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H. Fujino, Y. Kitaoka, H. Takeda, Y. Hayashi, Y. Munemasa, S. Ueno; Phosphorylation of CREB and Up-Regulation of BDNF in TNF--Induced Optic Nerve Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4937.
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Brain-derived neurotrophic factor (BDNF), a member of the potent survival and developmental factors whose expression is regulated by cyclic AMP-response element binding protein (CREB). Several reports indicate that BDNF prevents retinal ganglion cell body death. The purpose of the present study is to investigate whether BDNF has a neuroprotective effect on their axon in TNF-α-induced optic nerve degeneration.
Eight-week-old Wistar rats were received intravitreal injection of 10 ng TNF-α, and 0.1 or 1 µg BDNF simultaneously into one eye. PBS was administered as a control. Eyes were obtained from animals 1 day, 1 or 2 weeks after intravitreal injection. The acquired images of cross-sections of optic nerves were quantified on computer. The protein levels of p-CREB in the retina and the optic nerve were examined by Western blot analysis. Localization of p-CREB was detected by immunohistochemistry. BDNF mRNA in the optic nerve was examined by real-time PCR.
Western blot analysis showed transient but significant increase in the level of p-CREB protein in the retina and the optic nerve 1day after TNF-α injection compared with those after PBS injection. Immunohistochemistry of p-CREB confirmed an increase of p-CREB immunoreactivity in the optic nerve 1 day after TNF-α injection. Double-labeling immunohistochemical study showed substantial colocalization of p-CREB and neurofilament. BDNF mRNA expression was significantly increased in the optic nerve 1 day after TNF-α injection. The reduction in the number of axons induced by TNF-α was significantly prevented by the exogenous BDNF .
Early transient increase in p-CREB may be a manifestation for endogenous protective function as accompanied with up-regulation of BDNF in the optic nerve. Although BDNF has been reported to have beneficial effect on neuronal cell body, our data suggest that BDNF also may rescue axonal death.
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