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1.
PLoS One ; 14(4): e0215871, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002704

RESUMO

Tubule-interstitial injury (TII) is a critical step in the progression of renal disease. It has been proposed that changes in proximal tubule (PT) albumin endocytosis plays an important role in the development of TII. Some reports have shown protective effects of lithium on kidney injury animal models that was correlated to proteinuria. We tested the hypothesis that lithium treatment ameliorates the development of TII due to changes in albumin endocytosis. Two experimental models were used: (1) TII induced by albumin overload in an animal model; (2) LLC-PK1 cells, a PT cell line. Lithium treatment ameliorates TII induced by albumin overload measured by (1) proteinuria; (2) collagen deposition; (3) area of tubule-interstitial space, and (4) macrophage infiltration. Lithium treatment increased mTORC2 activity leading to the phosphorylation of protein kinase B (PKB) at Ser473 and its activation. This mechanism enhanced albumin endocytosis in PT cells, which decreased the proteinuria observed in TII induced by albumin overload. This effect did not involve changes in the expression of megalin, a PT albumin receptor. In addition, activation of this pathway decreased apoptosis in LLC-PK1 cells, a PT cell line, induced by higher albumin concentration, similar to that found in pathophysiologic conditions. Our results indicate that the protective role of lithium treatment on TII induced by albumin overload involves an increase in PT albumin endocytosis due to activation of the mTORC2/PKB pathway. These results open new possibilities in understanding the effects of lithium on the progression of renal disease.


Assuntos
Túbulos Renais Proximais/efeitos dos fármacos , Carbonato de Lítio/farmacologia , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Substâncias Protetoras/farmacologia , Proteinúria/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Albuminas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Túbulos Renais Proximais/lesões , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/agonistas , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/agonistas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Artigo em Inglês | MEDLINE | ID: mdl-29981775

RESUMO

Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50-kHz emitted by rats are thought to index the subject's positive affective state. Fifty-kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post-mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50-kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency-modulated 50-kHz USV, which may indicate the mania-like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50-kHz USV emission, an effect prevented by acute lithium administration. This suggests 50-kHz USV as a new marker for mania-like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment).


Assuntos
Transtorno Bipolar/etiologia , Privação do Sono/complicações , Vocalização Animal/fisiologia , Animais , Antimaníacos/uso terapêutico , Monoaminas Biogênicas/metabolismo , Transtorno Bipolar/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Carbonato de Lítio/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Comportamento Materno/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo , Estriado Ventral/efeitos dos fármacos , Estriado Ventral/metabolismo
3.
Bull Exp Biol Med ; 165(6): 758-762, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30353339

RESUMO

We studied antidiabetic effects and cytoprotective activity of two lithium salts (lithium chloride and lithium carbonate) on the model of streptozotocin-induced diabetes mellitus type 2 in Wistar rats. Using the method of ß-cells detection with antibodies to insulin, we demonstrated that streptozotocin reduced the number of ß-cells and impaired their morphological structure. Both lithium preparations administered to diabetic animals for 28 days in doses of 10 and 8.9 mg/kg, respectively, attenuated the damaging effect of streptozotocin. This cytoprotective effect of lithium salts manifested in weakening of hyperglycemia, polyphagia, polydipsia, and weight loss. A satisfactory correlation between the morphometric data and blood glucose levels was revealed. The mechanisms of the multitarget action of lithium salts are discussed.


Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , Carbonato de Lítio/farmacologia , Cloreto de Lítio/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Glicemia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Imuno-Histoquímica , Insulina/sangue , Fígado/patologia , Masculino , Ratos , Ratos Wistar , Estreptozocina
4.
J Pharmacol Sci ; 138(3): 167-175, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30322800

