ABSTRACT The present study investigated the antioxidant effect of a new class of quinoline derivatives (a-d) on assays in vitro. Lipid peroxidation, thiol peroxidase-like and free radical scavenging activities were determined to evaluate antioxidant activity of compounds. Thiol oxidase-like and δ-aminolevulinate dehydratase activities were performed as a toxicological parameter. A second objective of this study was to evaluate the in vivo antinociceptive effect of the compound with better antioxidant effect and without toxic effects in a model of nociception induced by formalin in mice. In liver, at 100 µM, compound a reduced the lipid peroxidation to the control levels, while compounds c and d partially reduced it. In brain, only compound d partially reduced the lipid peroxidation at 50 and 100 µM. Compound b did not have an effect on the lipid peroxidation. Thiol peroxidase-like and free radical scavenging activities are not involved in the antioxidant mechanisms of these compounds. Compounds did not present thiol oxidase-like activity and effect on the δ-aminolevulinate dehydratase. In vivo experiments showed that compound a caused an inhibition of licking time in the first and second phases, and edema formation induced by formalin. In conclusion, quinoline derivative without selenium presented better in vitro antioxidant effect and in vivo antinociceptive activity.

We describe herein our results on the synthesis and antioxidant properties of 7-chloroquinoline-1,2,3-triazoyl-4-carboxylates. This class of compounds have been synthesized in moderated to excellent yields by the reaction of 4-azido-7-chloroquinoline with a range of β-ketoesters in the presence of a catalytic amount of pyrrolidine (10 mol%). The synthesized compounds ethyl 1-(7-chloroquinolin-4-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylate and ethyl 1-(7-chloroquinolin-4-yl)-5-phenyl-1H-1,2,3-triazole-4-carboxylate were screened for their in vitro antioxidant activity and the results demonstrated that the first compound reduces the lipid peroxidation levels induced by sodium nitroprusside in liver of mice, while the second compound shown nitric oxide scavenging activity. This is an efficient method to produce new heterocyclic compounds with potential antioxidant activities.

RESUMO Considerando que a doença de Alzheimer é uma doença neurodegenerativa prevalente em todo o mundo, buscou-se investigar o envolvimento da atividade de três quinases: creatinaquinase, piruvatoquinase e adenilatoquinase no hipocampo e no córtex cerebral em um modelo da doença de Alzheimer. Os camundongos Swiss, machos, adultos, receberam β-amiloide ou solução salina. Um dia depois, os camundongos foram tratados com nanocápsulas vazias (17 ml/kg) ou nanocápsulas contendo meloxicam (5 mg/kg) ou meloxicam livre (5 mg/kg). Os tratamentos foram realizados em dias alternados, até o final do ptotocolo experimental. No décimo quarto dia, as atividades das quinases foram avaliadas. A β-amiloide não alterou a atividade das quinases no hipocampo e no córtex cerebral dos camundongos. No entanto, o meloxicam livre diminuiu a atividade da creatinaquinase na fração mitocondrial no grupo induzido pela β-amiloide, mas na fração citosólica observou-se um aumento na atividade da piruvatoquinase no córtex cerebral. Além disso, o tratamento com as nanocápsulas contendo meloxicam diminuiu a atividade da adenilatoquinase no hipocampo dos camundongos induzidos pela β-amiloide. Em conclusão, observamos ausência de efeitos de curto prazo nas atividades das quinases do metabolismo energético no hipocampo e no córtex cerebral de camundongos, no modelo induzido com o peptídeo amiloide-β. Esses resultados estabeleceram uma base para um estudo mais aprofundado das quinases em alterações na rede de fosforiltransferência observadas nos cérebros de pacientes pós-morte com a doença de Alzheimer.

ABSTRACT Considering that Alzheimer's disease is a prevalent neurodegenerative disease worldwide, we investigated the activities of three key kinases: creatine kinase, pyruvate kinase and adenylate kinase in the hippocampus and cerebral cortex in Alzheimer's disease model. Male adult Swiss mice received amyloid-β or saline. One day after, mice were treated with blank nanocapsules (17 ml/kg) or meloxicam-loaded nanocapsules (5 mg/kg) or free meloxicam (5 mg/kg). Treatments were performed on alternating days, until the end of the experimental protocol. In the fourteenth day, kinases activities were performed. Amyloid-β did not change the kinases activity in the hippocampus and cerebral cortex of mice. However, free meloxicam decrease the creatine kinase activity in mitochondrial-rich fraction in the group induced by amyloid-β, but for the cytosolic fraction, it has raised in the activity of pyruvate kinase activity in cerebral cortex. Further, meloxicam-loaded nanocapsules administration reduced adenylate kinase activity in the hippocampus of mice injected by amyloid-β. In conclusion we observed absence in short-term effects in kinases activities of energy metabolism in mice hippocampus and cerebral cortex using amyloid-β peptide model. These findings established the foundation to further study the kinases in phosphoryltransfer network changes observed in the brains of patients post-mortem with Alzheimer's disease.

