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1.
Ecotoxicol Environ Saf ; 207: 111101, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32905937

RESUMO

To regulate the presence of contaminants in Brazilian water, the Brazilian Environmental Council (CONAMA) promulgates regulations regarding the concentrations of given compounds that are supposed to be safe for aquatic life. Considering these regulations, this study tested the effects of considered safe levels of lithium (2.5 mgL-1) and selenium (0.01 mgL-1), isolated and mixed, on the American bullfrog (Lithobates catesbeianus) tadpoles. The evaluation was done through the use of biomarkers of larval development as total wet weight (TWW), snout-vent-length (SVL), hind-limb-length (HLL), activity level (AL), histologic evaluation of the thyroid gland and the mortality rate. The tadpoles were allocated into four groups (n = 20 each): a control group (CT); a group exposed to lithium (LI), a group exposed to selenium (SE), and a group exposed to both lithium and selenium (SELI). The whole assay was carried out over 21 days, with two rounds of data collection (on 7th and 21st day) to evaluate the responses over time. A statistical reduction in the AL was observed in the tadpoles from the LI and SELI groups after 7 days of exposure, the same pattern was observed after 21 days. Histological analyses of the thyroid gland showed signs of up-regulation (i.e. statistic reduction in number and area of the follicles, as well a significant reduction in the area of the gland) in all exposed groups, which represents an endocrine response as an adaptative strategy to deal with polluted aquatic environment. The stress triggered by the polluted medium is discussed.


Assuntos
Lítio/toxicidade , Metamorfose Biológica/efeitos dos fármacos , Rana catesbeiana/fisiologia , Selênio/toxicidade , Poluentes Químicos da Água/toxicidade , Aceleração , Animais , Bioensaio , Brasil , Poluentes Ambientais , Larva/fisiologia , Metamorfose Biológica/fisiologia , Glândula Tireoide , Estados Unidos
2.
Environ Sci Pollut Res Int ; 27(33): 42124-42132, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32705564

RESUMO

Many xenobiotics in the environment affect the human body in various ways. Among those xenobiotics, lithium chloride (Li, LiCl) and monosodium glutamate (L-glutamic acid monosodium salt, MSG) compounds affect the crucial processes of stem cell differentiation, cell proliferation, developmental gene expression, and overall development in animals. In this study, we aimed to examine the developmental effects of exposure to flavor enhancer MSG and LiCI medicament on Xenopus embryos using the frog embryo teratogenesis assay of Xenopus test. To this purpose, Xenopus laevis embryos were exposed to four different concentrations of MSG (120, 500, 750, 1000 mg/dL) and Li (0.02 g/L) alone and in combinations for a period of 96 h, and then normal, abnormal, and death ratios were determined in all exposure groups. Besides, length values of all groups and membrane potentials of fertilized and non-fertilized oocyte groups treated with 120- and 500-mg/dL MSG doses and 0.02-g/L LiCI dose were measured. Treatment with ADI (acceptable daily intake) dose of MSG alone did not lead to a substantial effect on the development of Xenopus laevis embryos. But, exposure to daily doses exceeding the ADI level (500, 750, 1000 mg/dL) caused significant harmful effects. Besides, Li-involving treatments caused dramatic deleterious effects on embryo development. MSG attenuated harmful effects of Li in MSG+Li combined treatments. Membrane potentials of non-fertilized oocytes and fertilized eggs were significantly changed in all groups that their membrane potentials were measured. Extrapolating these results into humans require similarly designed studies conducted on human embryos.


Assuntos
Ácido Glutâmico , Teratogênese , Animais , Embrião não Mamífero , Humanos , Lítio/toxicidade , Xenopus laevis
3.
Int J Mol Sci ; 21(3)2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32050593

