Drug administration at the appropriate time of the day could prove more efficient in the treatment against hearing loss
Dexamethasone, a synthetic glucocorticoid, may be more effective in protecting the auditory system when delivered during the active phase. A novel study shows how the time of the day impacts on the treatment outcome. The study is published in Current Biology and has been conducted by researchers at Karolinska Institutet.
Glucocorticoid levels vary across the day, peaking at the onset of the active phase (daytime in humans, nighttime in nocturnal rodents). These levels may predict the efficacy of dexamethasone treatment against noise-induced hearing loss.
Researchers at Karolinska Institutet have investigated in mice what controls circadian rhythms in the cochlea, the organ responsible for hearing. The Canlon lab previously evidenced the existence of strong circadian rhythms in the cochlea, correlating with greater vulnerability to noise trauma during the active phase.
The results show that circulating glucocorticoids have a major contribution to this greater sensitivity. Dexamethasone treatment was most effective when endogenous glucocorticoid levels were at the lowest levels during the inactive phase.
“This could explain the mixed success of glucocorticoid treatment, which is the only approved approach for treating auditory disorders”, says Christopher R. Cederroth, researcher at the Department of Physiology and Pharmacology at Karolinska Institutet.
Chronopharmacological approaches for the treatment of auditory disorders.
“In our initial study, which investigated the involvement of neurotrophins in the circadian vulnerability to hearing loss, we found that treatment was most effective during the active phase. Here, we find the opposite is true for dexamethasone and illustrates that it is not the bioavailability that dictates the outcome, rather the circadian status of the cell’s target,” says Professor Barbara Canlon.
“The mechanisms behind the greater vulnerability of mice during the active phase are still unclear, but our work suggests a correlation with greater inflammatory signals expressed in the cochlea at the onset of the active phase.”
The researchers believe that by adapting the dexamethasone treatment at nighttime in humans could prove more effective than the current dosing during daytime.
“Further studies are now needed to test how dexamethasone treatment can be tailored to patients’ endogenous glucocorticoid levels. The heterogeneity in glucocorticoid profiles in humans and across different rodent species and strains is important. Glucocorticoid measures across 24h will be essential to determine a person’s chronotype when considering timed treatments.” says Barbara Canlon. “This probably applies to many disorders other than hearing loss.”
The research was funded by the NIDCD at NIH, the Department of Defense, USA, the Swedish Medical Research Council, Tysta Skolan, and Hörselforskningsfonden.
Circadian Regulation of Cochlear Sensitivity to Noise by Circulating Glucocorticoids
Cederroth C, Park J-S, Basinou V, Weger B, Tserga E, Sarlus H, Magnusson A, Kadri N, Gachon F, Canlon B
Current Biology, 25 July 2019, DOI: https://doi.org/10.1016/j.cub.2019.06.057