RESUMO
Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM).
Assuntos
Compostos de Fenilureia , Pirazóis/síntese química , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Antirreumáticos/síntese química , Antirreumáticos/química , Técnicas de Química Combinatória , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/química , Humanos , Hidrocarbonetos Clorados/química , Concentração Inibidora 50 , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Osteoporose/tratamento farmacológico , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Pirazóis/farmacologia , Solubilidade , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
The neuronal redox status influences the expression of genes involved in neuronal survival. We previously showed that antioxidants may reduce the number of dying ganglion cells following axotomy in chick embryos. In the present study, we show that various antioxidants, including the new spin trap azulenyl nitrone and 1,3-dimethyl-2-thiourea, protect axotomized ganglion cells, confirming that neuronal death involves an imbalance of the cellular redox status towards oxidation. However, high concentrations of antioxidants did not protect ganglion cells, suggesting that excessive reduction is detrimental for neurons. Simultaneous injections of two different antioxidants gave results only partly supporting this view. Combinations of azulenyl nitrone and N-acetyl cysteine in fact gave greater protection than either antioxidant alone, whereas N-acetyl cysteine lost its neuroprotective effects and diminished those of alpha-phenyl-N-tert-butyl nitrone when the two compounds were injected simultaneously. The results of the combined treatments suggest that azulenyl nitrone and alpha-phenyl-N-tert-butyl nitrone do not have the same chemical effects within the ganglion cells. Moreover, N-acetyl cysteine's own antioxidant properties enhance the spin trapping effects of azulenyl nitrone but potentiate the toxicity of alpha-phenyl-N-tert-butyl nitrone. Our main conclusion is that neuronal survival requires the maintenance of the redox status near an optimal set-point. "Reductive stress" may be as dangerous as oxidative stress.
Assuntos
Retina/citologia , Retina/crescimento & desenvolvimento , Células Ganglionares da Retina/fisiologia , Acetilcisteína/farmacocinética , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Axotomia , Azulenos , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Embrião de Galinha , Óxidos N-Cíclicos , Olho/metabolismo , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Óxidos de Nitrogênio/farmacocinética , Óxidos de Nitrogênio/farmacologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Retina/efeitos dos fármacos , Degeneração Retiniana/fisiopatologia , Degeneração Retiniana/prevenção & controle , Células Ganglionares da Retina/efeitos dos fármacos , Sesquiterpenos/farmacocinética , Sesquiterpenos/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacocinética , Tioureia/farmacologiaRESUMO
Azulenyl nitrones are a unique class of free radical spin-trapping compounds. We administered both a water-soluble and a lipid-soluble azulenyl nitrone to mice prior to administration of MPTP. Both compounds produced significant neuroprotection against depletions of dopamine and its metabolites measured 1 week after MPTP administration. There were no effects on MPP+ levels. These findings provide further evidence that free radical scavengers can produce significant neuroprotection against MPTP neurotoxicity.
