The distribution and morphology of neuronal degeneration were observed and analyzed in each sector of the zona incerta in a lithium‐pilocarpine (LiCl) Wistar rat model of status epilepticus in 12, 15, 18, 21, and 25‐day‐old rats and survival intervals of 4, 8, 12, 24, and 48 hours. Status epilepticus was induced via intraperitoneal (IP) injection of LiCl (3 mmol/kg) 24 hours before an injection of pilocarpine (40 mg/kg, IP). Motor seizures were suppressed by paraldehyde (0.3‐0.6 ml/kg, IP) two hours after status epilepticus onset. Animals were anesthetized using urethane and perfused with phosphate‐buffered saline followed by 4% paraformaldehyde. Brains were sectioned and Nissl stained for map guidance, with fluoro‐Jade B fluorescence used to detect degenerated neurons. Fluoro‐jade B‐positive neurons were plotted to a standard stereotaxic atlas, their distribution was quantified, and their long‐axis diameter was measured. Fluoro‐jade B‐positive neurons were found in pups aged 15 days and older 24 hours after status epilepticus, in which their numbers increased, and their perikaryon size decreased with advancing age. Thus, neuronal damage severity was dependent on age and survival interval. Neuronal damage was only found in the rostral sector of the zona incerta, a region that exhibits a small number of inhibitory neurons and is reciprocally connected to the limbic cortex. This system of hyperactivity, coupled with inhibitory neurons, may be the underlying cause of the neuronal degeneration and explain why it was confined to the rostral sector of the zona incerta.

• MeSH
• chlorid lithný toxicita   MeSH
• degenerace nervu * patologie   etiologie   MeSH
• fluoresceiny MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• neurony * patologie   MeSH
• novorozená zvířata MeSH
• pilokarpin toxicita   MeSH
• potkani Wistar MeSH
• status epilepticus * patologie   chemicky indukované   komplikace   MeSH
• věkové faktory MeSH
• zona incerta * patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Glucocorticoids are commonly used in children with different chronic diseases. Growth failure represents a so far untreatable undesired side-effect. As lithium chloride (LiCl) is known to induce cell renewal in various tissues, we hypothesized that LiCl may prevent glucocorticoid-induced growth failure. METHODS: We monitored growth of fetal rat metatarsals cultured ex-vivo with dexamethasone and/or LiCl, while molecular mechanisms were explored through RNA sequencing by implementing the differential gene expression and gene set analysis. Quantification of β-catenin in human growth plate cartilage cultured with dexamethasone and/or LiCl was added for verification. RESULTS: After 14 days of culture, the length of dexamethasone-treated fetal rat metatarsals increased by 1.4 ± 0.2 mm compared to 2.4 ± 0.3 mm in control bones (p < 0.001). The combination of LiCl and dexamethasone led to bone length increase of 1.9 ± 0.3 mm (p < 0.001 vs. dexamethasone alone). By adding lithium, genes for cell cycle and Wnt/β-catenin, Hedgehog and Notch signaling, were upregulated compared to dexamethasone alone group. CONCLUSIONS: LiCl has the potential to partially rescue from dexamethasone-induced bone growth impairment in an ex vivo model. Transcriptomics identified cell renewal and proliferation as candidates for the underlying mechanisms. Our observations may open up the development of a new treatment strategy for bone growth disorders. IMPACT: LiCl is capable to prevent glucocorticoid-induced growth failure in rat metatarsals in vitro. The accompanying drug-induced transcriptomic changes suggested cell renewal and proliferation as candidate underlying mechanisms. Wnt/beta-catenin pathway could be one of those novel mechanisms.

• MeSH
• beta-katenin * metabolismus   MeSH
• chlorid lithný * farmakologie   MeSH
• dexamethason * farmakologie   MeSH
• glukokortikoidy farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• metatarzální kosti * účinky léků   MeSH
• potkani Sprague-Dawley MeSH
• proliferace buněk účinky léků   MeSH
• růstová ploténka účinky léků   metabolismus   MeSH
• signální dráha Wnt účinky léků   MeSH
• vývoj kostí účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

• MeSH
• antimanika farmakologie   terapeutické užití   MeSH
• bipolární porucha * farmakoterapie   genetika   MeSH
• celogenomová asociační studie * metody   MeSH
• farmakogenetika metody   MeSH
• fokální adheze * účinky léků   genetika   MeSH
• genomika metody   MeSH
• genové regulační sítě * účinky léků   genetika   MeSH
• indukované pluripotentní kmenové buňky účinky léků   metabolismus   MeSH
• lidé MeSH
• lithium * farmakologie   terapeutické užití   MeSH
• multiomika MeSH
• neurony metabolismus   účinky léků   MeSH
• sloučeniny lithia farmakologie   terapeutické užití   MeSH
• stanovení celkové genové exprese metody   MeSH
• transkriptom * genetika   účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