RESUMO

Lithium salt is the first-line therapeutic option for bipolar disorder and has been proposed as a potential antitumoral drug. The effects of LiCl treatment were investigated in SH-SY5Y, a human neuroblastoma cell line and an in vitro model of dopaminergic neuronal differentiation. LiCl, at the dosage used in psychiatric treatment, does not affect cell proliferation, while at higher doses it delays the SH-SY5Y cell division cycle and for prolonged usage reduces cell viability. Moreover, the ion treatment affects DNA integrity as demonstrated by accumulation of p53 and γH2AX (the phosphorylated form of H2AX histone), two important markers of genome damage. p57Kip2, a CIP/Kip protein, is required for proper neuronal maturation and represents a main factor of response to stress including genotoxicity. We evaluated the effect of lithium on p57Kip2 levels. Unexpectedly, we found that lithium downregulates the level of p57Kip2 in a dose-dependent manner, mainly acting at the transcriptional level. A number of different approaches, mostly based on p57Kip2 content handling, confirmed that the CKI/Kip reduction plays a key role in the DNA damage activated by lithium and suggests the unanticipated view that p57Kip2 might be involved in DNA double-strand break responses. In conclusion, our study identified novel roles for p57Kip2 in the molecular mechanism of lithium at high concentration and, more in general, in the process of DNA repair.


Assuntos
Inibidor de Quinase Dependente de Ciclina p57/genética , Dano ao DNA , Lítio/farmacologia , Neurônios/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Humanos , Lítio/toxicidade , Neurônios/metabolismo
5.
J Neurosci Nurs ; 51(6): 283-286, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31469707

RESUMO

BACKGROUND: In patients presenting with neurological deficits, identifying the cause can be challenging. METHODS: This case study discusses a condition that is not commonly seen. DISCUSSION: Although lithium toxicity syndrome is not as familiar as other causes of neurological issues, this should be considered for any patient who presents with unexplained neurological deficits and a history of taking this medication. CONCLUSION: If toxicity is not recognized early, the patient can be left with irreversible neurological symptoms, also known as syndrome of irreversible lithium-effectuated neurotoxicity, which impacts quality of life or can even cause death.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Lítio , Idoso , Feminino , Humanos , Lítio/uso terapêutico , Lítio/toxicidade , Síndromes Neurotóxicas , Tremor/etiologia
6.
Int Rev Psychiatry ; 31(3): 295-304, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31180257

RESUMO

The continuation of lithium while breastfeeding is a controversial topic, and clinical recommendations vary. A systematic review was completed of available data on lithium and breastfeeding to determine the degree of lithium exposure through breast milk and assess the potential risk to the infant. Databases, including PubMed MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane CENTRAL Register of Controlled Trials databases, were searched for articles on lithium and breastfeeding from the start dates of the databases through December 2018. Articles were included if the report included at least one maternal serum/plasma and/or breast milk lithium concentration and one infant serum/plasma lithium concentration. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Twelve articles, all case reports, were selected for inclusion out of 441 articles that were found and 230 that were reviewed from the search. Data are limited on the safety of lithium continuation while breastfeeding. Among the adverse effects reported, it is difficult to differentiate poor outcomes from factors affecting infant health, concomitant medications, and gestational lithium exposure. Recommendations on whether to continue lithium while breastfeeding must be personalized to the individual woman and her infant.


Assuntos
Aleitamento Materno/efeitos adversos , Lítio/toxicidade , Lítio/uso terapêutico , Leite Humano/química , Medição de Risco , Feminino , Humanos , Lactente , Lítio/sangue
7.
Biointerphases ; 14(2): 021007, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053032

RESUMO

Gelatin methacryloyl (GelMA) and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) photoinitiator are commonly used in combination to produce a photosensitive polymer but there are concerns that must be addressed: the presence of unreacted monomer is well known to be cytotoxic, and lithium salts are known to cause acute kidney injury. In this study, acellular 10% GelMA hydrogels cross-linked with different LAP concentrations and cross-linking illumination times were evaluated for their cytotoxicity, photosensitizing potential, and elastic moduli. Alamar Blue and CyQuant Direct Cell viability assays were performed on human primary renal proximal tubule epithelial cells (hRPTECs) exposed to extracts of each formulation. UV exposure during cross-linking was not found to affect extract cytotoxicity in either assay. LAP concentration did not affect extract cytotoxicity as determined by the Alamar Blue assay but reduced hRPTEC viability in the CyQuant Direct cell assay. Photocatalytic activity of formulation extracts toward NADH oxidation was used as a screening method for photosensitizing potential; longer UV exposure durations yielded extracts with less photocatalytic activity. Finally, elastic moduli determined using nanoindentation was found to plateau to approximately 20-25 kPa after exposure to 342 mJ/cm2 at 2.87 mW of UV-A exposure regardless of LAP concentration. LAP at concentrations commonly used in bioprinting (<0.5% w/w) was not found to be cytotoxic although the differences in cytotoxicity evaluation determined from the two viability assays imply cell membrane damage and should be investigated further. Complete cross-linking of all formulations decreased photocatalytic activity while maintaining predictable final elastic moduli.


