use of GTE, the thyroid gland regained its structure and function. The protecting role of GTE is through antioxidant, antifibrotic, anti-inflammatory, and antiproliferative effects.

A influência dos aspectos subjetivos na adesão ao tratamento do transtorno bipolar: uma revisão sistemática / The influence of subjective aspects on adherence to the treatment of bipolar disorder: a systematic review

OBJETIVO: Evidenciar a influência dos aspectos subjetivos na adesão ao tratamento do transtorno bipolar. MÉTODOS: Foi realizada revisão sistemática com base nas diretrizes PRISMA. A identificação dos estudos foi realizada por meio da busca nos bancos de dados PubMed, Scopus e SciELO, com base nos descritores "Bipolar Disorder" AND "Treatment Adherence and Compliance" AND "Mental Health". A busca contemplou todos os artigos publicados até o ano 2020, sem restrição de idioma. RESULTADOS: Foram localizados 743 artigos, 714 foram excluídos no processo de seleção, 29 foram lidos na íntegra e 11 foram elegíveis para a composição da amostra. A influência dos aspectos subjetivos na adesão ao tratamento foi associada (1) às atitudes resultantes das percepções do sujeito sobre o transtorno e o tratamento e (2) as atitudes por influência de pessoas próximas. Os estudos apontam para a ocorrência de atitudes negativas em ambas as esferas, tendo a má adesão ao tratamento como desfecho. Na esfera da percepção do sujeito, evidenciam-se: presença de comportamentos intencionais e não intencionais; percepção de consequências; medo dos efeitos colaterais; sentimentos negativos; falta de compreensão sobre o transtorno e negação do diagnóstico. Na esfera da influência das pessoas próximas, destacam-se a baixa qualidade da aliança terapêutica e o suporte ineficaz oferecido pela família. CONCLUSÕES: Para melhorar a adesão ao tratamento do transtorno bipolar, é salutar que os esforços terapêuticos estejam centrados na experiência particular do sujeito, na sua satisfação e na colaboração pactuada com o tratamento.

OBJECTIVE: Evidence the influence of subjective aspects on adherence to the treatment of bipolar disorder. METHODS: A systematic review was performed based on the PRISMA guidelines. The identification of studies was performed by searching the PubMed, Scopus and Scielo databases based on the descriptors "Bipolar Disorder" AND "Treatment Adherence and Compliance" AND "Mental Health". The selection included all articles published up to the year 2020 and without language restrictions. RESULTS: A total of 743 articles were found, 714 were excluded from the selection process, 29 articles were read in full and 11 were eligible for sample composition. The influence of subjective aspects on treatment adherence was associated (1) with attitudes resulting from the subject's perceptions about the disorder and treatment and (2) attitudes influenced by people close to them. Studies point to the occurrence of negative attitudes in both spheres, with poor adherence to treatment as an outcome. In the sphere of the subject's perception, they show the presence of intentional and unintentional behaviors; perception of consequences; fear of side effects; negative feelings; lack of understanding about the disorder and denial of diagnosis. In the sphere of influence of those close to them, they highlight the low quality of the therapeutic alliance and the ineffective support offered by the family. CONCLUSIONS: To improve adherence to treatment for bipolar disorder, it is beneficial that therapeutic efforts are centered on the individual's particular experience, on their satisfaction and on the agreed collaboration with the treatment.

The influence of Li+ ions on pepsin and trypsin activity in vitro.

BACKGROUND: The paper presents a study on the influence of different lithium carbonate and lithium citrate concentration on proteolytic enzymes, namely pepsin and trypsin, in vitro. Lithium can directly affect enzyme activity. Its influence on many bodily functions in both ill and healthy people has been proven. METHODS: To assess the influence of Li+ ions concentration and the substrate/enzyme ratio on pepsin and trypsin activity in vitro, 60 factorial experiments were conducted (each repeated 30 times). MAIN FINDINGS: For both enzymes, statistically significant changes in their activity under the influence of lihium carbonate and lithium citrate were observed. The biggest increase in enzyme activity reached even 198.6 % and the largest decrease in enzyme activity reached about 50 %. CONCLUSIONS: The study shows that both organic and inorganic forms of lithium salts cause changes in the activity of digestive enzymes. Different concentrations of lithium carbonate and lithium citrate stimulate or inhibit the activity of trypsin and pepsin.

