Metallothionein (MT)-III is associated with resistance to neuronal injury. However, the underlying mechanism for its effects is unclear. The present study investigated the mechanisms of MT-III protection of neuronal cells from hypoxia or DNA damage-induced cell death. MT-III reduced the hydrogen peroxide- or DNA damage-induced effects on neuronal cells, including the cell death, the activation of caspase-3 and -9, and the release of mitochondrial cytochrome c to the cytoplasm in a dose-dependent manner. MT-III also increased the activation of Akt, the phosphorylation and degradation of IkappaB, the nuclear translocation/accumulation and the transcriptional activity of nuclear factor-kappaB (NF-kappaB) in neuronal cells in a dose-dependent manner. The MT-III-induced antiapoptotic effects and increase in NF-kappaB activity were blocked by specific inhibitors of TrkA, phosphatidylinositol-3 kinase (PI3K), Akt, or NF-kappaB, indicating that MT-III provides neuronal protection by activating NF-kappaB through the TrkA/PI3K/Akt signaling pathway.