Assuntos
Células Epiteliais/efeitos dos fármacos , Gelatina/toxicidade , Hidrogéis/toxicidade , Lítio/toxicidade , Ácidos Fosfínicos/toxicidade , Poli-Hidroxietil Metacrilato/toxicidade , Tecidos Suporte , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Elasticidade , Gelatina/química , Humanos , Hidrogéis/síntese química , Teste de Materiais , Poli-Hidroxietil Metacrilato/síntese química
8.
Biol Trace Elem Res ; 191(2): 412-418, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30600502

RESUMO

Long-term lithium treatment was associated with chronic kidney disease and renal failure although the underlying pathogenic mechanisms are not certainty known. The aim of this study was to evaluate changes in oxidative stress measures as well as renal functional and structural alterations associated with chronic use of lithium in rats. Forty Wistar male rats were randomized into four groups: control groups fed ad libitum powered standard diet for 1 and 3 months and experimental groups fed ad libitum the same diet supplemented with 60 mmol/kg diet for 1 and 3 months. Histopathological changes, laboratory parameters, and oxidative stress measurements were assessed at months 1 and 3. The experimental animals showed alteration of the cortical tubules from the first month of lithium-treatment and a decrease in the glomerular filtration rate and in the glomerular area at the third month. There was an increase in thiobarbituric acid reactive substances and carbonyls, as well as an increase in reduced glutathione, in the kidney of rats exposed to lithium. These changes were evident from the first month of treatment and remained throughout the experiment. Our results suggest that, oxidative stress could be one of the pathogenic mechanisms involved in the structural and functional alterations of the kidney associated with prolonged use of lithium. The study of the pathogenic mechanisms involved in lithium-induced nephropathy is a critical issue for the development of new strategies for prevention and/or early detection.


Assuntos
Nefropatias/sangue , Nefropatias/induzido quimicamente , Lítio/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Taxa de Filtração Glomerular/efeitos dos fármacos , Glutationa/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Masculino , Ratos , Ratos Wistar , Insuficiência Renal/sangue , Insuficiência Renal/induzido quimicamente , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
9.
Turk Neurosurg ; 29(1): 95-105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30614506

RESUMO

AIM: To investigate possible correlations between serum S100B levels and microglial/astrocytic activation in status epilepticus (SE) in lithium-pilocarpine-exposed rat hippocampi and whether serum S100B levels linearly reflect neuroinflammation. Additionally, to assess the effects of minocycline (M), an inhibitor of neuroinflammation. MATERIAL AND METHODS: Rats were divided into 4 groups (6/group), namely, control (C), sham, SE, and SE+M. Animals were exposed to lithium-pilocarpine to induce SE in the SE and SE+M groups. Cardiac blood was collected to measure S100B levels, and coronal brain sections including the hippocampus were prepared to examine microglial/astrocytic activation and to evaluate neuroinflammation at day 7 of SE. RESULTS: Serum S100B levels, OX42 (+) microglia in CA1, and GFAP (+) astrocytes in both CA1 and dentate gyrus (DG) were higher in the SE+M group than in the C group. Most importantly, highly positive correlations were found between S100B levels and microglial activation in CA1, apart from astrocytic activation in CA1 and DG. Unexpectedly, microglial activation in CA1 and astrocytic activation in DG were also enhanced in the SE+M group compared with the C group. Moreover, M administration reversed the neuronal loss observed in DG during SE. CONCLUSION: These results suggest that serum S100B is a candidate biomarker for monitoring neuroinflammation and that it may also help predict diagnosis and prognosis.


