Activation of Wnt/β-catenin signaling by lithium chloride attenuates d-galactose-induced neurodegeneration in the auditory cortex of a rat model of aging.

Degeneration of the central auditory system, which is characterized by reduced understanding of speech and source localization of sounds, is an important cause of age-related hearing loss (presbycusis). Accumulating evidence has demonstrated that Wnt/β-catenin signaling plays an essential role in the development of the auditory system but its potential role in presbycusis remains unclear. In this study, we used a rat model of aging, created by chronic systemic exposure to d-galactose (d-gal), and explored changes in Wnt/β-catenin signaling in the auditory cortex. A decrease in Wnt/β-catenin signaling in the auditory cortex was found in both naturally aging and d-gal-mimetic aging rats, as indicated by increased GSK3β activity and decreased β-catenin activity. Moreover, lithium chloride (Licl), an activator of Wnt signaling pathway, was administered long term to 15-month-old d-gal-treated rats. Activation of Wnt/β-catenin signaling by Licl attenuated d-gal-induced auditory cortex apoptosis and neurodegeneration. Bmi1, a transcription factor implicated in antiaging and resistance to apoptosis, can be modulated by β-catenin activity. Here, we showed that the expression of Bmi1 was reduced and the expression of its downstream genes, p16INK4a , p19Arf , and p53 were increased in the auditory cortex both of naturally aging and d-gal-mimetic aging rats. In addition, Licl significantly increased Bmi1 expression and reduced p16INK4a, p19Arf, and p53 expression. Our results indicated that decreased Wnt/β-catenin signaling might participate in the pathogenesis of central presbycusis through modulating the expression of Bmi1. Wnt/β-catenin signaling might be used as a potential therapeutic target against presbycusis.