Unraveling Endocannabinoid Signaling Pathways in Cisplatin-Induced Ototoxicity

Area of Science:

• Oto-neuroscience
• Chemotherapy side effects
• Endocannabinoid system research

Background:

• Cisplatin chemotherapy can cause ototoxicity, leading to irreversible hearing loss.
• Currently, no effective treatments exist for cisplatin-induced ototoxicity.
• The role of the endocannabinoid system (ECS) in hearing function is largely unexplored.

Purpose of the Study:

• To investigate the involvement of the endocannabinoid system in cisplatin-induced ototoxicity.
• To identify potential therapeutic targets within the ECS for mitigating hearing damage caused by chemotherapy.

Main Methods:

• Molecular profiling of the ECS in auditory hair cell-like UB/OC1 cells.
• Establishment of an in vitro model of cisplatin-induced ototoxicity.
• Validation of findings in an in vivo model of cisplatin-induced ototoxicity.
• Pharmacological blockade of cannabinoid receptor 2 (CB2R) using SR144528.

Main Results:

• The ECS, including receptors and major endocannabinoids, is present in auditory hair cells.
• Cisplatin treatment downregulated key ECS components (CB2R, DAGLβ, ABHD6) and induced hair cell damage.
• Pharmacological blockade of CB2R protected against cisplatin-induced hair cell damage by inhibiting caspase-3.
• In vivo studies confirmed the in vitro findings, highlighting the physiological relevance of CB2R in ototoxicity.

Conclusions:

• Selective elements of the endocannabinoid system are involved in cisplatin-induced ototoxicity.
• Cannabinoid receptor 2 (CB2R) plays a significant role in chemotherapy-induced hearing damage.
• Targeting CB2R represents a potential therapeutic strategy to prevent or treat cisplatin-induced ototoxicity.