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W. Cao, L. Kong, J. F. McGinnis, X. Zhou; Involvment of MAPK/NF-E2 Related Factor 2/Thioredoxin Cascade in Sulforaphane-Mediated Photoreceptor Protection in the Retina of Tubby Mouse. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1542.
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Thioredoxin (Trx) has neurotrophic factor-like activity and may play a crucial role in maintaining neuronal cell integrity. Nrf2 (NF-E2 related factor 2), a basic leucine zipper transcription factor, is a key player in the activation of a variety of detoxifying enzyme genes. Sulforaphane (SF), a hydrolysis product of glucoraphanin in cruciferous vegetables like broccoli, is able to induce phase II detoxification enzymes including Trx. In this study, the neuroprotective effect of SF on photoreceptor degeneration in the tubby mouse, a phenotypical model of sensorineural deafness/retinal dystrophic syndromes, was examined.
The tubby mice were intraperitoneally injected with different doses of SF once a day for 4 or 10 days. MAPK signaling in SF-mediated Trx expression was also examined using ERK inhibitor PD98059. Protective effects of SF were evaluated morphologically by quantitative histology and functionally by electroretinogram (ERG). Immunohistochemistry was performed to localize the expression of Trx in the retina. Real-Time qPCR, RT-PCR and Western blot analysis were used to examine SF-mediated gene and protein expression.
The mRNA and protein expression of Trx, thioredoxin reductase (TrxR) and Nrf2 were significantly reduced in the retinas of tubby mice, even prior to significant photoreceptor cell degeneration. Intraperitoneal injection with SF significantly up-regulated retinal levels of Trx, TrxR, and Nrf2, and effectively protected photoreceptor cells in tubby mice as evaluated functionally by electroretinography and morphologically by quantitative histology. Treatment with PD98059 blocked SF-mediated ERKs activation and up-regulation of Trx/TrxR/Nrf2 in the retinas of tubby mice.
Systemic administration of SF effectively up-regulates the Trx system and delays photoreceptor degeneration in tubby mice via ERKs and Nrf2 signaling. Intensification and induction of endogenous Trx, TrxR and possible other phase II enzymes by SF treatment may be a novel therapeutic strategy to delay retinal degeneration and to prolong useful vision.
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