Members of the nuclear factor-kappa B (NF-kB)/Rel family, which act as transcriptional regulators, play important roles in neuronal cell death and survival. NF-kBp50 knockout (p50-KO) mice exhibit many of the features of human Normal Tension Glaucoma (NTG). The developmental mechanism of human NTG remains unclear, and a radical curative treatment has yet to be established. Therefore, the signal cascade that mediates spontaneous optic neuropathy in p50-KO mice, as a model of NTG, needs to be elucidated in more detail for the development of clinical therapies. In order to obtain a deeper understanding of NF-kB-mediated death signaling, the effects of chemical reagents on spontaneous optic neuropathy have been examined histopathologically. Constitutively active cleaved forms of Calcineurin (CN), which have been reported to induce apoptosis, were detected in the retinas of p50-KO mice. Spontaneous retinal Ganglion Cell (RGC) death and degenerative changes to the optic nerve in p50-KO mice were both significantly reduced by the chronic administration of tacrolimus, a CN inhibitor. Experiments with cultured RGC cells supported the results of histological examinations on p50-KO mice, suggesting that CN activation leads to the activation of NF-kB-induced Bax and caspase 3 and mediates spontaneous optic neuropathy in p50-KO mice. Previous studies demonstrated that the chronic administration of tacrolimus significantly reduced spontaneous optic neuropathy in p50-KO mice. A potential CN signal cascade spontaneously induces agedependent RGC death and degenerative optic nerve changes in p50-KO mice. Novel research findings may provide new targets for therapeutic interventions in human NTG.