PROTEIN-TYROSINE KINASE INHIBITORS SYNERGIZE WITH NERVE GROWTH-FACTORIN EMBRYONIC CHICK SENSORY NEURONAL CELL-SURVIVAL

The survival of developing sensory neurons is dependent upon target-de rived growth factors, in their absence neurons undergo programmed cell death. The molecular mechanisms underpinning neuronal cell survival a nd death are poorly understood. Tyrosine kinases are important signall ing 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 tyro sine kinase inhibitors, herbimycin, genistein and tyrphostin. In low c oncentrations 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 mu M) and tyrphostin (8 mu M). In the prese nce of each of these inhibitors, sensory neurons exhibited typical pha se bright morphology and fibre outgrowth was increased. These results demonstrate that the tyrosine kinase inhibitors support the survival o f neurons in the presence of low concentrations of NGF. Herbimycin was used at lower concentrations than previously reported, and at this co ncentration it has been shown to be noncytotoxic in animals. Therefore it will be important to determine if herbimycin can be used as a ther apeutic agent for enhancing nerve regeneration following injury. (C) 1 997 Elsevier Science Ireland Ltd.