RESUMO

Na+, K+-ATPase is a highly expressed membrane protein. Dysfunction of Na+, K+-ATPase has been implicated in the pathophysiology of several neurodegenerative and psychiatric disorders, however, the underlying mechanism of neuronal cell death resulting from Na+, K+-ATPase dysfunction is poorly understood. Here, we investigated the mechanism of neurotoxicity due to Na+, K+-ATPase inhibition using rat organotypic hippocampal slice cultures. Treatment with ouabain, a Na+, K+-ATPase inhibitor, increased the ratio of propidium iodide-positive cells among NeuN-positive cells in the hippocampal CA1 region, which was prevented by MK-801 and d-AP5, specific blockers of the N-methyl-d-aspartate (NMDA) receptor. EGTA, a Ca2+-chelating agent, also protected neurons from ouabain-induced injury. We observed that astrocytes expressed the glutamate aspartate transporter (GLAST), and ouabain changed the immunoreactive area of GFAP-positive astrocytes as well as GLAST. We also observed that ouabain increased the number of Iba1-positive microglial cells in a time-dependent manner. Furthermore, lithium carbonate, a mood-stabilizing drug, protected hippocampal neurons and reduced disturbances of astrocytes and microglia after ouabain treatment. Notably, lithium carbonate improved ouabain-induced decreases in GLAST intensity in astrocytes. These results suggest that glial cell abnormalities resulting in excessive extracellular concentrations of glutamate contribute to neurotoxicity due to Na+, K+-ATPase dysfunction in the hippocampal CA1 region.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Morte Celular/efeitos dos fármacos , Transportador 1 de Aminoácido Excitatório/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Astrócitos/metabolismo , Contagem de Células , Células Cultivadas , Maleato de Dizocilpina/farmacologia , Ácido Egtázico/farmacologia , Técnicas In Vitro , Carbonato de Lítio/farmacologia , Ouabaína/antagonistas & inibidores , Ouabaína/farmacologia , Ratos , Valina/análogos & derivados , Valina/farmacologia
5.
Bull Exp Biol Med ; 165(4): 470-473, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30121932

RESUMO

The study examined the effects of a novel neurotropic medication based on a lithium complex composed of lithium citrate, polymethylsiloxane, and aluminum oxide on electrophysiological parameters of the rat brain. In contrast to lithium carbonate (the reference drug), the novel preparation resulted in a wave-like dynamics of electrical activity in the visual cortex. Rhythmic photic stimulation of the rats treated with lithium carbonate resulted in appearance of the signs attesting to up-regulation of excitability of cerebral cortex in all examined ranges. In contrast, the complex lithium preparation diminished the delta power spectrum, which was the only affected frequency band. It is hypothesized that the complex lithium medication induces milder activation of the cerebral cortex in comparison with lithium carbonate. The novel medication composed of lithium citrate, aluminum oxide, and polymethylsiloxane, is characterized by greater efficacy and safety than the preparation based on inorganic lithium salt (lithium carbonate).


Assuntos
Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Lítio/farmacologia , Óxido de Alumínio/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citratos/farmacologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Lítio/química , Carbonato de Lítio/farmacologia , Masculino , Ratos , Silicones/farmacologia
6.
Neuropsychopharmacology ; 43(11): 2256-2263, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946107

RESUMO

The need for treatment response predictive biomarkers is being increasingly recognized in children and adolescents with psychiatric disorders. Structural gray matter abnormalities as a predictor of treatment outcome in pediatric bipolar disorder have not been systematically investigated, especially early in the illness course. With a prospective longitudinal study design, the present study enrolled 52 bipolar adolescents with no history of treatment with mood stabilizers or a therapeutic dose of antipsychotic drugs and 31 healthy controls. Patients were randomly assigned to treatment with quetiapine or lithium after pretreatment data collection. A hierarchical cluster analysis was performed using pretreatment cortical thickness data that identified two discrete patient subgroups. Compared to healthy subjects, patients in subgroup 1 (n = 16) showed widespread greater cortical thickness mainly across heteromodal cortex but also involving some regions of unimodal cortex, while those in subgroup 2 (n = 36) showed regional cortical thinning mainly in superior temporal and superior parietal regions. Patients within subgroup 1 showed a significantly higher response rate to quetiapine than those in subgroup 2 (100% vs 53%). No statistically significant difference was found in lithium response rate between the patient subgroups (63% vs 53%). Pretreatment clinical ratings and neuropsychological data did not differ across subgroups. Our findings suggest the existence of distinct and clinically relevant subgroups of pediatric bipolar patients, as defined by pattern of cortical thickness. These groups appear to differentially respond to antipsychotic treatment-notably with greater cortical thickness relative to controls predicting better treatment response.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/tratamento farmacológico , Córtex Cerebral/diagnóstico por imagem , Carbonato de Lítio/uso terapêutico , Fumarato de Quetiapina/uso terapêutico , Adolescente , Antidepressivos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Criança , Feminino , Humanos , Carbonato de Lítio/farmacologia , Imagem por Ressonância Magnética/métodos , Masculino , Tamanho do Órgão , Valor Preditivo dos Testes , Fumarato de Quetiapina/farmacologia , Resultado do Tratamento
7.
Neurosci Lett ; 664: 34-37, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29126775

