Evaluation of the selective glucocorticoid receptor agonist compound A for ototoxic effects.
OBJECTIVE
To evaluate the selective glucocorticoid receptor agonist (SEGRA) compound A, a potential novel therapeutic for inner ear disorders, for ototoxic effects.


METHODS
Laboratory animal study.


METHODS
Experimental guinea pigs were grouped as follows: Systemic application of compound A (1.5 mg/kg and 4.5 mg/kg; n = 6/group) and intratympanic application of compound A (1 mM and 10 mM; n = 6/group). Contralateral ears in topically treated animals served as controls. Hearing thresholds were determined by auditory brainstem response before and directly after the application of compound A, as well as on days 3, 7, 14, 21, and 28. At the end of the experiments, temporal bones were harvested for histological evaluation.


RESULTS
Systemic administration of compound A (1.5 mg/kg and 4.5 mg/kg) did not cause hearing threshold shifts, whereas the intratympanic injection (1 mM and 10 mM) resulted in a hearing loss. Histological analysis of the middle and inner ears after topical compound A application showed alterations in the tympanic membranes, the auditory ossicles, and the round window membranes, whereas spiral ganglion cells and hair cells were not affected.


CONCLUSIONS
SEGRAs such as compound A could provide novel therapeutic options for the treatment of inner ear disorders and reduce metabolic side effects. Whereas the intratympanic application of compound A resulted in a hearing loss, the systemic application of compound A merits evaluation for otoprotective effects in trauma models.
Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria.
Clemens
C
Honeder
Elisabeth
E
Engleder
Hanna
H
Schöpper
Markus
M
Krause
Lukas David
LD
Landegger
Roberto
R
Plasenzotti
Franz
F
Gabor
Wolfgang
W
Gstoettner
Christoph
C
Arnoldner
D000225:Adenine / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D001309:Auditory Threshold / Q000502:physiology; D001707:Biopsy, Needle; D002951:Citrates / Q000494:pharmacology; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006168:Guinea Pigs; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D010710:Phosphates / Q000494:pharmacology; D011897:Random Allocation; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D012016:Reference Values; D014432:Tympanic Membrane / Q000187:drug effects* / Q000473:pathology*
C034876:CPDA solutions; D002951:Citrates; D010710:Phosphates; D011965:Receptors, Glucocorticoid; D005947:Glucose; D000225:Adenine
SEGRAs; Selective glucocorticoid receptor agonists; compound A; ototoxicity