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Caspase inhibitors prevent cisplatin-induced apoptosis of auditory sensory cells
1Department of Otolaryngology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Abstract:
In vitro studies tested the efficacy of three caspase inhibitors, Ac-VAD-cmk (caspase-1 inhibitor), z-DEVD-fmk (caspase-3 inhibitor) and B-D-fmk (BOCDFK, a general inhibitor), for protecting auditory sensory cells from cisplatin-damage induced loss. Treatment of 3-day-old rat organ of Corti explants with these caspase inhibitors protected > 80% of the auditory hair cells from cisplatin-damage initiated apoptosis. Dissociated cell cultures of 3-day-old rat spinal ganglia treated with any of these three caspase inhibitors in addition to exogenous neurotrophin have highly significant increases in neuronal survival following cisplatin exposure. These results indicate that loss of auditory sensory cells as a result of cisplatin-induced damage involves apoptosis and that blocking of this cell death pathway at the caspase level effectively rescues both hair cells and neurons.
Insights
Caspase inhibitors protected auditory sensory cells from cisplatin damage by blocking apoptosis. This finding offers potential therapeutic strategies for preventing cisplatin-induced hearing loss and neuronal damage.
Area of Science:
- Ototoxicology
- Neuroscience
- Cell Biology
Background:
- Cisplatin is a widely used chemotherapy agent with ototoxicity as a significant side effect.
- Cisplatin-induced ototoxicity leads to the loss of auditory sensory hair cells and neurons.
- Apoptosis, or programmed cell death, is a key mechanism in cisplatin-induced auditory damage.
Purpose of the Study:
- To investigate the efficacy of caspase inhibitors in protecting auditory sensory cells from cisplatin-induced damage.
- To determine if blocking apoptosis at the caspase level can prevent hair cell and neuronal loss.
- To explore potential therapeutic interventions against cisplatin ototoxicity.
Main Methods:
- In vitro studies using organ of Corti explants and dissociated spinal ganglia cultures from 3-day-old rats.
- Treatment with three caspase inhibitors: Ac-VAD-cmk (caspase-1 inhibitor), z-DEVD-fmk (caspase-3 inhibitor), and B-D-fmk (general caspase inhibitor).
- Assessment of hair cell and neuronal survival following cisplatin exposure in the presence of caspase inhibitors and/or neurotrophin.
Main Results:
- > 80% protection of auditory hair cells in organ of Corti explants treated with caspase inhibitors.
- Highly significant increases in neuronal survival in dissociated spinal ganglia cultures treated with caspase inhibitors and neurotrophin.
- Evidence that cisplatin-induced auditory sensory cell loss involves apoptosis.
Conclusions:
- Caspase inhibitors effectively protect auditory hair cells and neurons from cisplatin-induced damage in vitro.
- Blocking the caspase-mediated apoptosis pathway is a viable strategy to mitigate cisplatin ototoxicity.
- These findings suggest potential therapeutic applications for caspase inhibitors in preventing chemotherapy-induced hearing loss and neurotoxicity.