Bortezomib-induced neuropathy is in part mediated by the sensitization of TRPV1 channels
Jared M Sprague1,2, Ajay S Yekkirala1,2, Bhagat Singh1,2
1F.M. Kirby Neurobiology Center, Boston Children's Hospital, 3 Blackfan Circle, Boston, MA, USA.
Abstract:
TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30-50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent.
Insights
Bortezomib causes long-term sensitization of the TRPV1 channel, leading to nerve damage and loss of sensation. TRPV1 knockout mice show protection, indicating TRPV1
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Transient Receptor Potential Vanilloid 1 (TRPV1) is a key ion channel in sensory neurons, involved in pain and heat sensation.
- TRPV1 sensitization can lead to cellular toxicity via calcium influx, particularly after tissue injury or inflammation.
- Small fiber sensory neurons expressing TRPV1 are crucial for skin innervation.
Purpose of the Study:
- To identify compounds that trigger TRPV1 sensitization after prolonged exposure.
- To investigate the role of TRPV1 sensitization in bortezomib-induced neuropathy.
- To explore potential therapeutic targets for chemotherapy-induced nerve damage.
Main Methods:
- Development of a phenotypic assay in mouse primary sensory neurons.
- Unbiased screening of a 480-compound library to identify TRPV1 sensitizers.
- In vitro and in vivo studies using bortezomib and TRPV1 knockout mice.
Main Results:
- Chemotherapeutic agents, calcium ion deregulators, and protein synthesis inhibitors were identified as long-acting TRPV1 sensitizers.
- Proteasome inhibitors, including bortezomib, were potent TRPV1 sensitizers.
- Bortezomib induced prolonged TRPV1 sensitization, neurite retraction, and nerve damage in mice, which was prevented in TRPV1 knockout mice.
Conclusions:
- Long-term TRPV1 sensitization is a significant contributor to bortezomib-induced neuropathy.
- TRPV1 plays a critical role in the development of sensory deficits associated with bortezomib treatment.
- Targeting TRPV1 may offer a strategy to mitigate chemotherapy-induced nerve damage.
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