RESUMEN
We previously showed that neuregulin-1 (NRG-1) protected neurons from death in vivo following focal ischemia. The goal of this study was to develop an in vitro rat ischemia model to examine the cellular and molecular mechanisms involved in the neuroprotective effects of NRG-1 on ischemia-induced neuronal death. Rat B-35 neuroblastoma cells differentiated by serum withdrawal, developed enhanced neuronal characteristics including, neurite extension and upregulation of neuronal markers of differentiation. When B35 neurons were subjected to oxygen glucose deprivation (OGD)/reoxygenation or glutamate, widespread neuronal death was seen after both treatments. Treatment with NRG-1 immediately after OGD significantly increased neuronal survival. NRG-1 administration also resulted in a significant decrease in annexin V, an early marker of apoptosis. However, the neurotoxic actions of glutamate were unaffected by NRG-1. The neuroprotective effects of NRG-1 were prevented by an inhibitor of the phosphatidylinositol-3-kinase/Akt pathway. These results provide a new model to gain insight into the mechanisms employed by NRG-1 to protect neurons from ischemic brain injury.
Asunto(s)
Infarto Encefálico/metabolismo , Isquemia Encefálica/metabolismo , Citoprotección/efectos de los fármacos , Degeneración Nerviosa/metabolismo , Proteínas del Tejido Nervioso/farmacología , Neuronas/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/fisiopatología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/fisiopatología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citoprotección/fisiología , Inhibidores Enzimáticos/farmacología , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/fisiopatología , Modelos Biológicos , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/fisiopatología , Neurregulina-1 , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Nerve growth factor (NGF) is required for the survival of developing sympathetic and sensory neurons. In the absence of NGF, these neurons undergo protein synthesis-dependent apoptosis. Ten years have gone by since the first reports of specific genes being upregulated during NGF deprivation-induced cell death. Over the last decade, a few additional genes (DP5, Bim, SM-20) have been added to a list that began with cyclin D1 and c-jun. In this chapter, we discuss the evidence that these genes act as regulators of neuronal cell death. We also suggest a hypothesis for how one gene, SM-20, may function to suppress a self-protection mechanism in NGF-deprived neurons.