title: 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.
authors.affiliation: Department of Ophthalmology and Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Kong
authors.forename: Guang-Di
authors.initials: GD
authors.lastname: Chen
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhou
authors.forename: James F
authors.initials: JF
authors.lastname: McGinnis
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D017879:Isothiocyanates; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology* / Q000627:therapeutic use; D054481:Thioredoxin Reductase 1 / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D013454:Sulfoxides; D013861:Thiocyanates; D013879:Thioredoxins; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; C016766:sulforaphane