RESUMO
Activation of the brain angiotensin II type 1 receptor (AT1R) triggers pro-oxidant and pro-inflammatory mechanisms which are involved in the neurobiology of bipolar disorder (BD). Candesartan (CDS) is an AT1 receptor antagonist with potential neuroprotective properties. Herein we investigated CDS effects against oxidative, neurotrophic inflammatory and cognitive effects of amphetamine (AMPH)-induced mania. In the reversal protocol adult mice were given AMPH 2 mg/kg i.p. or saline and between days 8 and 14 received CDS 0.1, 0.3 or 1 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention treatment, mice were pretreated with CDS, Li or saline prior to AMPH. Locomotor activity and working memory performance were assessed. Glutathione (GSH), thiobarbituric acid-reactive substance (TBARS) and TNF-α levels were evaluated in the hippocampus (HC) and cerebellar vermis (CV). Brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase 3-beta (GSK-3beta) levels were measured in the HC. CDS and Li prevented and reversed the AMPH-induced increases in locomotor activity. Only CDS prevented and reversed AMPH-induced working memory deficits. CDS prevented AMPH-induced alterations in GSH (HC and CV), TBARS (HC and CV), TNF-α (HC and CV) and BDNF (HC) levels. Li prevented alterations in BDNF and phospho-Ser9-GSK3beta. CDS reversed AMPH-induced alterations in GSH (HC and CV), TBARS (HC), TNF-α (CV) and BDNF levels. Li reversed AMPH-induced alterations in TNF-α (HC and CV) and BDNF (HC) levels. CDS is effective in reversing and preventing AMPH-induced behavioral and biochemical alterations, providing a rationale for the design of clinical trials investigating CDS׳s possible therapeutic effects.
Assuntos
Antimaníacos/farmacologia , Benzimidazóis/farmacologia , Transtorno Bipolar/tratamento farmacológico , Tetrazóis/farmacologia , Anfetamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antimaníacos/sangue , Antioxidantes/farmacologia , Compostos de Bifenilo , Transtorno Bipolar/fisiopatologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Compostos de Lítio/sangue , Compostos de Lítio/farmacologia , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Fatores de Crescimento Neural/farmacologia , Distribuição AleatóriaRESUMO
BACKGROUND: The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium. METHODS: Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. RESULTS: At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49 mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with "standard" lithium levels (≥ 0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time. CONCLUSIONS: These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.
Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Ácido Glutâmico/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Compostos de Lítio/uso terapêutico , Adolescente , Adulto , Afeto/efeitos dos fármacos , Antimaníacos/sangue , Transtorno Bipolar/sangue , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Brasil , Monitoramento de Medicamentos , Feminino , Hipocampo/metabolismo , Humanos , Compostos de Lítio/sangue , Masculino , Projetos Piloto , Espectroscopia de Prótons por Ressonância Magnética , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Lithium has been successfully employed to treat bipolar disorder for decades, and recently, was shown to attenuate the symptoms of other pathologies such as Alzheimer's disease, Down's syndrome, ischemic processes, and glutamate-mediated excitotoxicity. However, lithium's narrow therapeutic range limits its broader use. Therefore, the development of methods to better predict its dose becomes essential to an ideal therapy. METHOD: the performance of adult Wistar rats was evaluated at the open field and elevated plus maze after a six weeks treatment with chow supplemented with 0.255%, or 0.383% of lithium chloride, or normal feed. Thereafter, blood samples were collected to measure the serum lithium concentration. RESULTS: Animals fed with 0.255% lithium chloride supplemented chow presented a higher rearing frequency at the open field, and higher frequency of arms entrance at the elevated plus maze than animals fed with a 50% higher lithium dose presented. Nevertheless, both groups presented similar lithium plasmatic concentration. DISCUSSION: different behaviors induced by both lithium doses suggest that these animals had different lithium distribution in their brains that was not detected by lithium serum measurement. CONCLUSION: serum lithium concentration measurements do not seem to provide sufficient precision to support its use as predictive of behaviors.
