Intra-cochlear trafficking of aminoglycosides.

Cochlear sensory hair cells are pharmacologically sensitive to aminoglycoside antibiotics that are used for treating life-threatening bacterial sepsis. Cochlear tissues are compartmentalized behind an impermeable paracellular barrier called the blood-labyrinth barrier (BLB). Most macromolecules cannot cross the blood-labyrinth barrier; however, aminoglycosides can cross this barrier into the cochlear fluids and enter hair cells, inducing hair cell death and consequent permanent hearing loss or deafness. The trafficking routes and cellular mechanisms required for aminoglycoside trafficking across the blood-labyrinth barrier remain unknown.Aminoglycosides enter cochlear hair cells across their apical membranes that are bathed in endolymph, a hitherto unexpected trafficking route. The stria vascularis, a component of the blood- labyrinth barrier, preferentially loads with aminoglycosides. Our recent work demonstrates that the stria vascularis exhibits high expression of the cation-selective ion channel TRPV4, and that this channel is permeable to aminoglycosides. However, aminoglycosides must employ more than one cellular mechanism to cross the blood-labyrinth barrier into endolymph against the electrical gradient.