Nerve growth factor protects oligodendrocytes from tumor necrosis factor-alpha-induced injury through Akt-mediated signaling mechanisms

Tumor necrosis factor-alpha is thought to be one of the most important infl ammatory cytokines associated with the demyelinating disease multiple scler osis, We determined whether neurotrophins could protect oligodendrocytes fr om tumor necrosis factor-alpha-mediated cytotoxicity. Among the neurotrophi ns tested, nerve growth factor was most effective at preventing cell death. Nerve growth factor also prevented the tumor necrosis factor-induced loss of mitochondrial membrane potential. Overexpression of constitutively activ e Akt, a downstream target of phosphatidylinositol 3-kinase, but not of con stitutively active MEK, protected oligodendrocytes from tumor necrosis fact or-induced injury. Moreover, overexpression of dominant-negative Akt negate d the protective effects of nerve growth factor on tumor necrosis factor-me diated oligodendrocyte cytotoxicity. These findings indicate that the Akt p athway is crucial in nerve growth factor-mediated oligodendrocyte protectio n.