Assuntos
Anti-Inflamatórios/farmacologia , Microglia/metabolismo , Minociclina/farmacologia , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Estado Epiléptico/sangue , Animais , Astrócitos/efeitos dos fármacos , Biomarcadores/sangue , Convulsivantes/toxicidade , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lítio/toxicidade , Masculino , Microglia/efeitos dos fármacos , Pilocarpina/toxicidade , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia
10.
Ir J Med Sci ; 188(3): 1103-1109, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30632028

RESUMO

INTRODUCTION: Lithium is a medication indicated for the treatment of bipolar disorder and treatment-resistant depression, with a narrow therapeutic index. Overdose, either acute or chronic can result in neurological symptoms, requiring dialysis and admission to intensive care in some cases. Lithium toxicity is avoidable with careful monitoring. However, we have noted several recent cases of lithium toxicity in our local service and thus sought to investigate this issue in a more systematic manner. AIM: We aimed to quantify the incidence of lithium toxicity in our local population over a single year and identify the patients most at risk. We also aimed to generate clinical recommendations on the prevention of lithium toxicity to improve patient safety. METHOD: We identified the incidence of lithium toxicity in our local population, by searching the hospital pathology database for patients with serum lithium levels greater than 1.0 mmol/L. We examined the available clinical notes for these patients. RESULTS: We identified 74 serum lithium readings above 1.0 mmol/L measured in 44 individual patients. The highest recorded level was 3.2 mmol/L. Of these, 11 patients were aged 65 years or older. Hospital admission was required in 14 cases. There were missing data of note: 29.5% had no renal function/eGFR measurement at time of toxicity and 52.3% without a baseline eGFR. CONCLUSION: Lithium toxicity is common in our population. Given the narrow therapeutic index, this demonstrates the need for careful monitoring and prescribing, especially patients aged 65 and over.


Assuntos
Lítio/toxicidade , Centros de Atenção Terciária/normas , Idoso , Feminino , Humanos , Masculino , Estudos Retrospectivos
11.
BMJ Case Rep ; 12(1)2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30659009

RESUMO

After 25 years of continuous lithium therapy, a woman with moderate intellectual disability and bipolar disorder developed symptoms suggestive of dementia. In fact, she had developed lithium neurotoxicity, but this was overlooked for 18 months as serial lithium levels were in the therapeutic range.


Assuntos
Demência/induzido quimicamente , Lítio/toxicidade , Síndromes Neurotóxicas/etiologia , Transtorno Bipolar/tratamento farmacológico , Feminino , Humanos , Lítio/administração & dosagem , Pessoa de Meia-Idade , Resultado do Tratamento
12.
J Pharmacol Exp Ther ; 368(3): 326-337, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552296

RESUMO

Ganaxolone (GNX) is the 3ß-methylated synthetic analog of the naturally occurring neurosteroid, allopregnanolone (ALLO). GNX is effective in a broad range of epilepsy and behavioral animal models and is currently in clinical trials designed to assess its anticonvulsant and antidepressant activities. The current studies were designed to broaden the anticonvulsant profile of GNX by evaluating its potential anticonvulsant activities following i.v. administration in treatment-resistant models of status epilepticus (SE), to establish a pharmacokinetic (PK)/pharmacodynamic (PD) relationship, and to compare its PK and anticonvulsant activities to ALLO. In PK studies, GNX had higher exposure levels, a longer half-life, slower clearance, and higher brain penetrance than ALLO. Both GNX and ALLO produced a sedating response as characterized by loss of righting reflex, but neither compound produced a full anesthetic response as animals still responded to painful stimuli. Consistent with their respective PK properties, the sedative effect of GNX was longer than that of ALLO. Unlike other nonanesthetizing anticonvulsant agents indicated for SE, both GNX and ALLO produced anticonvulsant activity in models of pharmacoresistant SE with administration delay times of up to 1 hour after seizure onset. Again, consistent with their respective PK properties, GNX produced a significantly longer anticonvulsant response. These studies show that GNX exhibited improved pharmacological characteristics versus other agents used as treatments for SE and position GNX as a uniquely acting treatment of this indication.


