Abstract
Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic nerve degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway.
Highlights
Glaucoma is, in developed countries, one of the most common diseases that can lead to irreversible blindness
Because the NFATc1 protein level was shown to be significantly increased in the optic nerve 7 days after tumor necrosis factor (TNF) injection, we examined the effect of tacrolimus on the NFATc1 levels at this time point
The present study demonstrated a significant increase in NFATc1 expression in optic nerves after TNF injection
Summary
In developed countries, one of the most common diseases that can lead to irreversible blindness. It is characterized by a slowly progressive retinal ganglion cell (RGC) pathology in which axonal degeneration of RGCs in the optic nerve precedes death of the RGC body. Calcineurin (CaN) is a serine/threonine phosphatase, dependent on Ca2+/calmodulin (CaM). It is composed of two subunits, CaNA and CaNB. CaNA which has a CaMbinding domain, acts as a 60-kDa catalytic subunit. There are three isoforms (α, β, γ) of CaNA, with CaNAγ expression limited to testis and CaNAα and CaNAβ expressed in all tissues, but in varying ratios. For example, CaNAα is more abundant than CaNAβ in brain [3, 4]
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