Protective Effect of Honokiol in Noise-Induced Hearing Loss

Noise-induced hearing loss (NIHL) is a common and often underestimated environmental and occupational threat to human health. According to the data from the World Health Organization, some 1.1 billion young individuals are at risk of hearing loss due to the unsafe use of personal audio devices. In Europe, 40% of the population is exposed to dangerous road traffic noise. In the United States, the number of people exposed to dangerous noise levels every day is 30-50 million. NIHL, as well as most other hearing impairments such as drug-induced and age-related, is due to irreversible loss of the sensory hair cells and synapses of the nerve fibers connecting the hair cells to the brain. The molecular mechanism of these cochlear damage is related to the excessive generation of free radicals called reactive oxygen species (ROS) in mitochondria after intense metabolic activities. Cochlear hair cells, especially outer hair cells (OHCs) are extremely sensitive to ROS. These free radicals drive the OHCs into oxidative stress and eventually trigger the apoptosis. Antioxidant agents working as free radical scavengers may help to clean up the cellular environment and keep the health of the cells. However, various challenges have been encountered for these agents, such as cytotoxicity, poor bioavailability and limited effect in vivo. Honokiol is a multifunctional molecule extracted from herbal medicine. It is recently shown that honokiol exerts its function through directly activating sirtuin 3 (SIRT3), a critical enzyme exclusively expressed in mitochondria for ROS detoxification. Studies have shown that honokiol is nontoxic, effective in vivo and protects various tissues and organs, such as brain, liver, kidney and heart, from oxidative stress. Moreover, honokiol can penetrate through the blood-brain barrier, which strongly indicated its permeability to the inner ear. However, honokiol has not been tested in hearing protection yet. The mitochondria in cochlear hair cells are abundant in number in a highly organized distribution, indicating an active metabolism and the vulnerability to ROS. In this regard, hearing protection may be the most valuable application of honokiol. In our pilot studies, the hearing protective effect of honokiol has been verified in both drug-induced hearing loss and NIHL in our pilot studies. In this proposal, the protective effect and the mechanism of honokiol in NIHL will be further investigated for a complete understanding of its potential value in hearing protection. The results will lay the ground work for the systemic application of HNK to protect hearing from multiple insults. NIH R01 grant application will be submitted following this study.