Effect of a New Lithium Preparation on the Behavior of CBA/CaLac Mice in an Experimental Conflict Model.

The use of lithium drugs in clinical practice requires constant monitoring of lithium plasma concentration, because toxicity is sometimes observed at therapeutic concentrations of lithium. This is often associated with fluctuations of plasma concentration of lithium ions after intake of individual doses. Therefore, the use of a porous carrier providing a stable blood level of the drug is extremely promising and important for clinical practice. We studied activity of a new lithium drug (lithium complex) consisting of aluminum-silicon base and lithium citrate immobilized on its surface. Lithium carbonate served as the reference drug. It was shown that lithium carbonate and lithium complex exhibited no anxiolytic activity in the conflict model, but produced an antidepressant effect and improved exploratory behavior of animals.

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.

In Vitro Effects of Lithium Carbonate on Cell Cycle, Apoptosis, and Autophagy in Hepatocellular Carcinoma-29 Cells.

We studied the effects of lithium carbonate on the cell cycle, apoptosis, and autophagy in hepatocellular carcinoma-29 cells (HCC-29) in vitro. Flow cytofluorometry analysis revealed accumulation of G2/M-phase HCC-29 cells and increase in the number of apoptotic cells in 48 h after administration of 5 mM lithium carbonate. Induction of autophagy in HCC-29 cells was detected by transmission electron microscopy and immunofluorescence staining. Thus, lithium carbonate produces an antitumor effect by arresting cell cycle in the G2/M-phase and induction of apoptosis and autophagy in HCC-29 cells, which confirms the lithium potential as a promising drug for the treatment of hepatocellular carcinoma.

Effect of lithium carbonate on the function of the thyroid gland: mechanism of action and clinical implications.

Lithium carbonate, a drug known for more than 100 years, has been successfully used as a psychiatric medication. Currently, it is a commonly used drug to treat patients with unipolar and bipolar depression, and for the prophylaxis of bipolar disorders and acute mania. Lithium salts may cause the development of goiter, hypothyroidism, or rarely hyperthyroidism. The present review examined the current state of knowledge on the effect of lithium carbonate on the thyroid gland. The Pubmed database and Google Scholar were searched for articles related to the effects of lithium therapy on the thyroid gland function published up to February 2020. Studies that examined the mechanism of action of lithium at the molecular level, including pharmacokinetics, and focused on its effects on the thyroid gland were included. Lithium as a mood-stabilizing drug has a complex mechanism of action. Because of the active transport of Na+/I- ions, lithium, despite its concentration gradient, is accumulated in the thyroid gland at a concentration 3 - 4 times higher than that in the plasma. It can inhibit the formation of colloid in thyrocytes, change the structure of thyroglobulin, weaken the iodination of tyrosines, and disrupt their coupling. In addition, it reduces the clearance of free thyroxine in the serum, thereby indirectly reducing the activity of 5-deiodinase type 1 and 2 and reducing the deiodination of these hormones in the liver. Taken together, this review provides recommendations for monitoring the thyroid gland in patients who require long-term lithium therapy. Prior to the initiation of lithium therapy, thyroid ultrasound should be performed, and the levels of thyroid hormones (fT3 and fT4), TSH, and antithyroid peroxidase and antithyroglobulin antibodies should be measured. If the patient shows normal thyroid function, TSH level measurement and thyroid ultrasound should be performed at 6- to 12-month intervals for long term.

Na+/K+-ATPase and lipid peroxidation in forebrain cortex and hippocampus of sleep-deprived rats treated with therapeutic lithium concentration for different periods of time.