Assuntos
Diazepam/uso terapêutico , Lítio/toxicidade , Pilocarpina/toxicidade , Pregnanolona/análogos & derivados , Pregnanolona/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Administração Intravenosa , Anestésicos/administração & dosagem , Animais , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/induzido quimicamente , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Masculino , Agonistas Muscarínicos/toxicidade , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia
13.
Acta Physiol (Oxf) ; 225(2): e13191, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30257062

RESUMO

AIM: Therapeutic use of lithium in bipolar disorder is limited by the development of nephrogenic diabetes insipidus (NDI). We reported that pharmacological blockade of P2Y12 receptor (R) with clopidogrel or prasugrel significantly ameliorated lithium-induced NDI in rodents. Using mice genetically lacking P2Y12 -R we evaluated whether the observed amelioration is mediated through P2Y12 -R METHODS: P2ry12-/- mouse line (C57/BL6) was rederived from cryopreserved embryos of the knockout (KO) mice generated by Deltagen Inc. Syngeneic wild type (WT) mice obtained by heterozygous crossing were inbred. Groups of adult WT and KO mice were fed lithium-added (40 mmol LiCl/kg food) or regular diet, and euthanized after 2 or 4 weeks. Twenty-four hour urine samples and terminal blood and kidney samples were analyzed. RESULTS: At both time points, lithium-induced polyuria and decrease in aquaporin-2 (AQP2) protein abundance in the kidney medulla were less marked in KO vs WT mice. Immunofluorescence microscopy revealed that lithium-induced alterations in the cellular disposition of AQP2 protein in the medullary collecting ducts of WT mice were blunted in KO mice. Serum lithium, sodium and osmolality were similar in both genotypes after lithium treatment. After 2 weeks, lithium induced marked increases in urinary excretion of Na, K, and arginine vasopressin in WT mice but not in KO mice. CONCLUSION: Taken together, our data show that similar to pharmacological blockade, deletion of P2Y12 -R significantly ameliorates lithium-induced NDI, without reducing serum lithium levels. Hence, targeting P2Y12 -R with currently available drugs in the market offers a novel and safer method for treating NDI.


Assuntos
Diabetes Insípido Nefrogênico/induzido quimicamente , Lítio/toxicidade , Receptores Purinérgicos P2Y12/fisiologia , Animais , Aquaporina 2/metabolismo , Arginina Vasopressina/urina , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/metabolismo , Diabetes Insípido Nefrogênico/prevenção & controle , Dinoprostona/urina , Feminino , Lítio/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Natriurese/efeitos dos fármacos , Potássio/urina , Receptores Purinérgicos P2Y12/genética
14.
Sci Total Environ ; 652: 202-211, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30366321

RESUMO

The nano forms of the metals molybdenum oxide (MoO3), nickel oxide (NiO) and lithium oxide (Li2O) are finding wide application in advanced technologies including batteries and fuel cells. We evaluated soil responses to nanoMoO3, nanoNiO, and nanoLi2O as some environmental release of the materials, either directly or following the land application of biosolids, is expected. Using Drummer soil (Fine-silty, mixed, superactive, mesic Typic Endoaquolls), we evaluated the impacts of the three nanometals on soil gas (N2O, CH4, and CO2) emissions, enzyme activities (ß-glucosidase and urease), and microbial community structure (bacterial, archaeal, and eukaryal) in a 60 day microcosms incubation. Soil treated with nanoLi2O at 474 µg Li/g soil, released 3.45 times more CO2 with respect to the control. Additionally, ß-glucosidase activity was decreased while urease activity increased following nanoLi2O treatment. While no clear patterns were observed for gas emissions in soils exposed to nanoMoO3 and nanoNiO, we observed a temporary suppression of ß-glucosidase activity in soil treated with either metal. All three domains of microbial community were affected by increasing metal concentrations. This is the first evaluation of soil responses to nanoMoO3, nanoNiO, or nanoLi2O.


Assuntos
Microbiota , Nanoestruturas/toxicidade , Poluentes do Solo/toxicidade , Lítio/toxicidade , Molibdênio/toxicidade , Níquel/toxicidade , Solo/química , Microbiologia do Solo
15.
Neurotherapeutics ; 15(4): 1093-1111, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30112701

