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Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Protective Effects of Fasudil Against Cisplatin-Induced Ototoxicity in Zebrafish: An In Vivo Study
Kang Hyeon Lim1, Saemi Park1, Eunjung Han1
1Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Ansan Hospital, Ansan 15355, Republic of Korea.
Abstract:
While cisplatin is an effective anti-tumor treatment, it induces ototoxicity through mechanisms involving DNA damage, oxidative stress, and programmed cell death. Rho-associated coiled-coil-containing protein kinase (ROCK) is essential for numerous cellular processes, including apoptosis regulation. Studies have suggested that ROCK inhibitors could prevent apoptosis and promote regeneration. We aimed to investigate the protective effects of the ROCK inhibitor fasudil against cisplatin-induced ototoxicity in a zebrafish model. The zebrafish larvae were exposed to 1 mM cisplatin alone or 1 mM cisplatin co-administered with varying concentrations of fasudil for 4 h. The surviving hair cell counts, apoptosis, reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), caspase 3 activity, and autophagy activation were assessed. Rheotaxis behavior was also examined. Cisplatin reduced hair cell counts; increased apoptosis, ROS production, and ΔΨm loss; and activated caspase 3 and autophagy. Fasudil (100 and 500 µM) mitigated cisplatin-induced hair cell loss, reduced apoptosis, and inhibited caspase 3 and autophagy activation. Rheotaxis in zebrafish was preserved by the co-administration of fasudil with cisplatin. Cisplatin induces hair cell apoptosis in zebrafish, whereas fasudil is a promising protective agent against cisplatin-induced ototoxicity.
Insights
Fasudil, a ROCK inhibitor, protects against cisplatin-induced ototoxicity by reducing hair cell death and preserving hearing function in zebrafish. This study highlights fasudil as a potential therapeutic agent for preventing chemotherapy-related hearing damage.
Area of Science:
- Ototoxicity research
- Pharmacology
- Zebrafish models
Background:
- Cisplatin is a potent anti-tumor drug but causes ototoxicity via DNA damage, oxidative stress, and apoptosis.
- Rho-associated coiled-coil-containing protein kinase (ROCK) plays a role in apoptosis regulation, with inhibitors potentially preventing cell death.
Purpose of the Study:
- To investigate the protective effects of the ROCK inhibitor fasudil against cisplatin-induced ototoxicity in zebrafish.
- To evaluate fasudil's impact on hair cell survival, apoptosis, oxidative stress, and auditory function.
Main Methods:
- Zebrafish larvae were exposed to cisplatin alone or with varying concentrations of fasudil.
- Assessed hair cell counts, apoptosis markers, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), caspase 3 activity, and autophagy.
- Rheotaxis behavior was used to evaluate auditory function.
Main Results:
- Cisplatin significantly reduced hair cell counts and increased apoptosis, ROS, ΔΨm loss, caspase 3 activity, and autophagy.
- Fasudil (100 and 500 µM) mitigated cisplatin-induced hair cell loss, apoptosis, caspase 3 activation, and autophagy.
- Fasudil preserved rheotaxis behavior in cisplatin-exposed zebrafish.
Conclusions:
- Cisplatin induces hair cell apoptosis and ototoxicity in zebrafish.
- Fasudil demonstrates significant protective effects against cisplatin-induced ototoxicity.
- Fasudil is a promising agent for preventing cisplatin-related hearing damage.
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