RESUMO

We examined whether lithium carbonate (Li2CO3, 100mg/L) is able to prevent memory impairment induced by scopolamine. Moreover, we evaluated the effects of lithium on anxiety-like behavior and acetylcholinesterase activity in adult zebrafish. We demonstrated that lithium prevents the memory impairment induced by scopolamine, decreases exploration and increases the activity of acetylcholinesterase in zebrafish. Collectively, this contributes to a better understanding of the pharmacology of lithium, its interaction with cholinergic neurotransmission, and its possible application to therapeutic treatments aimed at improving cognition.


Assuntos
Carbonato de Lítio/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Escopolamina/toxicidade , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Carbonato de Lítio/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/psicologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Antagonistas Muscarínicos/toxicidade , Peixe-Zebra
8.
J Neurosci Methods ; 296: 23-31, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29274793

RESUMO

BACKGROUND: Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. The zebrafish is an ideal model for aggression research. Zebrafish are small, amenable to genetic and pharmacological manipulation, and agonistic behaviour can be measured reliably. NEW METHOD: In this study we have established a novel setup to automatically quantify aggression and locomotion in one-month old juvenile zebrafish, a stage at which fish exhibit adult-like behaviour but are small so that one camera can film several animals. RESULTS: We have validated our novel software by comparison to manual quantification of behaviour, characterised the aggression of one-month old fish, and demonstrated that we can detect alterations to aggression caused by mutation or drug application. COMPARISON WITH OTHER METHODS: The ability to record up to 12 juvenile fish allows us to speed up and standardise data acquisition compared to studies of single fish. CONCLUSIONS: This setup appears to be suitable to screen for drugs that decrease zebrafish aggression as a first step toward developing novel treatments for this behaviour.


Assuntos
Agressão , Automação Laboratorial/métodos , Comportamento Animal , Reconhecimento Automatizado de Padrão/métodos , Peixe-Zebra , Agressão/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Etanol/farmacologia , Carbonato de Lítio/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/genética , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Mutação , Psicotrópicos/farmacologia , Distribuição Aleatória , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Software , Gravação em Vídeo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/genética
9.
Ann Nucl Med ; 31(10): 744-751, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28895066