RESUMO

Inflammation is implicated in epileptogenesis. Activated microglia and macrophages (MG/MΦ) are found in the brains of patients with epilepsy-related diseases and animal models of epilepsy. It is not yet known how the MG/MΦ activation phenotype affects pathological changes in the brain after a single seizure. In this study, we had 2 main purposes: first, to characterize post-status epilepticus (SE) inflammation by tracking MG/MΦ polarization, and, second, to explore the role of an innate immune receptor adaptor protein, namely, myeloid differentiation primary response gene 88 (MyD88), in the induction of SE in a mouse model. A lithium-pilocarpine model of seizure conditions was generated in C57BL/6 mice. The intensity and distribution of MG/MΦ polarization were tracked by fluorescent immunohistochemistry and Western blotting for the polarization markers inducible nitrogen oxygenized synthase, arginase-1, CD163, and mannose receptor. We observed steadily increasing M1 MG/MΦ along with MyD88 signal upregulation after SE in the hippocampi of mice, whereas the M2 marker arginase-1 was localized mainly in astrocytes rather than in MG/MΦ. Inhibition or gene knockout of MyD88 reduced M1 MG/MΦ and gliosis although increasing M2 MG/MΦ in the hippocampi of SE mice. MyD88 inhibition also augmented glutamate transporter 1 expression and reduced N-methyl-D-aspartate receptor NR1 subunit expression in the hippocampus to protect pyramidal neurons from apoptosis. These data suggest that MG/MΦ polarization after SE impacts the pathological outcome of the hippocampus via MyD88 signaling and point to MyD88 as a potential neuroprotective target for epilepsy therapy.


Assuntos
Apoptose/fisiologia , Hipocampo/metabolismo , Macrófagos/patologia , Microglia/patologia , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Neurônios/patologia , Transdução de Sinais/genética , Estado Epiléptico/patologia , Animais , Apoptose/genética , Polaridade Celular/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica em Archaea/efeitos dos fármacos , Regulação da Expressão Gênica em Archaea/genética , Hipocampo/patologia , Marcação In Situ das Extremidades Cortadas , Lítio/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/química , Fator 88 de Diferenciação Mieloide/deficiência , Peptídeos/uso terapêutico , Pilocarpina/toxicidade , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/genética , Receptor 4 Toll-Like/metabolismo
16.
Environ Geochem Health ; 40(5): 1841-1851, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29948536

RESUMO

Rubidium and lithium are rather rare elements in environmental research, despite their affiliation with a group of chemically active metals and the abundance of Rb in the environment. A growing body of evidence, although controversial, has indicated that both elements possess unique essential and neurophysiological characteristics in biota and humans. Both elements may concentrate in soil and vegetation of sub-arid environments. We investigated the content and (potential) availability of Rb and Li in the soils and natural waters of Galilee, the Coastal Plain, and the northern Negev of Israel. A newly developed chromatographic technique for the separation of truly dissolved Rb and Li compounds has been applied. High concentrations of Rb, together with high values of the potentially vital Rb-to-K ratio, were found in the soils, the soil solutions, rainwater, throughfall water, and the plant litter leachates, but not in the surface and spring waters. This may indicate a sequestration of Rb in the local soils and a semi-closed Rb turnover in the soil-plant system with a major input from sea aerosols. Low Li bulk and available concentrations were determined in all the natural compartments. Possible implications of such specific environmental features on the local population health were discussed.


Assuntos
Lítio/análise , Rubídio/análise , Solo/química , Exposição Ambiental , Humanos , Israel , Lítio/toxicidade , Plantas/química , Potássio/análise , Rubídio/toxicidade , Água/química
17.
Arch Toxicol ; 92(5): 1673-1684, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29550861

RESUMO

Rechargeable Li-ion batteries (LIB) are increasingly produced and used worldwide. LIB electrodes are made of micrometric and low solubility particles, consisting of toxicologically relevant elements. The health hazard of these materials is not known. Here, we investigated the respiratory hazard of three leading LIB components (LiFePO4 or LFP, Li4Ti5O12 or LTO, and LiCoO2 or LCO) and their mechanisms of action. Particles were characterized physico-chemically and elemental bioaccessibility was documented. Lung inflammation and fibrotic responses, as well as particle persistence and ion bioavailability, were assessed in mice after aspiration of LIB particles (0.5 or 2 mg); crystalline silica (2 mg) was used as reference. Acute inflammatory lung responses were recorded with the 3 LIB particles and silica, LCO being the most potent. Inflammation persisted 2 m after LFP, LCO and silica, in association with fibrosis in LCO and silica lungs. LIB particles persisted in the lungs after 2 m. Endogenous iron co-localized with cobalt in LCO lungs, indicating the formation of ferruginous bodies. Fe and Co ions were detected in the broncho-alveolar lavage fluids of LFP and LCO lungs, respectively. Hypoxia-inducible factor (HIF) -1α, a marker of fibrosis and of the biological activity of Co ions, was upregulated in LCO and silica lungs. This study identified, for the first time, the respiratory hazard of LIB particles. LCO was at least as potent as crystalline silica to induce lung inflammation and fibrosis. Iron and cobalt, but not lithium, ions appear to contribute to LFP and LCO toxicity, respectively.


