Reduction of Potassium Currents and Phosphatidylinositol 3-Kinase-Dependent Akt Phosphorylation by Tumor Necrosis Factor-α Rescues Axotomized Retinal Ganglion Cells from Retrograde Cell DeathIn Vivo

Tumor-necrosis-factor-α (TNF-α) prevented secondary death of retinal ganglion cells (RGCs) after axotomy of the optic nervein vivo. This RGC rescue was confirmed in vitro in a mixed retinal culture model. In accordance with our previous findings, TNF-α decreased outward potassium currents in RGCs. Antagonism of the TNF-α-induced decrease in outward potassium currents with the potassium channel opener minoxidilsulfate (as verified by electrophysiology) abolished neuroprotection. Western blot analysis revealed an upregulation of phospho-Akt as a consequence of TNF-α-induced potassium current reduction. Inhibition of the phosphatidylinositol 3-kinase–Akt pathway with wortmannin decreased TNF-α-promoted RGC survival. These data point to a functionally relevant cytokine-dependent neuroprotective signaling cascade in adult CNS neurons.