• MeSH
• acetylcholin metabolismus   MeSH
• antimanika terapeutické užití   farmakologie   MeSH
• Bayesova věta MeSH
• bipolární porucha * farmakoterapie   genetika   MeSH
• celogenomová asociační studie metody   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kohortové studie MeSH
• kyselina glutamová metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lithium * terapeutické užití   farmakologie   MeSH
• multifaktoriální dědičnost * genetika   MeSH
• sloučeniny lithia terapeutické užití   farmakologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• design s pomocí počítače MeSH
• lidé MeSH
• návrh zubní protézy metody   přístrojové vybavení   MeSH
• sloučeniny lithia * terapeutické užití   MeSH
• stomatologická protetika metody   přístrojové vybavení   MeSH
• výsledek terapie MeSH
• zubní korunky * MeSH
• zubní porcelán MeSH
• zubní protéza - design MeSH
• zubní technika otisková MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Lithium is used in the treatment of bipolar disorder. We previously demonstrated that two types of transporters mediate the tubular reabsorption of lithium in rats, and suggested that sodium-dependent phosphate transporters play a role in lithium reabsorption with high affinity. In the present study, we examined sex differences in lithium reabsorption in rats. When lithium chloride was infused at 60 μg/min, creatinine clearance and the renal clearance of lithium were lower, and the plasma concentration of lithium was higher in female rats. These values reflected the higher fractional reabsorption of lithium in female rats. In rats infused with lithium chloride at 6 μg/min, the pharmacokinetic parameters of lithium examined were all similar in both sexes. The fractional reabsorption of lithium was decreased by foscarnet, a representative inhibitor of sodium-dependent phosphate transporters, in male and female rats when lithium chloride was infused at the low rate. Among the candidate transporters mediating lithium reabsorption examined herein, the mRNA expression of only PiT2, a sodium-dependent phosphate transporter, exhibited sexual dimorphism. The present results demonstrated sex differences in the tubular reabsorption of lithium with low affinity in rats.

• MeSH
• chlorid lithný aplikace a dávkování   metabolismus   farmakokinetika   MeSH
• intravenózní infuze MeSH
• kotransportní proteiny pro sodík a fosfát genetika   metabolismus   MeSH
• ledvinové kanálky metabolismus   MeSH
• pohlavní dimorfismus MeSH
• potkani Wistar MeSH
• renální reabsorpce * MeSH
• sexuální faktory MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

• MeSH
• bipolární porucha * diagnóza   farmakoterapie   genetika   MeSH
• farmakogenetika MeSH
• lidé MeSH
• lithium terapeutické užití   MeSH
• prospektivní studie MeSH
• sloučeniny lithia terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with "exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

• MeSH
• antimanika terapeutické užití   MeSH
• bipolární porucha * farmakoterapie   genetika   MeSH
• fenotyp MeSH
• lidé MeSH
• lithium terapeutické užití   MeSH
• sloučeniny lithia terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• MeSH
• antimanika aplikace a dávkování   farmakologie   MeSH
• bipolární porucha farmakoterapie   MeSH
• časové faktory MeSH
• erytrocyty účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• ledviny účinky léků   metabolismus   MeSH
• lithiumkarbonát aplikace a dávkování   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• mozek účinky léků   metabolismus   MeSH
• peroxidace lipidů účinky léků   MeSH
• potkani Wistar MeSH
• sodíko-draslíková ATPasa metabolismus   MeSH
• spánková deprivace psychologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• sekundární nefrotický syndrom,
• MeSH
• anxiolytika aplikace a dávkování   terapeutické užití   MeSH
• biologické markery krev   moč   MeSH
• biopsie metody   využití   MeSH
• diuréza fyziologie   účinky léků   MeSH
• edém diagnóza   etiologie   komplikace   MeSH
• farmakoterapie MeSH
• hyperkalemie diagnóza   etiologie   terapie   MeSH
• lidé MeSH
• lithiumkarbonát * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• mladiství MeSH
• nefrologie MeSH
• nefrotický syndrom diagnóza   etiologie   MeSH
• nežádoucí účinky léčiv etiologie   komplikace   MeSH
• proteinurie diagnóza   etiologie   komplikace   MeSH
• úzkostné poruchy * diagnóza   farmakoterapie   komplikace   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH