{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T02:26:19Z","timestamp":1777515979222,"version":"3.51.4"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005191","name":"Craig H. Neilsen Foundation","doi-asserted-by":"publisher","award":["383428"],"award-info":[{"award-number":["383428"]}],"id":[{"id":"10.13039\/100005191","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA208765"],"award-info":[{"award-number":["CA208765"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-14-1-0593"],"award-info":[{"award-number":["W81XWH-14-1-0593"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Traumatic spinal cord injury (SCI) results in immediate tissue necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progressive hemorrhagic necrosis (PHN) and excessive excitation are the main sources of secondary neural injury. Recent approaches to attenuate PHN by glibenclamide can improve locomotor function after SCI. However, use of glibenclamide can exacerbate development of SCI-induced chronic pain by inhibiting K<jats:sub>ATP<\/jats:sub> channels to increase neuronal excitation and glial activation. In this study, we explored a treatment strategy involving administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals following spinal cord contusion. Our goal was to determine whether this combined approach enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult rats. We found that K<jats:sub>ATP<\/jats:sub> channels opener, diazoxide, decreased the hyperexcitability of primary sensory neurons after SCI by electrophysiology. Timed application of glibenclamide and diazoxide following contusion significantly improved locomotor function and mitigated development of SCI-induced chronic pain, as shown by behavioral evidence. Finally, we found that timed application of glibenclamide and diazoxide attenuates the inflammatory activity in the spinal cord and increases the survival of spinal matters following SCI. These preclinical studies introduce a promising potential treatment strategy to address SCI-induced dysfunction.<\/jats:p>","DOI":"10.3389\/fphar.2024.1440198","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T04:45:14Z","timestamp":1722487514000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Timed sulfonylurea modulation improves locomotor and sensory dysfunction following spinal cord injury"],"prefix":"10.3389","volume":"15","author":[{"given":"Guo-Ying","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manjit","family":"Maskey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zizhen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1089\/neu.1996.13.343","article-title":"MASCIS evaluation of open field locomotor scores: effects of experience and teamwork on reliability. Multicenter Animal Spinal Cord Injury Study","volume":"13","author":"Basso","year":"1996","journal-title":"J. Neurotrauma"},{"key":"B2","doi-asserted-by":"publisher","first-page":"14870","DOI":"10.1523\/JNEUROSCI.2428-10.2010","article-title":"Chronic spontaneous activity generated in the somata of primary nociceptors is associated with pain-related behavior after spinal cord injury","volume":"30","author":"Bedi","year":"2010","journal-title":"J. Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.pain.2009.09.030","article-title":"Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury","volume":"147","author":"Carlton","year":"2009","journal-title":"Pain"},{"key":"B4","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw","volume":"53","author":"Chaplan","year":"1994","journal-title":"J. Neurosci. Methods"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2296","DOI":"10.1161\/01.str.28.11.2296","article-title":"Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice","volume":"28","author":"Choudhri","year":"1997","journal-title":"Stroke"},{"key":"B6","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1111\/j.1365-2125.1990.tb03688.x","article-title":"Pharmacokinetic and pharmacodynamic studies of glibenclamide in non-insulin dependent diabetes mellitus","volume":"29","author":"Coppack","year":"1990","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1115726","DOI":"10.3389\/fneur.2023.1115726","article-title":"Research progress of endogenous hematoma absorption after intracerebral hemorrhage","volume":"14","author":"Fu","year":"2023","journal-title":"Front. Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nm.1899","article-title":"De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury","volume":"15","author":"Gerzanich","year":"2009","journal-title":"Nat. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"815347","DOI":"10.3389\/fnagi.2022.815347","article-title":"Microglia polarization from M1 to M2 in neurodegenerative diseases","volume":"14","author":"Guo","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"4308","DOI":"10.1523\/JNEUROSCI.0003-06.2006","article-title":"Activated microglia contribute to the maintenance of chronic pain after spinal cord injury","volume":"26","author":"Hains","year":"2006","journal-title":"J. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41392-023-01477-6","article-title":"Spinal cord injury: molecular mechanisms and therapeutic interventions","volume":"8","author":"Hu","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"B12","doi-asserted-by":"publisher","first-page":"18543","DOI":"10.1523\/JNEUROSCI.4306-11.2011","article-title":"Conduction failure following spinal cord injury: functional and anatomical changes from acute to chronic stages","volume":"31","author":"James","year":"2011","journal-title":"J. Neurosci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.3892\/mmr.2020.11003","article-title":"Modulators of microglia activation and polarization in ischemic stroke (review)","volume":"21","author":"Jiang","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"81","DOI":"10.3390\/ph15010081","article-title":"Pharmacological modulation and (Patho)Physiological roles of TRPM4 channel-part 1: modulation of TRPM4","volume":"15","author":"Kov\u00e1cs","year":"2022","journal-title":"Pharm. (Basel)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1089\/089771503770195867","article-title":"Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat","volume":"20","author":"Lee","year":"2003","journal-title":"J. Neurotrauma"},{"key":"B18","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/j.atherosclerosis.2012.11.016","article-title":"Up-regulated ATP-sensitive potassium channels play a role in increased inflammation and plaque vulnerability in macrophages","volume":"226","author":"Ling","year":"2013","journal-title":"Atherosclerosis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.neuroscience.2016.07.032","article-title":"Diazoxide enhances excitotoxicity-induced neurogenesis and attenuates neurodegeneration in the rat non-neurogenic hippocampus","volume":"333","author":"Martinez-Moreno","year":"2016","journal-title":"Neuroscience"},{"key":"B20","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/0006-8993(89)90542-8","article-title":"Distribution and time course of protein extravasation in the rat spinal cord after contusive injury","volume":"482","author":"Noble","year":"1989","journal-title":"Brain Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.expneurol.2010.11.016","article-title":"Independent evaluation of the effects of glibenclamide on reducing progressive hemorrhagic necrosis after cervical spinal cord injury","volume":"233","author":"Popovich","year":"2012","journal-title":"Exp. Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1089\/089771501300227314","article-title":"Cyclosporin A treatment following spinal cord injury to the rat: behavioral effects and stereological assessment of tissue sparing","volume":"18","author":"Rabchevsky","year":"2001","journal-title":"J. Neurotrauma"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3786","DOI":"10.1111\/ejn.12382","article-title":"Phagocytic microglial phenotype induced by glibenclamide improves functional recovery but worsens hyperalgesia after spinal cord injury in adult rats","volume":"38","author":"Redondo-Castro","year":"2013","journal-title":"Eur. J. Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"194546","DOI":"10.1155\/2013\/194546","article-title":"Targeting microglial K(ATP) channels to treat neurodegenerative diseases: a mitochondrial issue","volume":"2013","author":"Rodriguez","year":"2013","journal-title":"Oxid. Med. Cell Longev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.2353\/ajpath.2006.050569","article-title":"The mitochondrial K-ATP channel opener, diazoxide, prevents ischemia-reperfusion injury in the rabbit spinal cord","volume":"168","author":"Roseborough","year":"2006","journal-title":"Am. J. Pathol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1089\/08977150360547099","article-title":"Experimental modeling of spinal cord injury: characterization of a force-defined injury device","volume":"20","author":"Scheff","year":"2003","journal-title":"J. Neurotrauma."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3689","DOI":"10.4049\/jimmunol.1102969","article-title":"The TRPM4 channel controls monocyte and macrophage, but not neutrophil, function for survival in sepsis","volume":"189","author":"Serafini","year":"2012","journal-title":"J. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2105","DOI":"10.1172\/JCI32041","article-title":"Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury","volume":"117","author":"Simard","year":"2007","journal-title":"J. Clin. Invest."},{"key":"B29","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.expneurol.2011.11.044","article-title":"Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury","volume":"233","author":"Simard","year":"2012","journal-title":"Exp. Neurol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"28ra29","DOI":"10.1126\/scitranslmed.3000522","article-title":"Brief suppression of Abcc8 prevents autodestruction of spinal cord after trauma","volume":"2","author":"Simard","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1007\/s00125-006-0307-3","article-title":"Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular K(ATP) channels","volume":"49","author":"Stephan","year":"2006","journal-title":"Diabetologia"},{"key":"B32","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1682\/JRRD.2008.03.0048","article-title":"Early microglial inhibition preemptively mitigates chronic pain development after experimental spinal cord injury","volume":"46","author":"Tan","year":"2009","journal-title":"J. Rehabil. Res. Dev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"ENEURO.0450","DOI":"10.1523\/ENEURO.0450-17.2018","article-title":"Optogenetic activation of non-nociceptive A\u03b2 fibers induces neuropathic pain-like sensory and emotional behaviors after nerve injury in rats","volume":"5","author":"Tashima","year":"2018","journal-title":"eNeuro"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2580","DOI":"10.1523\/JNEUROSCI.21-08-02580.2001","article-title":"Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia","volume":"21","author":"Tikka","year":"2001","journal-title":"J. Neurosci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e75189","DOI":"10.1371\/journal.pone.0075189","article-title":"K(ATP) channel opener diazoxide prevents neurodegeneration: a new mechanism of action via antioxidative pathway activation","volume":"8","author":"Virgili","year":"2013","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3655","DOI":"10.1074\/jbc.M112.428219","article-title":"The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel","volume":"288","author":"Woo","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1016\/j.pain.2011.08.003","article-title":"Reopening of ATP-sensitive potassium channels reduces neuropathic pain and regulates astroglial gap junctions in the rat spinal cord","volume":"152","author":"Wu","year":"2011","journal-title":"Pain"},{"key":"B38","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1124\/jpet.119.264010","article-title":"Enhancing KCNQ channel activity improves neurobehavioral recovery after spinal cord injury","volume":"373","author":"Wu","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B39","doi-asserted-by":"crossref","first-page":"14870","DOI":"10.1523\/JNEUROSCI.2428-10.2010","article-title":"Chronic spontaneous activity generated in the somata of presumptive nociceptors is associated with allodynia and hyperalgesia following spinal cord injury","volume":"30","author":"Yang","year":"2010","journal-title":"Soc. Neurosci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"10765","DOI":"10.1523\/JNEUROSCI.5316-13.2014","article-title":"Persistent pain after spinal cord injury is maintained by primary afferent activity","volume":"34","author":"Yang","year":"2014","journal-title":"J. Neurosci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/s0079-6123(02)37019-5","article-title":"Spinal cord contusion models","volume":"137","author":"Young","year":"2002","journal-title":"Prog. Brain Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2401","DOI":"10.2147\/NDT.S169940","article-title":"The microglial activation profile and associated factors after experimental spinal cord injury in rats","volume":"14","author":"Zhou","year":"2018","journal-title":"Neuropsychiatr. Dis. Treat."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1440198\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T04:45:19Z","timestamp":1722487519000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1440198\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,1]]},"references-count":40,"alternative-id":["10.3389\/fphar.2024.1440198"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1440198","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,1]]},"article-number":"1440198"}}