resumo Para se assegurar que um método analítico produzirá informação confiável e interpretável sobre a amostra este deve ser inicialmente validado, tornando claro que os resultados podem ser confiados e rastreados. Neste estudo, propomos validar um método de cromatografia líquida de alta eficiência (CLAE) para a quantificação do meloxicam encapsulado em nanocápsulas PEGuiladas (M-PEGNC). Efetuamos a validação, avaliando parâmetros de especificidade, linearidade, limite de quantificação, limite de detecção, exatidão, precisão e robustez. As nanocápsulas PEGuiladas foram preparadas por deposição interfacial do polímero pré-formado e caracterizaram-se o tamanho da partícula, índice de polidispersão, potencial zeta, pH e eficiência de encapsulação. O método de CLAE proposto fornece resultados seletivos e lineares na faixa de 1,0-40,0 mg/mL; limites de quantificação e detecção de 1,78 mg/mL e 0,59 mg/mL, respectivamente; desvio padrão relativo para a repetibilidade de 1,35% e precisão intermediária de 0,41% e 0,61% para o analista 1 e analista 2, respectivamente; exatidão entre 99,23 e 101,79%; robustez entre 97,13 e 98,45% para a quantificação de M-PEGNC. Os diâmetros médios das partículas foram 261 ± 13 nm e 249 ± 20 nm; índice de polidispersão de 0,15 ± 0,07 e 0,17 ± 0,06, valores de pH de 5,0 ± 0,2 e 5,2 ± 0,1 e valores do potencial zeta de -37,9 ± 3,2 mV e -31,8 ± 2,8 mV para o M-PEGNC e o placebo(B-PEGNC), respectivamente. Concluindo, o método analítico proposto é adequado para o controle de qualidade do M-PEGNC. Além disso, suspensões mostraram distribuição de tamanho monomodal e baixo índice de polidispersão, indicando alta homogeneidade das formulações com distribuição estreita de tamanho, pH e potencial zeta apropriados. O processo de extração foi eficiente para a liberação do meloxicam dos sistemas nanoestruturados.

abstract A method to ensure that an analytical method will produce reliable and interpretable information about the sample must first be validated, making sure that the results can be trusted and traced. In this study, we propose to validate an analytical high performance liquid chromatography (HPLC) method for the quantitation of meloxicam loaded PEGylated nanocapsules(M-PEGNC). We performed a validation study, evaluated parameters including specificity, linearity, quantification limit, detection limit, accuracy, precision and robustness. PEGylated nanocapsules were prepared by interfacial deposition of preformed polymer, and the particle size, polydispersity index, zeta potential, pH value and encapsulation efficiency were characterized. The proposed HPLC method provides selective, linear results in the range of 1.0-40.0 μg/mL; quantification and detection limits were 1.78 μg/mL and 0.59 μg/mL, respectively; relative standard deviation for repeatability was 1.35% and intermediate precision was 0.41% and 0.61% for analyst 1 and analyst 2, respectively; accuracy between 99.23 and 101.79%; robustness between 97.13 and 98.45% for the quantification of M-PEGNC. Mean particle diameters were 261 ± 13 nm and 249 ± 20 nm, polydispersity index was 0.15 ± 0.07 and 0.17 ± 0.06, pH values were 5.0 ± 0.2 and 5.2 ± 0.1, and zeta-potential values were -37.9 ± 3.2 mV e -31.8 ± 2.8 mV for M-PEGNC and placebo(B-PEGNC), respectively. In conclusion, the proposed analytical method is suitable for the quality control of M-PEGNC. Moreover, suspensions showed monomodal size distributions and low polydispersity index indicating high homogeneity of formulations with narrow size distributions, and appropriate pH and zeta potential. The extraction process was efficient for release of meloxicam from nanostructured systems.

O objetivo deste estudo foi investigar se a exposição aguda ao ditelureto de difenila [(PhTe)2] causaria prejuízo no desenvolvimento comportamental de filhotes de ratos. Os filhotes receberam uma injeção subcutânea de (PhTe)2 (0,1 mg kg-1, 3 mL kg-1) ou veículo (3 mL kg-1) no 14º dia após o nascimento (DPN). Do 15º ao 21º DPN, foram realizados testes comportamentais nos filhotes e, imediatamente após estes testes, os filhotes foram submetidos à eutanásia. As análises histológicas, a determinação do conteúdo de mielina e a atividade da acetilcolinesterase (AChE) foram realizadas. O período crítico de intoxicação ocorreu no 4º e 5º dias após a injeção de (PhTe)2, quando os sinais de toxicidade foram mais evidentes, caracterizados pelo aparecimento de sinais sistêmicos de toxicidade, disfunções comportamentais, neurotoxicidade e uma alteração no sistema colinérgico. Desta forma, conclui-se que o (PhTe)2 induziu neurotoxicidade e prejuízos no desenvolvimento comportamental de filhotes de ratos.

The purpose of the present study was to investigate if acute exposure to diphenyl ditelluride (PhTe)2 causes impairment of developmental behavioral performance in rat pups. Rat pups received a single subcutaneous injection of (PhTe)2 (0.1 mg kg-1, 3 mL kg-1) or vehicle (3 mL kg-1) at 14th postnatal day. After exposure to (PhTe)2, the general parameters of neurotoxicity, behavioral tasks, cerebral myelin content, histological analysis and acetilcholinesterase (AChE) activity were performed during seven days. The appearance of classic signs of toxicity, behavioral alterations and the reduction in myelin content were dependent on the time after (PhTe)2 exposure to pups. Neuronal damage, reduction of myelin content, and the increase in AChE activity occurred mainly at 4th and 5th day after (PhTe)2 exposure, indicating that the critical period of neurotoxicity is coincident with the major behavioral alterations. In conclusion, exposure to (PhTe)2 induced neurotoxicity and impairment of developmental behavioral in rat pups.