Addition of exogenous NAD+ prevents mefloquine-induced neuroaxonal and hair cell degeneration through reduction of caspase-3-mediated apoptosis in cochlear organotypic cultures.
BACKGROUND
Mefloquine is widely used for the treatment of malaria. However, this drug is known to induce neurological side effects including depression, anxiety, balance disorder, and sensorineural hearing loss. Yet, there is currently no treatment for these side effects.


RESULTS
In this study, we show that the coenzyme NAD(+), known to play a critical role in maintaining the appropriate cellular redox environment, protects cochlear axons and sensory hair cells from mefloquine-induced degeneration in cultured rat cochleae. Mefloquine alone destroyed hair cells and nerve fiber axons in rat cochlear organotypics cultures in a dose-dependent manner, while treatment with NAD(+) protected axons and hair cells from mefloquine-induced degeneration. Furthermore, cochlear organs treated with mefloquine showed increased oxidative stress marker levels, including superoxide and protein carbonyl, and increased apoptosis marker levels, including TUNEL-positive nuclei and caspases-3. Treatment with NAD(+) reduced the levels of these oxidative stress and apoptosis markers.


CONCLUSIONS
Taken together, our findings suggest that that mefloquine disrupts the cellular redox environment and induces oxidative stress in cochlear hair cells and nerve fibers leading to caspases-3-mediated apoptosis of these structures. Exogenous NAD(+) suppresses mefloquine-induced oxidative stress and prevents the degeneration of cochlear axons and sensory hair cells caused by mefloquine treatment.
Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, New York, United States of America ; Sixth People's Hospital, Shanghai Oriental Otolaryngology Institute, Shanghai Jiao Tong University, Shanghai, China ; Xiangya Hospital, Central South University, Changsha, Hunan, China ; Department of Applied Biological Chemistry, University of Tokyo, Yayoi, Tokyo, Japan.
Dalian
D
Ding
Weidong
W
Qi
Dongzhen
D
Yu
Haiyan
H
Jiang
Chul
C
Han
Mi-Jung
MJ
Kim
Kana
K
Katsuno
Yun Hua
YH
Hsieh
Takuya
T
Miyakawa
Richard
R
Salvi
Masaru
M
Tanokura
Shinichi
S
Someya
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D003051:Cochlea / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D015767:Mefloquine / Q000494:pharmacology*; D009243:NAD / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D009243:NAD; D053148:Caspase 3; D015767:Mefloquine