RESUMO
Gap junctions (GJs) are intercellular junctions that allow the direct transfer of ions and small molecules between neighboring cells, and GJs between astrocytes play an important role in the development of various pathologies of the brain, including regulation of the pathological neuronal synchronization underlying epileptic seizures. Recently, we found that a pathological change is observed in astrocytes during the ictal and interictal phases of 4-aminopyridin (4-AP)-elicited epileptic activity in vitro, which was correlated with neuronal synchronization and extracellular epileptic electrical activity. This finding raises the question: Does this signal depend on GJs between astrocytes? In this study we investigated the effect of the GJ blocker, carbenoxolone (CBX), on epileptic activity in vitro and in vivo. Based on the results obtained, we came to the conclusion that the astrocytic syncytium formed by GJ-associated astrocytes, which is responsible for the regulation of potassium, affects the formation of epileptic activity in astrocytes in vitro and epileptic seizure onset. This effect is probably an important, but not the only, mechanism by which CBX suppresses epileptic activity. It is likely that the mechanisms of selective inhibition of GJs between astrocytes will show important translational benefits in anti-epileptic therapies.
Assuntos
Anticonvulsivantes/uso terapêutico , Carbenoxolona/uso terapêutico , Epilepsia/tratamento farmacológico , 4-Aminopiridina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Eletrocorticografia , Epilepsia/patologia , Epilepsia/fisiopatologia , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Hipocampo/patologia , Humanos , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Potássio/metabolismoRESUMO
A series of syn-restricted polymethoxylated 4-heteroarylcoumarins--the isostuctural analogs of combretastatin A-4--was synthesized by Suzuki-Miyaura cross-coupling reaction and evaluated for antiproliferative activity. The 4-(1-methyl-1H-indol-5-yl)chromen-2-ones exhibit a potent cytotoxicity against HBL100 epithelial cell line with an IC(50) value amounting to 0.098 and 0.078 microM, respectively. The two compounds, having an indolyl moiety, potent inhibit in vitro microtubule assembly with a substoichiometric mode of action. A structure-activity relationship was discussed and the indolyl moiety was proved to be a good surrogate for the 3-hydroxy-4-methoxyphenyl ring of CA-4.
Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Estilbenos/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Sítios de Ligação , Neoplasias da Mama , Linhagem Celular Tumoral , Cumarínicos/síntese química , Reagentes de Ligações Cruzadas/química , Humanos , Concentração Inibidora 50 , Estilbenos/síntese química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Ensaio Tumoral de Célula-TroncoRESUMO
2-(methoxymethoxymethyl)aryllead triacetates, obtained in situ from the corresponding arylboronic acids, reacted with 4-hydroxycoumarins, leading to 3-(2-methoxymethoxymethyl)aryl-4-hydroxycoumarin derivatives in good to high yields. These compounds underwent a cascade sequence of reactions, deprotection-halogenation-annulation, to afford polyoxygenated tetracyclic 6H,11H-[2]benzopyrano-[4,3-c] [1]benzopyran-11-ones in good yields. Some compounds showed a moderate cytotoxicity against human epithelial mammary HBL100 cells.