Lithium (Li) is a typical mood stabilizer and the first choice for treatment of bipolar disorder (BD). Despite an extensive clinical use of Li, its mechanisms of action remain widely different and debated. In this work, we studied the time-course of the therapeutic Li effects on ouabain-sensitive Na+/K+-ATPase in forebrain cortex and hippocampus of rats exposed to 3-day sleep deprivation (SD). We also monitored lipid peroxidation as malondialdehyde (MDA) production. In samples of plasma collected from all experimental groups of animals, Li concentrations were followed by ICP-MS. The acute (1 day), short-term (7 days) and chronic (28 days) treatment of rats with Li resulted in large decrease of Na+/K+-ATPase activity in both brain parts. At the same time, SD of control, Li-untreated rats increased Na+/K+-ATPase along with increased production of MDA. The SD-induced increase of Na+/K+-ATPase and MDA was attenuated in Li-treated rats. While SD results in a positive change of Na+/K+-ATPase, the inhibitory effect of Li treatment may be interpreted as a pharmacological mechanism causing a normalization of the stress-induced shift and return the Na+/K+-ATPase back to control level. We conclude that SD alone up-regulates Na+/K+-ATPase together with increased peroxidative damage of lipids. Chronic treatment of rats with Li before SD, protects the brain tissue against this type of damage and decreases Na+/K+-ATPase level back to control level.

Effect of lithium carbonate on autophagy and proliferative activity of isolated hepatocytes.

The hepatocytes were cultivated in the presence of lithium carbonate (LC) for drugs testing or possible source for transplantation in the treatment of hereditary or terminal liver diseases. The LC, as an inducer of autophagy, is a promising drug for maintaining cell homeostasis and has a significant effect on the ultrastructural organization of hepatocyte cells. Within current investigation, new mechanisms of the biological effects of lithium and the ultrastructural analysis of the primary culture of hepatocytes were studied via flow cytofluorometry, light, and electron microscopy methods. Obtained results demonstrate the absence of the toxic effect of 5 mM of LC on the primary hepatocyte culture. In addition, LC does not block the cell cycle at the G0/G1 stage after 24 h of hepatocyte cultivation and promotes the preservation of their viability by 48 h of the experiment. Moreover, LC does not stimulate hepatocyte apoptosis, induces autophagy and the preserves the proliferative activity of hepatocytes.

Lithium effects on vesicular trafficking in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most commonly malignant tumors worldwide, characterized by the presence of many heterogeneous molecular cell events that contribute to tumor growth and progression. Endocytic processes are intimately involved in various pathological conditions, including cancer, since they interface with various cellular signaling programs. The ability of lithium to induce cell death and autophagy and affect cell proliferation and intracellular signaling has been shown in various experimental tumor models. The aim of this study was to evaluate the effects of lithium on vesicular transport in hepatocellular carcinoma cells. Using transmission electron microscopy we have characterized the endocytic apparatus in hepatocellular carcinoma-29 (HCC-29) cells in vivo and detailed changes in endocytotic vesicles after 20 mM lithium carbonate administration. Immunofluorescent analysis was used to quantify cells positive for EEA1-positive early endosomes, Rab11-positive recycling endosomes and Rab7-positive late endosomes. Lithium treatment caused an increase in EEA1- and Rab11-positive structures and a decrease in Rab7-positive vesicles. Thus, lithium affects diverse endocytic pathways in HCC-29 cells which may modulate growth and development of hepatocellular carcinoma.

Immunophenotypes associated with bipolar disorder and lithium treatment.

