RESUMO
Platelet activating factor (PAF; beta-acetyl-gamma-O-hexadecyl-l-alpha-phosphatidylcholine) triggers a rapid pro-inflammatory gene expression program in primary cultures of human neural (HN) cells. Two genes and gene products consistently induced after PAF treatment are the cytosoluble prostaglandin synthase cycloooxygenase-2 (COX-2) and the pro-apoptotic tumor necrosis factor alpha (TNFalpha). Both of these mediators are associated with the activation of inflammatory signaling, neural cell dysfunction, apoptosis and brain cell death, and both have been found to be up-regulated after brain injury in vivo. In this study we investigated the effects of the non-halogenated synthetic glucocorticoid budesonide epimer R (BUDeR), the novel PAF antagonist LAU-0901, and the electron spin trap and free radical scavenger phenyl butyl nitrone (PBN), upon early COX-2 and TNFalpha gene activation and prostaglandin E(2) (PGE(2)) release in PAF-stressed primary HN cells. The data indicate that these three biochemically unrelated classes of inflammatory repressors act synergistically in modulating PAF-induced up-regulation of COX-2, TNFalpha, and PGE(2) by quenching oxidative stress or inflammatory signaling, resulting in increased HN cell survival. These, or analogous classes of compounds, may be useful in the design of more effective combinatorial pharmacotherapeutic strategies in the treatment of complex neuro-inflammatory disorders.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Encefalite/metabolismo , Neurônios/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Estresse Fisiológico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Anti-Inflamatórios/farmacologia , Budesonida/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Óxidos N-Cíclicos/farmacologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Dinoprostona/metabolismo , Sinergismo Farmacológico , Encefalite/tratamento farmacológico , Encefalite/fisiopatologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Humanos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fator de Ativação de Plaquetas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estresse Fisiológico/fisiopatologia , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/fisiologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Interleukin-1beta (IL-1beta) and amyloid-beta peptide 42 (Abeta42) together induce a robust proinflammatory gene expression program in human neural cells in primary culture. One consistent genetic marker for this triggered inflammatory response is an increase in the expression of cycloooxygenase-2 (COX-2), a prostaglandin synthase also found to be up-regulated in neurological disorders such as Alzheimer's disease. In this study we provide data illustrating the combined effect of three independent classes of compounds: the glucocorticoid budesonide epimer R, the platelet-activating factor antagonist LAU-8080, and the free radical scavenger phenyl butyl nitrone, upon COX-2 gene activation and prostaglandin E2 (PGE2) levels in [IL-1beta+Abeta42]-stressed HN cells. The data indicate that specific combinations of repressors of COX-2 activity are synergistic in modulating the stress-induced up-regulation of COX-2 and PGE2, and this may be of potential therapeutic value in the design of treatment for complex neuroinflammatory disorders.
