Molecular mechanisms underlying cochlear degeneration in the tubby mouse and the therapeutic effect of sulforaphane

Abstract

As with Usher syndrome observed in humans, the two main phenotypes of the tubby mouse are progressive hearing loss and retinal degeneration. Yet, the mechanism underlying the tub-related cochlear degeneration is still unclear. The reduction/oxidation (redox) imbalance in the cell is related to many kinds of diseases. This study examined expressions of thioredoxin (Trx) and Trx reductase (TrxR), an important redox system in the cell, and the related upstream and downstream proteins of the Trx/TrxR in the tubby mouse cochlea. This report also examined the therapeutic effect of sulforaphane (SF) on the cochlear degeneration, which showed a protective effect on the tub-related retinal degeneration in our previous report. The results showed that the tub-mutation resulted in a significant suppression of Trx and TrxR expressions. Expression level of Nrf2 (NFE2 related factor 2), a transcription factor that regulates expression of Trx and TrxR and others, was also suppressed in the tubby mouse cochlea. Furthermore, a lowered level of activated extracellular signal-regulated kinase (p-ERK) was observed in the tubby mouse cochlea. In contrast, caspase-3 expression and activity were enhanced in the tubby mouse, suggesting apoptotic cell death. The tub-related molecular alterations in the cochlea were prevented by chronic treatment with SF. As a result, the SF-treatment significantly delayed the tub-related cochlear degeneration. Other unknown proteins may contribute to tubby-related degeneration because Nrf2 regulates many other antioxidants besides Trx/TrxR and sulforaphane did not prevent cochlear degeneration completely although it completely prevented alterations of Nrf2 and Trx/TrxR.

Expression pattern of oxidative stress and antioxidant defense-related genes in the aging Fischer 344/NHsd rat cochlea

“…Interestingly, Prdx2, the only peroxiredoxin isoform tested in the Hu et al (2009) study, was 1 of the 3 most highly expressed genes in young Sprague-Dawley rat cochlea. In addition, Kong et al (2009) reported decreases in thioredoxin and thioredoxin reductase gene expression and protein levels in tubby mice ( tub/tub ) compared with heterozygous ( tub/wt ) or wild type (wt/wt). The tubby phenotype expresses late-onset weight gain and progressive loss of hair cells and retinal degeneration (Ohlemiller et al, 1995, 1997).…”

“…Kong et al (2009) demonstrated that sulforaphane, a naturally occurring isothiocyanate, protected against tub -related cochlear degeneration thought to be caused by downregulation of the thioredoxin antioxidant system. Thioredoxin has not been extensively studied as a treatment for acquired hearing loss (noise-induced, drug-induced, and age-related hearing loss).…”

Protective effect of sulphoraphane against oxidative stress mediated toxicity induced by CuO nanoparticles in mouse embryonic fibroblasts BALB 3T3

“…Sulphoraphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate derived from cruciferous vegetables is a highly potent inducer of phase 2 cytoprotective enzymes and can protect against electrophiles including carcinogens, oxidative damage and inflammation (Juge et al, 2007). A broad series of cellular, animal and human studies have demonstrated the protective potential of SFN against cancer, retinal disease, skin damage, UV irradiation (Cornblatt et al, 2007;Dinkova-Kostova et al, 2007;Talalay et al, 2007;Kong et al, 2009). However, protective effect of SFN against the toxicity of NPs is not fully explored.…”

Electrophilic tuning of the chemoprotective natural product sulforaphane

“…The plant product sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], derived from glucosinolates present in broccoli and other cruciferous vegetables (3), has served as a prototype for our understanding of chemoprotection by induction of phase 2 cytoprotective enzymes including NAD(P)H:quinone oxidoreductase (NQO1) (4). A broad series of animal and human studies has demonstrated the potential of sulforaphane to protect against the onset, or reduce the severity, of cancer (5)(6)(7)(8), retinal disease (9), and skin damage (10)(11)(12) resulting from oxidative or electrophile damage (5,6,8), UV irradiation (10,11), or genetic predisposition (9,13).…”