Immune dysfunction is implicated in the etiology of bipolar disorder. The single-nucleotide polymorphism rs17026688 in the gene encoding glutamate decarboxylase-like protein 1 (GADL1) has been found to be associated with lithium response in Han Chinese patients with bipolar I disorder (BDI). However, whether patients with GADL1 polymorphisms have different immunophenotypes is unknown. To address this issue, differences in the immune profiles based on analysis of peripheral blood mononuclear cells (PBMCs) were compared among BDI patients and healthy controls who lack or carry the T allele of rs17026688. BDI patients had significantly higher percentages of total T cells, CD4+ T cells, activated B cells, and monocytes than healthy controls, suggesting that immunologic imbalance might be involved in BDI development or progression. Treatment of BDI patients-derived PBMCs with lithium in vitro increased the percentage of CD14+ monocytes and dendritic cells, suggesting that lithium plays an immunomodulatory role in CD14+ monocytes and dendritic cells. Among BDI patients, non-T carriers had a significantly higher percentage of CD11b+/CD33lo/HLA-DR- myeloid-derived suppressor cells than T carriers. Moreover, only T carriers exhibited differential sensitivity to lithium therapeutic use with respect to the percentage of myeloid cells. These findings suggest that rs17026688 polymorphisms in GADL1 are associated with immune dysfunction in BDI patients.

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.

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice.

Alzheimer's disease (AD) is characterized by progressive decline of cognition and associated neuropsychiatric signs including weight loss, anxiety, depression, agitation, and aggression, which is particularly pronounced in the female gender. Previously, we have shown that a novel ionic co-crystal of lithium salicylate proline (LISPRO) is an improved lithium formulation compared to the carbonate or salicylate form of lithium in terms of safety and efficacy in reducing AD pathology in Alzheimer's mice. The current study is designed to compare the prophylactic effects of LISPRO, lithium carbonate (LC), and lithium salicylate (LS) on cognitive and noncognitive impairments in female transgenic APPswe/PS1dE9 AD mice. Female APPswe/PS1dE9 mice at 4 months of age were orally treated with low-dose LISPRO, LS, or LC for 9 months at 2.25 mmol lithium/kg/day followed by determination of body weight, growth of internal organs, and cognitive and noncognitive behavior. No significant differences in body or internal organ weight, anxiety or locomotor activity were found between lithium treated and untreated APPswe/PS1dE9 cohorts. LISPRO, LC, and LS prevented spatial cognitive decline, as determined by Morris water maze and depression as determined by tail suspension test. In addition, LISPRO treatment was superior in preventing associative memory decline determined by contextual fear conditioning and reducing irritability determined by touch escape test in comparison with LC and LS. In conclusion, low-dose LISPRO, LC, and LS treatment prevent spatial cognitive decline and depression-like behavior, while LISPRO prevented hippocampal-dependent associative memory decline and irritability in APPswe/PS1dE9 mice.

Glycogen synthase kinase-3 inhibition as a potential pharmacological target for vascular dementia: In silico and in vivo evidence.

Vascular dementia is a serious problem as it creates significant disability and dependency in the affected person. Lives of these patients can be improved through the advent of novel drug targets which can be targeted by pharmacological therapies. However, finding a precise and druggable target for vascular dementia is experimentally impossible and challenging task owing to a complex and mostly unknown interplay between the cognitive abilities of the brain with a diversity of vascular diseases. To address this issue, we have systematically analyzed the literature reports by using well-known methods and approaches of bioinformatics (viz. network pharmacology, reverse pharmacology, enrichment analysis of KEGG pathways, biological processes of Gene Ontology and DIAMOnD algorithm). Because glycogen synthase kinase-3 (GSK-3) seems to be one of the most promising targets, therefore, we have tested the capacity of lithium carbonate, a classical inhibitor of GSK-3, for treatment of dementia resulting from mild chronic cerebral hypoperfusion in mice. To this end, our study shows in-vivo validation of predicted target, i.e., pharmacological deactivation of GSK-3 enzyme and its impact on cognitive abilities employing a behavioral test battery, i.e., object recognition task, step-through passive avoidance task, elevated plus maze task and water maze task. In this framework, we observed that lithium carbonate attenuates recognition, emotion, spatial and fear-motivated learning and memory impairments along with attenuation of oxidative stress, cholinergic dysfunction and glutamate-induced excitotoxicity in cerebral cortex and hippocampus. In conclusion, we propose GSK-3 as a promising drug target for vascular dementia in light of experimental results and in-silico predictions.