Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss.
Cochlear noise injury is the second most frequent cause of sensorineural hearing loss, after aging. Because calcium dysregulation is a widely recognized contributor to noise injury, we examined the potential of calcium channel blockers to reduce noise-induced hearing loss (NIHL) in mice. We focused on two T-type calcium blockers, trimethadione and ethosuximide, which are anti-epileptics approved by the Food and Drug Administration. Young C57BL/6 mice of either gender were divided into three groups: a 'prevention' group receiving the blocker via drinking water before noise exposure; a 'treatment' group receiving the blocker via drinking water after noise exposure; and controls receiving noise alone. Trimethadione significantly reduced NIHL when applied before noise exposure, as determined by auditory brainstem recording. Both ethosuximide and trimethadione were effective in reducing NIHL when applied after noise exposure. Results were influenced by gender, with males generally receiving greater benefit than females. Quantitation of hair cell and neuronal density suggested that preservation of outer hair cells could account for the observed protection. Immunocytochemistry and RT-PCR suggested that this protection involves direct action of T-type blockers on alpha1 subunits comprising one or more Ca(v)3 calcium channel types in the cochlea. Our findings provide a basis for clinical studies testing T-type calcium blockers both to prevent and treat NIHL.
Shen
Haiyan
H
Department of Otolaryngology, Center for Aging, Washington University, 4560 Clayton Avenue, St. Louis, MO 63110, USA.
Zhang
Baoping
B
Shin
June-Ho
JH
Lei
Debin
D
Du
Yafei
Y
Gao
Xiang
X
Wang
Qiuju
Q
Ohlemiller
Kevin K
KK
Piccirillo
Jay
J
Bao
Jianxin
J
D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects; D001483:Base Sequence; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D005013:Ethosuximide / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012727:Sex Characteristics; D014293:Trimethadione / Q000494:pharmacology* / Q000627:therapeutic use
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D017931:DNA Primers; D005013:Ethosuximide; D014293:Trimethadione