Natural Bizbenzoquinoline Derivatives Protect Zebrafish Lateral Line Sensory Hair Cells from Aminoglycoside Toxicity

Abstract

Moderate to severe hearing loss affects 360 million people worldwide and most often results from damage to sensory hair cells. Hair cell damage can result from aging, genetic mutations, excess noise exposure, and certain medications including aminoglycoside antibiotics. Aminoglycosides are effective at treating infections associated with cystic fibrosis and other life-threatening conditions such as sepsis, but cause hearing loss in 20–30% of patients. It is therefore imperative to develop new therapies to combat hearing loss and allow safe use of these potent antibiotics. We approach this drug discovery question using the larval zebrafish lateral line because zebrafish hair cells are structurally and functionally similar to mammalian inner ear hair cells and respond similarly to toxins. We screened a library of 502 natural compounds in order to identify novel hair cell protectants. Our screen identified four bisbenzylisoquinoline derivatives: berbamine, E6 berbamine, hernandezine, and isotetrandrine, each of which robustly protected hair cells from aminoglycoside-induced damage. Using fluorescence microscopy and electrophysiology, we demonstrated that the natural compounds confer protection by reducing antibiotic uptake into hair cells and showed that hair cells remain functional during and after incubation in E6 berbamine. We also determined that these natural compounds do not reduce antibiotic efficacy. Together, these natural compounds represent a novel source of possible otoprotective drugs that may offer therapeutic options for patients receiving aminoglycoside treatment.

Natural Compounds as Occult Ototoxins? Ginkgo biloba Flavonoids Moderately Damage Lateral Line Hair Cells

“…We also examined an additional mechanotransduction blocker, the quinoline derivative E6 berbamine. E6 attenuates aminoglycoside and FM 1-43 entry into hair cells, consistent with prior research on related quinoline-ring derivatives (Ou et al 2009(Ou et al , 2012Kruger et al 2016). Furthermore, the parent compound berbamine attenuates mechanotransduction current in mouse cochlear hair cells, consistent with a permeant channel block (C. Kros, personal communication).…”

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death

“…This more than doubles the number already identified as being wholly or partially effective in mouse hair cells using a similar approach, i.e., preselection using zebrafish lateral line neuromasts (16)(17)(18)(19)(20)(21)(22)(23), proving the value of this strategy and providing additional reagents that will help solve an ever-increasing clinical issue.…”

“…Recent studies (16)(17)(18)(19)(20)(21)(22)(23) have shown that the lateral line system of zebrafish larvae is a powerful model for discovering compounds that can protect sensory hair cells from the toxic side effects of aminoglycoside antibiotics. At least 24 compounds have been described that protect zebrafish lateral line hair cells, some of which (16,20,23) reduce or block the uptake of Texas red-conjugated gentamicin (GTTR) into Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear.…”

“…the neuromast hair cells, while others (16,19) block the uptake of both GTTR and FM 1-43, a styryl dye that, like the aminoglycoside antibiotics, acts as a permeant blocker of the hair cell MET channel (24).…”

Insights from zebrafish on human pigment cell disease and treatment

“…The ability to peer through transparent skin in live animals will allow the elucidation of drug movement and processing in live cells. Zebrafish have been used in several small molecule and DEVELOPMENTAL DYNAMICS drug screens, including efforts to find novel whitening agents (Choi et al, 2007;Cha et al, 2011;Chen et al, 2015;Gunia-Krzyzak et al, 2016), novel drug therapies (Kaufman et al, 2009;Ishizaki et al, 2010;Mathias et al, 2012;Tamplin et al, 2012) and to find compounds that prevent hair cell death (as targets for preventing hearing loss in humans [Ou et al, 2012;Kruger et al, 2016]).…”