Members of the nuclear factor-kappa B (NF-B)/Rel 
family, which act as transcriptional regulators, play important 
roles in neuronal cell death and survival. NF-Bp50 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-B-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-B-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 age
dependent RGC death and degenerative optic nerve changes in 
p50-KO mice. Novel research findings may provide new targets 
for therapeutic interventions in human NTG.