title: Caspase inhibitor facilitates recovery of hearing by protecting the cochlear lateral wall from acute cochlear mitochondrial dysfunction.
abstract: We recently showed that acute energy failure in the rat cochlea induced by local administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) causes hearing loss mainly due to degeneration of cochlear lateral-wall fibrocytes. In the present study, we analyzed the effect of the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethylketone (Z-VAD-FMK) on 3-NP-induced hearing loss in a model showing temporary threshold shifts at low frequencies and permanent threshold shifts at high frequencies. The model rats received an intraperitoneal injection of either Z-VAD-FMK or vehicle for 3 days starting 1 day prior to 3-NP treatment. One day after the administration of 3-NP, the auditory brain-stem response (ABR) threshold at 20 kHz was elevated to 70 dB in the Z-VAD-FMK group and to 85 dB in controls. The Z-VAD-FMK group completely recovered to the preoperative level within 14 days, whereas in the controls, the ABR threshold remained elevated at 50 dB even 28 days after the administration of 3-NP. Treatment with Z-VAD-FMK also improved recovery of hearing at 8 kHz but did not change recovery at 40 kHz. Histological examination demonstrated that treatment with Z-VAD-FMK inhibited progressive degeneration of the lateral-wall fibrocytes in the cochlear basal turn, as well as apoptosis of these fibrocytes. These results clearly indicate that caspase-dependent apoptosis of fibrocytes in the cochlear lateral wall plays an important role in hearing loss in the present animal model. Moreover, the results of the present study suggest that systemic administration of a caspase inhibitor may be an effective therapy for sensorineural hearing loss caused by acute energy failure such as that observed in cochlear ischemia.
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Mizutari
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Kazusaku
authors.initials: K
authors.lastname: Kamiya
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Fujinami
authors.forename: Masato
authors.initials: M
authors.lastname: Fujii
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001309:Auditory Threshold / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D003051:Cochlea / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009574:Nitro Compounds; D011422:Propionates; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D013136:Spiral Ganglion / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053148:Caspase 3; C015392:3-nitropropionic acid