RESUMO

OBJECTIVE: The outcome of radioiodine therapy (RIT) in Graves' hyperthyroidism (GH) mainly depends on radioiodine (131I) uptake and the effective half-life of 131I in the gland. Studies have shown that lithium carbonate (LiCO3) enhances the 131I half-life and increases the applied thyroid radiation dose without affecting the thyroid 131I uptake. We investigated the effect of short-term treatment with LiCO3 on the outcome of RIT in patients with long-lasting GH, its influence on the thyroid hormones levels 7 days after RIT, and possible side effects. METHODS: Study prospectively included 30 patients treated with LiCO3 and 131I (RI-Li group) and 30 patients only with 131I (RI group). Treatment with LiCO3 (900 mg/day) started 1 day before RIT and continued 6 days after. Anti-thyroid drugs withdrawal was 7 days before RIT. Patients were followed up for 12 months. We defined a success of RIT as euthyroidism or hypothyroidism, and a failure as persistent hyperthyroidism. RESULTS: In RI-Li group, a serum level of Li was 0.571 ± 0.156 mmol/l before RIT. Serum levels of TT4 and FT4 increased while TSH decreased only in RI group 7 days after RIT. No toxic effects were noticed during LiCO3 treatment. After 12 months, a success of RIT was 73.3% in RI and 90.0% in RI-Li group (P < 0.01). Hypothyroidism was achieved faster in RI-Li (1st month) than in RI group (3rd month). Euthyroidism slowly decreased in RI-Li group, and not all patients became hypothyroid for 12 months. In contrast, euthyroidism rapidly declined in RI group, and all cured patients became hypothyroid after 6 months. CONCLUSION: The short-term treatment with LiCO3 as an adjunct to 131I improves efficacy of RIT in patients with long-lasting GH. A success of RIT achieves faster in lithium-treated than in RI group. Treatment with LiCO3 for 7 days prevents transient worsening of hyperthyroidism after RIT. Short-term use of LiCO3 shows no toxic side effects.


Assuntos
Doença de Graves/radioterapia , Radioisótopos do Iodo/uso terapêutico , Carbonato de Lítio/farmacologia , Adulto , Idoso , Transporte Biológico/efeitos dos fármacos , Feminino , Humanos , Radioisótopos do Iodo/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
10.
Neuroscience ; 354: 1-10, 2017 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-28433650

RESUMO

Brain microvascular endothelial cell (BMEC) injury induced by ischemia-reperfusion (I/R) is the initial stage of blood-brain barrier (BBB) disruption, which results in a poor prognosis in ischemic stroke patients. Autophagy has been shown to have protective effects on BMECs against cerebral ischemic insults. However, molecular mechanism of BMEC autophagy during I/R is unclear. Long noncoding RNAs (lncRNAs) are emerging as new factors involved in cell autophagy. LncRNA Malat1 is one of the most highly upregulated I/R or OGD/R-responsive endothelial lncRNA and plays a protective role in BMECs against cerebral ischemic insults. Oxygen-glucose deprivation/reoxygenation (OGD/R) is used to mimic I/R injury in vitro. Based on these findings, we hypothesized that Malat1 might play a protective role by enhancing BMEC autophagy. We performed GFP-LC3 puncta formation, LC3 conversion, p62 expression, and cell death assays, and the results were consistent with our hypothesis that Malat1 promoted BMEC autophagy and survival under OGD/R condition. We further explored the molecular mechanisms by which Malat1 exerted regulatory effects, and found that Malat1 served as an endogenous sponge to downregulate miR-26b expression by binding directly to miR-26b. Furthermore, Malat1 overturned the inhibitory effect of miR-26b on BMEC autophagy and survival, which involved in promoting the expression of miR-26b target ULK2. Collectively, our study illuminated a new Malat1-miR-26b-ULK2 regulatory axis in which Malat1 served as a competing endogenous RNA by sponging miR-26b and upregulating ULK2 expression, thereby promoting BMEC autophagy and survival under OGD/R condition.


Assuntos
Autofagia/efeitos dos fármacos , Células Endoteliais/metabolismo , MicroRNAs/metabolismo , Neuroprostanos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Longo não Codificante/metabolismo , Regulação para Cima/fisiologia , Animais , Autofagia/fisiologia , Encéfalo/anatomia & histologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Células Endoteliais/efeitos dos fármacos , Endotélio/citologia , Inibidores Enzimáticos/farmacologia , Glucose/deficiência , Carbonato de Lítio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neuroprostanos/farmacologia , Neuroprostanos/uso terapêutico , Oxigênio/farmacologia , Ligação Proteica/fisiologia , Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/farmacologia , Regulação para Cima/efeitos dos fármacos
11.
Arch Ital Biol ; 155(4): 118-130, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29405035

RESUMO

In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium administration during a long-lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the long-term treatment of spinal muscle atrophy.