Assuntos
Antimaníacos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Cloreto de Lítio/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Análise de Variância , Animais , Antimaníacos/sangue , Transtorno Bipolar/sangue , Feminino , Cloreto de Lítio/sangue , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVE: Lithium has been successfully employed to treat bipolar disorder for decades, and recently, was shown to attenuate the symptoms of other pathologies such as Alzheimer's disease, Down's syndrome, ischemic processes, and glutamate-mediated excitotoxicity. However, lithium's narrow therapeutic range limits its broader use. Therefore, the development of methods to better predict its dose becomes essential to an ideal therapy. METHOD: the performance of adult Wistar rats was evaluated at the open field and elevated plus maze after a six weeks treatment with chow supplemented with 0.255 percent, or 0.383 percent of lithium chloride, or normal feed. Thereafter, blood samples were collected to measure the serum lithium concentration. RESULTS: Animals fed with 0.255 percent lithium chloride supplemented chow presented a higher rearing frequency at the open field, and higher frequency of arms entrance at the elevated plus maze than animals fed with a 50 percent higher lithium dose presented. Nevertheless, both groups presented similar lithium plasmatic concentration. DISCUSSION: different behaviors induced by both lithium doses suggest that these animals had different lithium distribution in their brains that was not detected by lithium serum measurement. CONCLUSION: serum lithium concentration measurements do not seem to provide sufficient precision to support its use as predictive of behaviors.
OBJETIVO: Além de ser usado há décadas para tratar distúrbio bipolar, o lítio, mais recentemente, demonstrou-se eficaz para Alzheimer, síndrome de Down, processos isquêmicos e excitotoxicidade mediada por glutamato. Contudo, a estreita janela terapêutica do lítio limita seu uso. Portanto, o estabelecimento de métodos preditivos de dose torna-se importante. MÉTODO: O desempenho de ratos Wistar adultos foi avaliado no campo aberto e labirinto em cruz elevado após seis semanas de tratamento com uma ração suplementada com 0,255 por cento ou 0,383 por cento de cloreto de lítio ou ração normal. Coletou-se amostras de sangue para dosagem plasmática do lítio. RESULTADOS: Os animais alimentados com a ração com 0,255 por cento de cloreto de lítio fizeram mais rearing no campo aberto e tiveram uma maior freqüência de entradas nos braços do labirinto elevado que os animais que ingeriram a dose mais alta. Apesar disso, verificou-se níveis plasmáticos de lítio semelhantes em ambos os grupos. DISCUSSÃO: A variação nos comportamentos destarte a presença de níveis plasmáticos semelhantes sugere que as diferentes doses produziram diferentes concentrações cerebrais não detectadas pela medida plasmática. CONCLUSÃO: Medidas da concentração plasmática de lítio não permitem prever de forma completa seus efeitos comportamentais.
