Arginine — and Even Viagra — Restore Hearing and Balance in Animal Models, Study Finds

Arginine — and Even Viagra — Restore Hearing and Balance in Animal Models, Study Finds

Researchers have identified mutations in a gene called CPD as a cause of inherited sensorineural hearing loss (SNHL). The gene helps regulate metabolic signaling in the inner ear, including the production of the amino acid arginine and the signaling molecule nitric oxide (NO). Disruption of this pathway in lab animals led to reduced NO, increased cell death in auditory tissues, and measurable hearing and balance deficits.

An international team led by Rong Grace Zhai at the University of Chicago traced identical CPD mutations in multiple unrelated families with early-onset SNHL and then tested the biological effects in animal models. In a paper published in The Journal of Clinical Investigation, the authors report that CPD dysfunction causes NO deficiency and apoptosis in cochlear cells, linking metabolic regulation directly to cell survival in the inner ear.

To test rescue strategies, the researchers turned to mice and fruit flies. In mice, CPD is highly expressed during cochlear development—particularly in hair cells (the sensory receptors for sound), the spiral ganglion neurons (which carry auditory signals), and the stria vascularis (which maintains the cochlear fluid environment). Mice with CPD disruption showed impaired arginine and NO production and elevated apoptosis; animals with complete deletion of the gene were not viable. When investigators supplemented mouse cells with L-arginine, NO levels were nearly restored, indicating a potential route to mitigating damage caused by the mutation.

In fruit flies, the CPD-equivalent gene is called silver, which is strongly expressed in the antennae and Johnston's organ—structures used for hearing and gravity sensing. Adult flies carrying silver mutations exhibited marked hearing loss, impaired motor coordination, and defective gravity perception. Mutant flies fed L-arginine showed improved motor-direction performance, and flies given both L-arginine and sildenafil (the drug marketed as Viagra, originally developed for cardiovascular conditions) demonstrated a significant recovery in gravity-sensing ability.

“The use of cross-species modeling and demonstration of rescue via L-arginine or sildenafil highlights the therapeutic potential of targeting the NO pathway,” Zhai and colleagues wrote. “Future work will focus on developing cellular and vertebrate models for in vivo auditory testing and evaluating combinatorial therapies involving metabolic supplementation and gene delivery.”

These experiments offer proof-of-concept that restoring arginine or modulating NO signaling can partially reverse sensory deficits in animal models caused by CPD dysfunction. However, the authors and other experts caution that results in mice and flies do not guarantee the same outcomes in humans. Further vertebrate testing, safety evaluation, dosing studies, and clinical trials will be required before any treatments—whether arginine supplementation or repurposed drugs that affect NO signaling—can be recommended for people with inherited SNHL.

Bottom line: The study identifies CPD as a critical metabolic regulator for cochlear cell survival and provides encouraging early evidence that metabolic and pharmacologic interventions targeting the NO pathway could become new avenues for treating certain forms of inherited hearing loss.