Assuntos
Carbonato de Lítio/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Medula Espinal/efeitos dos fármacos , Atrofias Musculares Espinais da Infância/patologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neurônios Motores/patologia , Medula Espinal/patologia
12.
Tsitologiia ; 59(3): 178-84, 2017.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-30183165

RESUMO

Hepatocellular carcinoma (HCC) is one of the aggressive and resistant to drug therapy cancer. It is believed that the development of HCC is correlated with dysregulation of programmed cell death. So, the search for effective inducers of HCC cell death is very important. The aim of the work was to identify structural changes leading to HCC cell death when exposed to nanoscale and original forms of lithium salts. Using light and electron microscopy and flow cytometry, structural features of autophagy and apoptosis in HCC cells after their incubation with various forms of lithium salts has been revealed. It is shown that a more pronounced effect on HCC-29 cells have nanoscale forms of lithium carbonate and lithium citrate. At the same time, nanoscale lithium citrate mainly induced apoptosis, and nanosized form of lithium carbonate, along with apoptosis, induced autophagic death of HCC-29cells.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Citratos/farmacologia , Carbonato de Lítio/farmacologia , Neoplasias Hepáticas/metabolismo , Nanopartículas , Animais , Carcinoma Hepatocelular/ultraestrutura , Linhagem Celular Tumoral , Feminino , Neoplasias Hepáticas/ultraestrutura , Camundongos , Camundongos Endogâmicos CBA
13.
Clin Pharmacokinet ; 56(1): 77-90, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27393139

RESUMO

BACKGROUND: Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients. METHODS: Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations. RESULTS: The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 %. The population mean (inter-individual variability) clearance was 1.64 L/h/53 kg LBW0.75 (19 %) and central volume of distribution 23.6 L/53 kg LBW (6.8 %). The average lithium concentration over a dosing interval required for a 50 % reduction in YMRS was 0.711 mEq/L (59 %). A maintenance dose of 25 mg/kg TBW/day lithium carbonate in two daily doses was predicted to achieve a ≥50 % reduction in YMRS in 74 % of patients, while ~8 % of patients would be expected to have trough concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore, therapeutic drug monitoring will still be required even with these dosing strategies. CONCLUSIONS: When accounting for body size, the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults. Pharmacokinetic/pharmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients.


Assuntos
Antimaníacos/farmacocinética , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Carbonato de Lítio/farmacocinética , Carbonato de Lítio/uso terapêutico , Adolescente , Antimaníacos/administração & dosagem , Antimaníacos/farmacologia , Peso Corporal , Criança , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Carbonato de Lítio/administração & dosagem , Carbonato de Lítio/farmacologia , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Método de Monte Carlo
14.
Biol Trace Elem Res ; 178(1): 79-85, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27957665

RESUMO

Lithium is widely used in medicine and the therapy is often long term. Apart from beneficial effects, its application can cause diverse side effects. The current study was performed with the aim of the evaluation of the effect of lithium and/or selenium administration on magnesium, calcium and silicon levels in rats. The study was performed on rats divided into four groups (six animals each): control-received saline, Li-received Li2CO3 (2.7 mg Li/kg b.w.), Se-received Na2SeO3·H2O (0.5 mg Se/kg b.w.), and Li+Se-received simultaneously Li2CO3 and Na2SeO3·H2O (2.7 and 0.5 mg Se/kg b.w.). The administration was performed in form of water solutions by a stomach tube once a day for 6 weeks. In the organs (liver, kidney, brain, spleen, heart, lung and femoral muscle), the concentrations of magnesium, calcium and silicon were determined. Lithium significantly increased Ca in the kidney, brain and spleen. Coadministration of selenium reversed this effect. No changes of magnesium in organs were observed. Silicon was affected only in spleen-an increase vs. control was observed in all studied groups. The beneficial influence of coadministration of selenium in case of calcium lets us suggest that an issue of its possible use as an adjuvant alleviating side effects in lithium-treated subjects is worth being continued.


