Lycium barbarum Glycopeptide Alleviates Neomycin-Induced Ototoxicity by Inhibiting Tryptophan Hydroxylase-Mediated Serotonin Biosynthesis

Aminoglycoside antibiotic-induced sensorineural hearing loss (SNHL) is a common sensory disorder that requires the development of prophylactic and therapeutic interventions. Lycium barbarum glycopeptide (LBGP) is a peptidoglycan isolated and purified from Lycium barbarum polysaccharides that exhibit significant anti-inflammatory, antioxidant, and neuroprotective effects, but the role of LBGP in aminoglycoside-induced SNHL has not been well investigated. Here it is shown that LBGP can protect against neomycin-induced hearing impairment and alleviate oxidative stress in a neomycin-induced SNHL mouse model. Moreover, it is further found that inhibition of tryptophan hydroxylase (Tph)-mediated serotonin (5-HT) biosynthesis plays a key role in the mechanism of action of LBGP in treating neomycin-induced hearing loss. Systemic delivery of 5-HT increased neomycin-induced apoptosis of cochlear hair cells and spiral ganglion neurons, and pharmacological Tph2 inhibition with P-chlorophenylalanine or Tph2 knock down by AAV-ie-Tph2 effectively attenuated neomycin-induced hearing dysfunction. Collectively, these results provide a promising strategy for the prevention of SNHL by using natural plant extract which is more available and exhibits lower side effects compared with other otoprotective drugs, and identify Tph2 as a potential pharmacological target for the treatment of aminoglycoside-induced ototoxicity.