Assuntos
Poluentes Atmosféricos/toxicidade , Cobalto/toxicidade , Fontes de Energia Elétrica , Lítio/toxicidade , Óxidos/toxicidade , Pneumonia/induzido quimicamente , Administração por Inalação , Poluentes Atmosféricos/química , Poluentes Atmosféricos/farmacocinética , Animais , Disponibilidade Biológica , Líquido da Lavagem Broncoalveolar/química , Cobalto/química , Cobalto/farmacocinética , Feminino , Fibrose/induzido quimicamente , Fibrose/patologia , Ferro/química , Ferro/farmacocinética , Ferro/toxicidade , Lítio/química , Lítio/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Óxidos/química , Óxidos/farmacocinética , Tamanho da Partícula , Pneumonia/patologia , Titânio/química , Titânio/farmacocinética , Titânio/toxicidade , Testes de Toxicidade
18.
Epilepsy Res ; 142: 45-52, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29549796

RESUMO

Glucagon-like peptide-1(GLP-1) is a growth factor that has neuroprotective and anti-inflammatory properties. The protease resistant GLP-1 analogue liraglutide has been shown to be neuroprotective in previous studies in animal models of Alzheimer's disease or Parkinson's disease. Status epilepticus (SE) is a complex disorder, involving many underlying pathological processes, including excitotoxic and chronic inflammatory events. The present pilot study aims to investigate whether liraglutide alleviates the chronic inflammation response and mitochondrial stress induced by SE in the lithium-pilocarpine animal model. We found that treatment with 25nmol/kg. i.p. once-daily after the induction of SE for 7 days reduced chronic inflammation as shown by reduced numbers of activated microglia and astrocytes, and reduced levels of TNF-α and IL-1ß in the hippocampus. The mitochondrial stress marker BAX was reduced and the survival factor Bcl-2 was enhanced by liraglutide. Blood glucose levels were not affected by liraglutide. We show for the first time that liraglutide can reduce the chronic inflammation and mitochondrial stress induced by SE, and the results suggest that GLP-1 receptor agonists such as liraglutide have restorative and protective effects in the brain after SE and could serve as a potential treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/etiologia , Inflamação/prevenção & controle , Liraglutida/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Convulsivantes/toxicidade , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lítio/toxicidade , Masculino , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Pilocarpina/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/complicações , Estado Epiléptico/patologia , Fatores de Tempo , Proteína X Associada a bcl-2
19.
Epilepsy Res ; 142: 64-72, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29571151

RESUMO

Folate is involved in metabolic processes and it has been implicated in both aggravation and amelioration of seizures. The aim of the current work was to study the effect of chronic temporal lobe epilepsy (TLE) on the plasma and brain concentrations of folate and on its uptake carriers in the brain - the reduced folate carrier (RFC), folate receptor α (FRα) and proton coupled folate transporter (PCFT). We utilized the rat lithium pilocarpine model for TLE. Approximately two months following status epilepticus, rats with spontaneous recurrent seizures (SRS) were sacrificed for brain and plasma folate concentration analyses and folate uptake carrier expression studies. RT-PCR and western blot analyses were utilized for quantification of folate carriers' mRNAs and proteins, respectively. The distribution of folate carriers in the brain was studied using immunohistochemistry. In the SRS rats we found lower plasma concentrations (10 ±â€¯0.9 in control vs. 6.6 ±â€¯1.6 ng/ml in SRS, P < 0.05), but preserved cortical and increased hippocampal levels of folate (0.5 ±â€¯0.1 in control vs. 0.9 ±â€¯0.2 ng/mg in SRS, P = 0.055). Hippocampus - to - plasma ratio of folate concentration was 3-fold higher in the SRS group, compared with the controls (0.13 ±â€¯0.03 vs. 0.04 ±â€¯0.02, respectively; P < 0.01). mRNA and protein levels of the folate uptake carriers did not differ between SRS rats and controls. However, immunofluorescent staining quantification revealed that the emission intensity of both RFC and FRα was elevated 8-fold and 4-fold, respectively, in hippocampal CA1 neurons of SRS rats, compared to controls (P < 0.01). PCFT was unquantifiable. If corroborated by complementary research in humans, the findings of this study may be utilized clinically for supplemental therapy planning, in imaging the epileptic focus, and for drug delivery into the epileptic brain. Further studies are required for better elucidating the clinical and mechanistic significance of altered folate balances in the epileptic brain.