Assuntos
Cálcio/sangue , Carbonato de Lítio/farmacologia , Magnésio/sangue , Silício/sangue , Selenito de Sódio/farmacologia , Animais , Lítio/farmacologia , Masculino , Especificidade de Órgãos/efeitos dos fármacos , Ratos , Ratos Wistar , Selênio/farmacologia
15.
Mol Psychiatry ; 22(12): 1714-1724, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27646265

RESUMO

Lithium responsivity in patients with bipolar disorder has been genetically associated with Phosphodiesterase 11A (PDE11A), and lithium decreases PDE11A mRNA in induced pluripotent stem cell-derived hippocampal neurons originating from lithium-responsive patients. PDE11 is an enzyme uniquely enriched in the hippocampus that breaks down cyclic AMP and cyclic GMP. Here we determined whether decreasing PDE11A expression is sufficient to increase lithium responsivity in mice. In dorsal hippocampus and ventral hippocampus (VHIPP), lithium-responsive C57BL/6J and 129S6/SvEvTac mice show decreased PDE11A4 protein expression relative to lithium-unresponsive BALB/cJ mice. In VHIPP, C57BL/6J mice also show differences in PDE11A4 compartmentalization relative to BALB/cJ mice. In contrast, neither PDE2A nor PDE10A expression differ among the strains. The compartment-specific differences in PDE11A4 protein expression are explained by a coding single-nucleotide polymorphism (SNP) at amino acid 499, which falls within the GAF-B homodimerization domain. Relative to the BALB/cJ 499T, the C57BL/6J 499A decreases PDE11A4 homodimerization, which removes PDE11A4 from the membrane. Consistent with the observation that lower PDE11A4 expression correlates with better lithium responsiveness, we found that Pde11a knockout mice (KO) given 0.4% lithium chow for 3+ weeks exhibit greater lithium responsivity relative to wild-type (WT) littermates in tail suspension, an antidepressant-predictive assay, and amphetamine hyperlocomotion, an anti-manic predictive assay. Reduced PDE11A4 expression may represent a lithium-sensitive pathophysiology, because both C57BL/6J and Pde11a KO mice show increased expression of the pro-inflammatory cytokine interleukin-6 (IL-6) relative to BALB/cJ and PDE11A WT mice, respectively. Our finding that PDE11A4 negatively regulates lithium responsivity in mice suggests that the PDE11A SNPs identified in patients may be functionally relevant.


Assuntos
3',5'-GMP Cíclico Fosfodiesterases/metabolismo , Resistência a Medicamentos/fisiologia , Carbonato de Lítio/farmacologia , Psicotrópicos/farmacologia , 3',5'-GMP Cíclico Fosfodiesterases/genética , Animais , Células COS , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Resistência a Medicamentos/genética , Feminino , Expressão Gênica , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Multimerização Proteica , RNA Mensageiro/metabolismo , Especificidade da Espécie
16.
Eur Neuropsychopharmacol ; 26(12): 1900-1908, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27842942

RESUMO

Drug-induced hyperlocomotion in rodents is frequently used as a behavioral model for mania. However, the use of locomotor activity as the single parameter in these animal models of mania may pose some limitations for developing new pharmacological treatments. Thus, alternative behavioral markers are required. Fifty-kHz ultrasonic vocalizations (USV), which are thought to represent positive affect, are increased by the administration of the psychostimulant d-amphetamine, an effect that can be prevented by lithium treatment, the gold standard antimanic drug for treating bipolar disorder. The aim of this study was to evaluate 50-kHz USV in two other pharmacological-induced animal models of mania: ketamine (KET)- and lisdexamfetamine (LDX)-induced hyperlocomotion. After systemic injection of LDX (10mg/kg, ip), racemic-ketamine (25mg/kg, ip) or S-ketamine (25mg/kg, ip), locomotor activity and 50-kHz USV emission were evaluated in rats. Furthermore, the effects of an antimanic treatment, namely lithium carbonate (100mg/kg, ip), on LDX-induced 50-kHz USV and hyperlocomotion were tested. Rats treated with racemic KET and S-KET showed increased locomotor activity, but these drug treatments did not significantly affect 50-kHz USV emission rates. On the other hand, LDX administration increased both locomotor activity and 50-kHz USV with both effects being reversed by lithium administration. The present findings suggest that 50-kHz USV can differentiate between drug-induced models of mania, which may represent different types of manic episodes. Thus, measuring 50-kHz USV might serve as an additional valuable behavioral variable to assess mania-like phenotypes in rat models.


