Wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase influences neurotrophin-induced spiral ganglion neurite growth

Background: Phosphatidylinositol 3-kinase (PI3K) is considered to be an important enzyme in cell signaling, mediating certain aspects of neurotrophin signals from the cell surface receptor to the nucleus. Methods: The participation of PI3K in the mediation of neurotrophin-induced effects in the spiralganglion (SG) of neonatal rats was investigated in vitro. SG explants were stimulated with neurotrophin (NT)-3 and treated with Wortmannin, a specific inhibitor of PI3K. After fixation and immunhistochemical staining, the growth of the SG neurites was evaluated. Results: Stimulation with NT-3 lead to significant increases in number and length of neurites, when compared to non-stimulated controls. Treatment of NT-3 stimulated SG explants resulted in a dose-dependent reduction of both parameters, whereas the neurite growth of non-stimulated control explants was not significantly influenced by the incubation with Wortmannin. Conclusions: The results demonstrate that neurotrophin-induced neurite growth from SG explants can be modulated with the PI3K inhibitor Wortmannin and indicate that PI3K is a key enzyme in the mediation of NT-3 effects in cochlear neurons. These observations together with results of previous studies suggest that the activation of PI3K as well as Ras and MEK are essential for neurite growth in cochlear neurons. Further knowledge of cell signaling mechanisms influencing SG neurite growth could lead to new therapeutical strategies for the treatment of inner ear diseases.