Aminoglycoside antibiotics are well-known ototoxic drugs most frequently prescribed for prophylaxis or for treating bacterial sepsis and tuberculosis. Sepsis in premature births and bacterial meningitis quickly become life-threatening, and aminoglycosides are injected systemically for bactericidal efficacy, and avoid poor uptake following oral delivery. Systemic aminoglycosides are rapidly absorbed by most cells, making them useful for treating tuberculosis, an intracellular infection. Proximal tubule cells in the kidney and the sensory hair cells of the inner ear efficiently take up aminoglycosides and are especially vulnerable to aminoglycoside toxicity and cell death.
Renal toxicity is typically acute because these epithelial cells can be regenerated; however, mammalian cochlear sensory cells cannot be spontaneously regenerated. This results in hearing loss and deafness that delays language acquisition, educational achievement, and psychosocial integration. The otologist or audiologist is unlikely to be involved in pharmacotherapeutic decisions despite these ramifications. Specialized medical centers with ototoxicity monitoring capabilities for diagnosing consequent auditory and vestibular dysfunction may offer more options for practitioners.
Systemic aminoglycosides have ready access to proximal tubule cells from the renal interstitial (extracellular) fluids and the glomerular ultrafiltration in the nephron lumen. In the inner ear, however, these drugs must first traverse a blood-labyrinth barrier, similar to the blood-brain barrier, prior to entering cochlear cells, including sensory hair cells, to induce their permanent ototoxic effect. The blood-labyrinth barrier comprises endothelial cells lining cochlear blood vessels coupled by tight junctions. Ions, nutrients, and drugs must pass through endothelial cells, which act as a selective filter, rather than between cells into the cochlear extracellular fluids (e.g., perilymph).
The stria vascularis is highly vascularized and is enclosed within tight, junction-coupled epithelial cells within the cochlear lateral wall. (Figure.) The stria vascularis regulates a unique extracellular fluid called endolymph that is rich in potassium (150 mM), and has an electrical potential of +80 mV. All cells lining the endolymphatic compartment (the scala media) are also joined by tight junctions to separate the two cochlear fluids electrochemically. Their apical membranes are bathed in endolymph, while their basolateral membranes are immersed in perilymph. These conditions are essential to drive a large cationic flux through the mechanically gated transduction channels of hair cells, ensuring auditory sensitivity experienced by those with typical hearing. Dysfunction in any of these essential components results in poor auditory thresholds and hearing loss. These critical features, however, also drive aminoglycosides into hair cells, and may result in ototoxicity under physiological circumstances.
Systemic Aminoglycosides Are Trafficked Via Endolymph into Hair Cells
Li H, Steyger PS Sci Rep 2011;1:159
Previously developed techniques were utilized to perfuse the cochlea in situ in two examples to clarify the predominant entry route into hair cells. A commonly used aminoglycoside, called gentamicin, was used in both conditions. We injected gentamicin intravenously while perfusing the scala tympani with artificial perilymph to prevent drug access to the basolateral surfaces of hair cells. In the second experiment, we perfused the scala tympani with matching perilymphatic levels of gentamicin. Strikingly, greater uptake of gentamicin by hair cells occurred, following intravenous administration, despite ready access of aminoglycosides to the basolateral surface of hair cells. The stria vascularis was richly endowed with gentamicin, following systemic administration, as expected from previous studies. (J Assoc Res Otolaryngol 2009;10:205.)
In vivo studies indicate that systemic aminoglycosides are predominantly trafficked across the strial blood-labyrinth barrier into endolymph and hair cells. The +80 mV endolymphatic potential electrically drives the cationic aminoglycosides into the negatively polarized hair cells. This accounts for low endolymph levels and preferential hair cell uptake via the aminoglycoside-permeant, mechanically gated transduction channels, and subsequent cytotoxicity compared with adjacent supporting cells.
It was not known until recently how aminoglycosides entered hair cells or from which compartment (i.e., endolymph or perilymph). Biochemical data in the 1980s suggested that aminoglycosides were deposited in perilymph at greater levels than endolymph. (Hear Res 1983;11:191; J Infect Dis 1981;143:476.) Immunohistochemical studies in the 1990s revealed aggregates of aminoglycosides in hair cells following systemic injection, which is suggestive of apical endocytosis. (Hear Res 1990;50[1-2]:35; Brain Res 1995;704:135; Acta Otolaryngol 1992;112:272.)
Several studies reported that aminoglycosides could enter hair cells via the mechanically gated transduction channels on the hair cell stereocilia to induce cytotoxicity in vitro. (J Physiol 2005;567[Pt 2]:505; PLoS One 2011;6:e22347.) These data implied that if aminoglycosides were to enter hair cells across their apical membranes in vivo, they needed to do so from the highly regulated endolymphatic compartment, in which only lower levels of aminoglycosides had been observed compared with perilymph. This highlighted paper strongly suggests that endolymph trafficking of systemic aminoglycosides is the predominant route into hair cells.
Key questions still remain to be answered: What are the molecular mechanisms that facilitate drug transport across the strial blood-labyrinth barrier? Which cells possess the key molecular trafficking mechanisms within the stria vascularis? How do loop diuretics, noise, vasoactive peptides, and inflammation (e.g., bacterial sepsis) synergistically enhance strial and hair cell uptake of aminoglycosides and subsequent ototoxicity? What are the binding targets of aminoglycosides that trigger the toxic generation of reactive oxygen species and signaling cascades that lead to hair cell death?
Answers will shed light on nutrient and drug transporting mechanisms in the cochlea and other tissues, such as the blood-retinal barrier, blood-brain barrier, renal resorption, and placental trafficking. Identification of trafficking and antioxidative mechanisms will enable the development of otoprotective strategies that promote hair cell and support cell longevity crucial for lifelong auditory function in the cochlea.
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