Assuntos
Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Ketamina/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Vocalização Animal/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Transtorno Bipolar/psicologia , Modelos Animais de Doenças , Hipercinese/psicologia , Carbonato de Lítio/farmacologia , Carbonato de Lítio/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar
17.
Braz J Med Biol Res ; 49(12): e5805, 2016 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-27878228

RESUMO

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials.


Assuntos
Ataxina-3/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Carbonato de Lítio/farmacologia , Doença de Machado-Joseph , Proteínas Repressoras/efeitos dos fármacos , Ubiquinona/análogos & derivados , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Doença de Machado-Joseph/tratamento farmacológico , Ubiquinona/farmacologia
18.
Braz. j. med. biol. res ; 49(12): e5805, 2016. graf
Artigo em Inglês | LILACS | ID: biblio-828178

RESUMO

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials.


Assuntos
Humanos , Ataxina-3/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Carbonato de Lítio/farmacologia , Doença de Machado-Joseph , Proteínas Repressoras/efeitos dos fármacos , Ubiquinona/análogos & derivados , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doença de Machado-Joseph/tratamento farmacológico , Ubiquinona/farmacologia
19.
Patol Fiziol Eksp Ter ; 59(2): 57-64, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26571809

RESUMO

Oxidant-antioxidant status in tumor tissue of male-mice CBA at spontaneous course of hepatocarcinoma-29 and after repeated injections of lithium carbonate nanosized particles was evaluated on changes of lipid peroxidation (LPO) products level reacted with 2-thiobarbituric acid (TBA) as indicator of oxidative stress and activity of superoxide dismutase (SOD) and catalase enzymes as indicators of antioxidant defense by spectrophotometer <> (Bio-Rad, USA). Tumor development after hepatocarcinoma-29 cells injection into muscle right leg changed the levels of LPO activity in two-phase manner. TBA-active products content were decreased in 2,4 times in comparison with the control indicates after invasion of tumor cells, it was raised in 2,1 times at excessive tumor growth and diminished at terminal stage. Catalase activity was significantly elevated, but SOD activity was reduced in tumor tissue samples at active growth of hepatocarcinoma. The repeated injections of lithium carbonate nanosized particles at hepatocarcinoma inhibited processes of lipid peroxidation in tumor tissue in 2,4 times, but didn't influence on activities of catalase and SOD. Thus the effects lithium carbonate nanosized particles injections referred on maintenance of balance between the oxidant and antioxidants may be of some help to limit the progression of precancerous condition toward malignancy and tumor growth.


Assuntos
Inibidores Enzimáticos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Carbonato de Lítio/farmacologia , Neoplasias Hepáticas Experimentais/metabolismo , Nanopartículas , Estresse Oxidativo/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Feminino , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos CBA , Proteínas de Neoplasias/metabolismo , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
20.
PLoS One ; 10(11): e0142267, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26605788

RESUMO

The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer's disease (AD) patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd)20Lms/2J) and their non-transgenic litter mate genetic controls were treated with lithium carbonate (0.25mg/Kg/day in drinking water) for 16 or 8 months starting at two and ten months of age, respectively [corrected]. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer's disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Amnésia/prevenção & controle , Transtornos Cognitivos/prevenção & controle , Carbonato de Lítio/farmacologia , Fármacos Neuroprotetores/farmacologia , Placa Amiloide/prevenção & controle , Administração Oral , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Amnésia/genética , Amnésia/patologia , Amnésia/fisiopatologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Esquema de Medicação , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia
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