Assuntos
Animais , Feminino , Masculino , Ratos , Antimaníacos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Cloreto de Lítio/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Análise de Variância , Antimaníacos/sangue , Transtorno Bipolar/sangue , Cloreto de Lítio/sangue , Ratos WistarRESUMO
Some studies suggest that mitochondrial dysfunction may be related to the pathophysiology of bipolar disorder. In this work, we evaluated the activity of citrate synthase in rats, and the effects of the treatment with mood stabilizers (lithium and valproate) on the enzyme activity. In the first experiment (reversal treatment), amphetamine or saline were administered to rats for 14 days, and between day 8 and 14, rats were treated with either lithium, valproate or saline. In the second experiment (prevention treatment), rats were pretreated with lithium, valproate or saline, and between day 8 and 14, rats were administered amphetamine or saline. In reversal and prevention models, amphetamine administration significantly inhibited citrate synthase activity in rat hippocampus. In amphetamine-pretreated animals, valproate administration reversed citrate synthase activity inhibition induced by amphetamine. In the prevention model, pretreatment with lithium prevented amphetamine-induced citrate synthase inhibition. Our results showed that amphetamine inhibited citrate synthase activity and that valproate reversed and lithium prevented the enzyme inhibition.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/patologia , Citrato (si)-Sintase/metabolismo , Hipocampo/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Ácido Valproico/farmacologia , Anfetamina , Análise de Variância , Animais , Antimaníacos/sangue , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Modelos Animais de Doenças , Interações Medicamentosas , Hipocampo/enzimologia , Cloreto de Lítio/sangue , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVE: The purpose of this study was to compare the maximum exposure and extent of bioavailability of two lithium carbonate (CAS 554-13-2) containing 300 mg tablet formulations (test and reference) for oral administration. METHOD: This bioequivalence study was conducted in a 2-period crossover design with a washout phase of 7 days. Plasma samples were obtained by blood sampling over 72 h in each period. Twenty-four healthy volunteers of both genders participated in the trial. Samples were analyzed by a flame atomic absorption spectrometer. Resulting Li+ concentrations were used for determination of the pharmacokinetic parameters AUC(last), AUC(inf) and C(max). RESULTS: 90 % confidence intervals for AUC(last), AUC(inf) and C(max) were 96.81-107.44%, 98.44-109.54% and 98.60-111.33%, respectively. CONCLUSION: All 90% and 95% confidence intervals were inside the limits defined by the FDA Guidance for Industry (80%-125%) and thus stated that test and reference formulation may be accepted as bioequivalent, with regard to both, maximum exposure and extent of bioavailability.
Assuntos
Antimaníacos/administração & dosagem , Antimaníacos/farmacocinética , Carbonato de Lítio/administração & dosagem , Carbonato de Lítio/farmacocinética , Adulto , Antimaníacos/sangue , Área Sob a Curva , Calibragem , Química Farmacêutica , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Carbonato de Lítio/sangue , Masculino , Pessoa de Meia-Idade , Controle de Qualidade , Equivalência TerapêuticaRESUMO
Pharmacological studies suggest that neurotrophins may play a role in the effects of lithium and valproate on mood regulation. In this study, we tested the hypotheses that lithium and valproate would reverse and prevent the behavioral and biochemical effects of amphetamine, using a rat model of mania. In the reversal treatment, male Wistar rats were first administered D-amphetamine or saline for 14 days, and then, between days 8-14, rats were treated with lithium, valproate or saline. In the prevention treatment, rats were pretreated with lithium, valproate or saline, and then, between days 8-14, rats were administered D-amphetamine or saline. Locomotor behavior was assessed using the open-field task and hippocampal nerve growth factor levels were determined by enzyme-linked immunosorbent assay. Both lithium and valproate reversed and prevented D-amphetamine-induced hyperactivity. Lithium increased nerve growth factor content in rat hippocampus in both experiments, but this effect was blocked with the co-administration of D-amphetamine. No significant effects on nerve growth factor levels were observed with valproate or D-amphetamine alone. These findings suggest that nerve growth factor may play a role in the neurotrophic effects of lithium but do not support the hypotheses that the nerve growth factor/TrkA pathway is involved in the pathophysiology of bipolar disorder.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/metabolismo , Hipocampo/metabolismo , Lítio/farmacologia , Fatores de Crescimento Neural/metabolismo , Anfetamina/antagonistas & inibidores , Anfetamina/farmacologia , Animais , Antimaníacos/sangue , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/psicologia , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/efeitos dos fármacos , Lítio/sangue , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Ácido Valproico/farmacologiaRESUMO
We present the case of a 72-year-old woman with a history of a bipolar mood disorder chronically treated with lithium. Upon having the dose increased, she developed an acute confusional state accompanied by blepharospasm (BS) and apraxia of eyelid opening. Gait instability with frequent falls, pyramid tract signs, and postural tremor in both hands were also evident. On withdrawing lithium, symptoms remitted within 2 weeks. This patient illustrates that BS and apraxia of eyelid opening may be triggered by lithium overdose. Our case warrants the inclusion of lithium in the list of drugs liable to induce such movement disorders.