Protein tyrosine kinase inhibitors synergize with nerve growth factor in embryonic chick sensory neuronal cell survival

Abstract

The survival of developing sensory neurons is dependent upon target-derived growth factors, in their absence neurons undergo programmed cell death. The molecular mechanisms underpinning neuronal cell survival and death are poorly understood. Tyrosine kinases are important signalling proteins that have been implicated in both cell survival and death. The aim of this study was to examine the effects of tyrosine kinase inhibition on embryonic chick sensory neuronal survival using the tyrosine kinase inhibitors, herbimycin, genistein and tyrphostin. In low concentrations of nerve growth factor, NGF (100 fg/ml), the majority of neurons die, however neuronal survival was significantly potentiated in the presence of each of the tyrosine kinase inhibitors, herbimycin (40 ng/ml), genistein (2.5 μM) and tyrphostin (8 μM). In the presence of each of these inhibitors, sensory neurons exhibited typical phase bright morphology and fibre outgrowth was increased. These results demonstrate that the tyrosine kinase inhibitors support the survival of neurons in the presence of low concentrations of NGF. Herbimycin was used at lower concentrations than previously reported, and at this concentration it has been shown to be non-cytotoxic in animals. Therefore it will be important to determine if herbimycin can be used as a therapeutic agent for enhancing nerve regeneration following injury.