Assuntos
Encéfalo/metabolismo , Ácido Fólico/metabolismo , Homeostase/fisiologia , Estado Epiléptico/metabolismo , Animais , Antígeno CD11b/metabolismo , Convulsivantes/toxicidade , Modelos Animais de Doenças , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Ácido Fólico/genética , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Homeostase/efeitos dos fármacos , Lítio/toxicidade , Masculino , Fosfopiruvato Hidratase/metabolismo , Pilocarpina/toxicidade , Transportador de Folato Acoplado a Próton/genética , Transportador de Folato Acoplado a Próton/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Estatísticas não Paramétricas , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia
20.
J Neuroinflammation ; 15(1): 68, 2018 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-29506554

RESUMO

BACKGROUND: Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and is accompanied, in one third of cases, by resistance to antiepileptic drugs (AED). Most AED target neuronal activity modulated by ionic channels, and the steroid sensitivity of these channels has supported the use of corticosteroids as adjunctives to AED. Assuming the importance of astrocytes in neuronal activity, we investigated inflammatory and astroglial markers in the hippocampus, a key structure affected in TLE and in the Li-pilocarpine model of epilepsy. METHODS: Initially, hippocampal slices were obtained from sham rats and rats subjected to the Li-pilocarpine model of epilepsy, at 1, 14, and 56 days after status epilepticus (SE), which correspond to the acute, silent, and chronic phases. Dexamethasone was added to the incubation medium to evaluate the secretion of S100B, an astrocyte-derived protein widely used as a marker of brain injury. In the second set of experiments, we evaluated the in vivo effect of dexamethasone, administrated at 2 days after SE, on hippocampal inflammatory (COX-1/2, PGE2, and cytokines) and astroglial parameters: GFAP, S100B, glutamine synthetase (GS) and water (AQP-4), and K+ (Kir 4.1) channels. RESULTS: Basal S100B secretion and S100B secretion in high-K+ medium did not differ at 1, 14, and 56 days for the hippocampal slices from epileptic rats, in contrast to sham animal slices, where high-K+ medium decreased S100B secretion. Dexamethasone addition to the incubation medium per se induced a decrease in S100B secretion in sham and epileptic rats (1 and 56 days after SE induction). Following in vivo dexamethasone administration, inflammatory improvements were observed, astrogliosis was prevented (based on GFAP and S100B content), and astroglial dysfunction was partially abrogated (based on Kir 4.1 protein and GSH content). The GS decrease was not prevented by dexamethasone, and AQP-4 was not altered in this epileptic model. CONCLUSIONS: Changes in astroglial parameters emphasize the importance of these cells for understanding alterations and mechanisms of epileptic disorders in this model. In vivo dexamethasone administration prevented most of the parameters analyzed, reinforcing the importance of anti-inflammatory steroid therapy in the Li-pilocarpine model and possibly in other epileptic conditions in which neuroinflammation is present.


Assuntos
Anticonvulsivantes/uso terapêutico , Dexametasona/uso terapêutico , Encefalite/tratamento farmacológico , Epilepsia , Gliose/tratamento farmacológico , Hipocampo/patologia , Análise de Variância , Animais , Citocinas/sangue , Dinoprostona/metabolismo , Modelos Animais de Doenças , Encefalite/etiologia , Epilepsia/induzido quimicamente , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/etiologia , Glutamato-Amônia Ligase/metabolismo , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Lítio/toxicidade , Masculino , Pilocarpina/toxicidade , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo
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