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dc.contributor.authorLudman, T.
dc.contributor.authorMelemedjian, O.K.
dc.date.accessioned2019-08-05T17:00:27Z
dc.date.available2019-08-05T17:00:27Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85065676479&doi=10.1177%2f1744806919850043&partnerID=40&md5=4f4f9d5533879a030e7cdd9c1a1cbbd0
dc.identifier.urihttp://hdl.handle.net/10713/10186
dc.description.abstractChemotherapy-induced painful peripheral neuropathy is a significant clinical problem that is associated with widely used chemotherapeutics. Unfortunately, the molecular mechanisms by which chemotherapy-induced painful peripheral neuropathy develops have remained elusive. The proteasome inhibitor, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons. This altered metabolic phenotype leads to the extrusion of metabolites which sensitize primary afferents and cause pain. Hypoxia-inducible factor alpha is a transcription factor that is known to reprogram cellular metabolism. Furthermore, hypoxia-inducible factor 1 alpha protein is constantly synthesized and undergoes proteasomal degradation in normal conditions. However, metabolic stress or hypoxia stabilizes the expression of hypoxia-inducible factor 1 alpha leading to the transcription of genes that reprogram cellular metabolism. This study demonstrates that treatment of mice with bortezomib stabilizes the expression of hypoxia-inducible factor 1 alpha. Moreover, knockdown of hypoxia-inducible factor 1 alpha, inhibition of hypoxia-inducible factor 1 alpha binding to its response element, or limiting its translation by using metformin prevent the development of bortezomib-induced neuropathic pain. Strikingly, the blockade of hypoxia-inducible factor 1 alpha expression does not attenuate mechanical allodynia in mice with existing bortezomib-induced neuropathic pain. These results establish the stabilization of hypoxia-inducible factor 1 alpha expression as the molecular mechanism by which bortezomib initiates chemotherapy-induced painful peripheral neuropathy. Crucially, these findings reveal that the initiation and maintenance of bortezomib-induced neuropathic pain are regulated by distinct mechanisms. Copyright The Author(s) 2019.en_US
dc.description.sponsorshipThis work is supported by grant from the Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore (OKM), and Future Leaders in Pain Research, American Pain Society (OKM).en_US
dc.description.urihttps://doi.org/10.1177/1744806919850043en_US
dc.language.isoen-USen_US
dc.publisherSAGE Publications Inc.en_US
dc.relation.ispartofMolecular Pain
dc.subjectaerobic glycolysisen_US
dc.subjectchemotherapy-induced painful peripheral neuropathyen_US
dc.subjectdorsal root ganglionen_US
dc.subjecthypoxia-inducible factor 1 alphaen_US
dc.subjectmetforminen_US
dc.subjectNeuropathyen_US
dc.titleBortezomib and metformin opposingly regulate the expression of hypoxia-inducible factor alpha and the consequent development of chemotherapy-induced painful peripheral neuropathyen_US
dc.typearticleen_US
dc.identifier.doi10.1177/1744806919850043
dc.identifier.pmid31041875


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