March 24, 2009 Feature

Advances in Otoprotective Drugs

The development of drugs that prevent or treat hearing loss is a growing enterprise. Up to the last five to 10 years, research was stymied by the challenges associated with drug delivery to the inner ear.

Both the ear and brain require a high amount of energy and a robust, steady blood supply. The network of small blood vessels (capillaries) in the brain and cochlea form the blood-brain (cochlea) barrier in which the capillaries have evolved so that gases and small molecules pass easily into the brain/cochlea, but larger molecules do not. The blood-brain barrier provides an advantage in protecting the brain and cochlea from many environmental toxins or bacteria. However, many large-molecule drugs cannot penetrate the blood-brain barrier, making it difficult to treat infections of the brain and to treat sudden hearing loss or other inner-ear pathologies.

Otoprotective Drug Challenges

Figure 1. The outer hair cell nuclei are shown in red. Arrows indicate apoptosis. Note that apoptotic nuclei are condensed and fragmented.

In the last five to 10 years, there has been a steadily growing interest in developing drugs to prevent noise-induced hearing loss (NIHL). This drug development research is based on two fundamental discoveries related to cochlear pathology caused by noise exposure. The first is the realization that death of the cochlear sensory cells following a noise exposure is not random, but rather occurs in a predictable pattern of programmed cell death called apoptosis (Figure 1). In apoptotic cell death, the cell disassembles itself, the nucleus becomes smaller, and the cell membrane remains intact.

The second finding is that exposure to noise triggers the death of sensory cells by producing a large, persistent increase in toxic reactive oxygen species (ROS) in the cochlea. ROS (superoxide, hydroxyl, and peroxynitrite) are molecules that have a free electron that can bind to a cell membrane, nucleus, or protein and initiate cellular damage. The increased ROS activity following the noise exposure (Figure 2) occurs mostly in the cochlear basal turn, which is the high-frequency region of the cochlea associated with typical high-frequency NIHL.

Figure 2. Image of cochlea after being subjected to traumatic noise exposure: (A) 30 minutes
post-noise, (B) two days post-noise, and (C) four days post-noise. The nucleus is stained red; green
florescence shows ROS activity. Note that ROS is intense for at least two days post-noise and
appears to contribute to the loss of outer hair cells. [Figure reprinted with permission from Henderson, D., Bielefeld, E. C., Harris, K. C., &Hu, B. H. (2006). The role of oxidative stress in noise-induced hearing loss. Ear and Hearing, 27(1), 1-19.]

Development of Otoprotective Drugs

The new knowledge about cochlear pathology has led to the development of two distinct classes of otoprotective drugs: antioxidants and antiapoptotic drugs. The antioxidant drugs prevent NIHL by neutralizing the ROS that are generated by noise exposures. Some of the antioxidant drugs being developed are N-acetyl-L-cystine (L-NAC), acetyl-L-carnitine (ALCAR), AuraquellTM, D-methionine (D-met), and ebselen.

The antiapoptotic drugs interrupt the molecular signaling used to initiate the cell death/apoptotic process. These drugs include Src inhibitors and AM-111. Src inhibitors prevent the cell death by blocking the apoptotic signal induced when cells are separated physically from each other. AM-111 is an inhibitor of c-Jun N-terminal kinases (JNK), one of the apoptosis-signaling molecules. Both classes of drugs have been used successfully with animal models of NIHL, and antioxidant supplements (e.g., the Hearing Pill TM,a special formulation of NAC) are available for human use. However, at this date, there is no FDA-approved otoprotective drug for the purpose of treating NIHL.

Fortunately, large-scale clinical trials are underway to study the efficacy of otoprotective drugs in preventing or treating hearing loss due to noise. For example, the U.S. Navy conducted clinical trials using the Hearing Pilland additional clinical trials are scheduled to study the effect of higher doses of NAC. The FDA has granted orphan drug status (a program designed to promote the research and development of drugs that treat rare diseases affecting fewer than 200,000 Americans) to AM-111 for the treatment of acute acoustic trauma or sudden deafness and a large-scale clinical trial is underway.

The programmed cell death (apoptosis) and increased ROS levels in the cochlea are reported as a common thread for acquired hearing loss (i.e., NIHL, age-related hearing loss, drug-induced hearing loss). Cisplatin, a chemotherapeutic drug, is known as an ototoxic drug that can cause apoptotic cell death and enhance ROS levels in the cochlea. A clinical trial is also underway using D-met to prevent cisplatin-induced hearing loss.

Education of Audiologists

Research related to the prevention of NIHL with drugs is rapidly expanding, and once these drugs are approved by FDA, physicians are able to prescribe these otoprotective drugs to patients. The otoprotective drugs may be approved as an over-the-counter medication in the future if their benefits outweigh their risks and if low potentials for misuse and abuse are shown.

In the future, use of otoprotective drugs may be more widespread in noisy conditions, such as in the construction industry, while hunting, and while playing music with a lot of percussion. Given this trend, instruction in human physiology and pharmacology is likely to become more significant in audiology education.

Donald Henderson, PhD, is a professor in the Department of Communicative Disorders and Sciences at the State University of New York at Buffalo. He teaches courses in advanced hearing science, industrial audiology, and medical audiology. Contact him at donaldhe@buffalo.edu.

Chiemi Tanaka, MA, CCC-A, is a PhD student in the Department of Communicative Disorders and Sciences at the State University of New York at Buffalo. Her research interest is mechanism and prevention of hearing loss caused by noise, aging, and ototoxicity. Contact her at ctanaka@buffalo.edu.

cite as: Henderson, D.  & Tanaka, C. (2009, March 24). Advances in Otoprotective Drugs . The ASHA Leader.

  

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