{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:43:26Z","timestamp":1768509806389,"version":"3.49.0"},"posted":{"date-parts":[[2023,12,23]]},"group-title":"Neuroscience","reference-count":43,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes mechanical hypersensitivity in mice by inducing the integrated stress response (ISR), which is characterized by phosphorylation of eukaryotic initiation factor 2\u03b1 (p-eIF2\u03b1). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant proteins that neutralize MGO. We hypothesized that activating Nrf2 using diroximel fumarate (DRF) would alleviate MGO-induced pain hypersensitivity. We pretreated male and female C57BL\/6 mice daily with oral DRF prior to intraplantar injection of MGO (20 ng). DRF (100 mg\/kg) treated animals were protected from developing MGO-induced mechanical and cold hypersensitivity. Using\n                  <jats:italic>Nrf2<\/jats:italic>\n                  knockout mice we demonstrate that Nrf2 is necessary for the anti-nociceptive effects of DRF. In cultured mouse and human dorsal root ganglion (DRG) sensory neurons, we found that MGO induced elevated levels of p-eIF2\u03b1. Co-treatment of MGO (1 \u00b5M) with monomethyl fumarate (MMF, 10, 20, 50 \u00b5M), the active metabolite of DRF, reduced p-eIF2\u03b1 levels and prevented aberrant neurite outgrowth in human DRG neurons. Our data show that targeting the Nrf2 antioxidant system with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Perspective<\/jats:title>\n                  <jats:p>\n                    This study demonstrates that activating Nrf2 with DRF prevents the development of pain caused by MGO in mice and reduces ISR in mouse and human DRG\n                    <jats:italic>in vitro<\/jats:italic>\n                    models. We propose that Nrf2 activators like DRF should be tested to alleviate diabetic neuropathic pain associated with elevated MGO in patients.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"572877v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Article Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>MGO induces mechanical and cold hypersensitivity in mice that is prevented with pre-treatment with DRF.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>DRF pre-treatment does not protect Nrf2-knockout mice from developing pain hypersensitivity suggesting that Nrf2 is necessary for DRF\u2019s antinociceptive effects.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        MMF, the active metabolite of DRF, prevents MGO-induced increase in p-eIF2a levels in mouse and human DRG neurons\n                        <jats:italic>in vitro<\/jats:italic>\n                        .\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>MMF prevents MGO-induced aberrant neurite outgrowth in human DRG neurons.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Nrf2 activators, like the FDA-approved DRF, is an option to alleviate neuropathic pain in patients with diabetes.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2023.12.22.572877","type":"posted-content","created":{"date-parts":[[2023,12,23]],"date-time":"2023-12-23T21:25:16Z","timestamp":1703366716000},"source":"Crossref","is-referenced-by-count":0,"title":["Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decreases ISR activation in DRG neurons"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0829-8182","authenticated-orcid":false,"given":"Muhammad Saad","family":"Yousuf","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marisol","family":"Mancilla 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M","family":"Grace","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-6221","authenticated-orcid":false,"given":"Theodore J","family":"Price","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023122723250474000_2023.12.22.572877v1.1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ackd.2017.10.011"},{"key":"2023122723250474000_2023.12.22.572877v1.2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41572-019-0092-1","article-title":"Diabetic neuropathy","volume":"5","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"2023122723250474000_2023.12.22.572877v1.3","doi-asserted-by":"publisher","DOI":"10.4239\/wjd.v6.i3.432"},{"key":"2023122723250474000_2023.12.22.572877v1.4","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s13300-018-0550-x","article-title":"Pregabalin in the 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