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Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain

Treatment with anti-neoplastic agents can lead to the development of chemotherapy induced peripheral neuropathy (CIPN), which is long lasting and often refractory to treatment. This neuropathic pain develops along dermatomes innervated by peripheral nerves with cell bodies located in the dorsal root...

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Autores principales: Braden, Kathryn, Stratton, Harrison J., Salvemini, Daniela, Khanna, Rajesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733339/
https://www.ncbi.nlm.nih.gov/pubmed/35024498
http://dx.doi.org/10.1016/j.ynpai.2021.100082
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author Braden, Kathryn
Stratton, Harrison J.
Salvemini, Daniela
Khanna, Rajesh
author_facet Braden, Kathryn
Stratton, Harrison J.
Salvemini, Daniela
Khanna, Rajesh
author_sort Braden, Kathryn
collection PubMed
description Treatment with anti-neoplastic agents can lead to the development of chemotherapy induced peripheral neuropathy (CIPN), which is long lasting and often refractory to treatment. This neuropathic pain develops along dermatomes innervated by peripheral nerves with cell bodies located in the dorsal root ganglia (DRG). The voltage-gated sodium channel NaV1.7 is expressed at high levels in peripheral nerve tissues and has been implicated in the development of CIPN. Efforts to develop novel analgesics directly inhibiting NaV1.7 have been unsuccessful, and our group has pioneered an alternative approach based on indirect modulation of channel trafficking by the accessory protein collapsin response mediator protein 2 (CRMP2). We have recently reported a small molecule, compound 194, that inhibits CRMP2 SUMOylation by the E2 SUMO-conjugating enzyme Ubc9 (Cai et al. , Sci. Transl. Med. 2021 13(6 1 9):eabh1314). Compound 194 is a potent and selective inhibitor of NaV1.7 currents in DRG neurons and reverses mechanical allodynia in models of surgical, inflammatory, and neuropathic pain, including spared nerve injury and paclitaxelinduced peripheral neuropathy. Here we report that, in addition to its reported effects in rats, 194 also reduces mechanical allodynia in male CD-1 mice treated with platinumcomplex agent oxaliplatin. Importantly, treatment with 194 prevented the development of mechanical allodynia when co-administered with oxaliplatin. No effects were observed on the body weight of animals treated with oxaliplatin or 194 throughout the study period. These findings support the notion that 194 is a robust inhibitor of CIPN that reduces established neuropathic pain and prevents the emergence of neuropathic pain during treatment with multiple anti-neoplastic agents in both mice and rats.
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spelling pubmed-87333392022-01-11 Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain Braden, Kathryn Stratton, Harrison J. Salvemini, Daniela Khanna, Rajesh Neurobiol Pain Short Communication Treatment with anti-neoplastic agents can lead to the development of chemotherapy induced peripheral neuropathy (CIPN), which is long lasting and often refractory to treatment. This neuropathic pain develops along dermatomes innervated by peripheral nerves with cell bodies located in the dorsal root ganglia (DRG). The voltage-gated sodium channel NaV1.7 is expressed at high levels in peripheral nerve tissues and has been implicated in the development of CIPN. Efforts to develop novel analgesics directly inhibiting NaV1.7 have been unsuccessful, and our group has pioneered an alternative approach based on indirect modulation of channel trafficking by the accessory protein collapsin response mediator protein 2 (CRMP2). We have recently reported a small molecule, compound 194, that inhibits CRMP2 SUMOylation by the E2 SUMO-conjugating enzyme Ubc9 (Cai et al. , Sci. Transl. Med. 2021 13(6 1 9):eabh1314). Compound 194 is a potent and selective inhibitor of NaV1.7 currents in DRG neurons and reverses mechanical allodynia in models of surgical, inflammatory, and neuropathic pain, including spared nerve injury and paclitaxelinduced peripheral neuropathy. Here we report that, in addition to its reported effects in rats, 194 also reduces mechanical allodynia in male CD-1 mice treated with platinumcomplex agent oxaliplatin. Importantly, treatment with 194 prevented the development of mechanical allodynia when co-administered with oxaliplatin. No effects were observed on the body weight of animals treated with oxaliplatin or 194 throughout the study period. These findings support the notion that 194 is a robust inhibitor of CIPN that reduces established neuropathic pain and prevents the emergence of neuropathic pain during treatment with multiple anti-neoplastic agents in both mice and rats. Elsevier 2021-12-27 /pmc/articles/PMC8733339/ /pubmed/35024498 http://dx.doi.org/10.1016/j.ynpai.2021.100082 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Short Communication
Braden, Kathryn
Stratton, Harrison J.
Salvemini, Daniela
Khanna, Rajesh
Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain
title Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain
title_full Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain
title_fullStr Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain
title_full_unstemmed Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain
title_short Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain
title_sort small molecule targeting nav1.7 via inhibition of the crmp2-ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733339/
https://www.ncbi.nlm.nih.gov/pubmed/35024498
http://dx.doi.org/10.1016/j.ynpai.2021.100082
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