{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T23:21:33Z","timestamp":1783120893796,"version":"3.54.6"},"reference-count":45,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Deanship of Scientific Research (DSR), at King Abduaziz University, Jeddah, Saudi Arabia","award":["G: 18-249-1441."],"award-info":[{"award-number":["G: 18-249-1441."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The risk of developing epilepsy is strongly linked to peripheral inflammatory disorders in humans. High-mobility group box protein 1 (HMGB1) has the most focus for being a suspect in this scenario. The current study aimed to detect the celecoxib effect, an anti-inflammatory drug, on decreasing seizure susceptibility and organ damage in lipopolysaccharides (LPS)\/pilocarpine (PILO) pretreated Wistar rats. Rats were divided into 6 groups (8 each): group 1 (control), group 2 (PILO), group 3 (PILO+LPS), group 4 (PILO+LPS+(VPA) Valproic acid), group 5 (PILO+LPS+Celecoxib), and group 6 (PILO+LPS+VPA+Celecoxib). LPS was used to induce sepsis and PILO to induce seizures. Oxidative stress markers, pro-inflammatory cytokines, and HMGB1 levels in serum and brain homogenate were evaluated. Histopathological studies were conducted on the hippocampus, liver, lung, and kidney. Treatment with celecoxib either alone or in combination with VPA significantly reduced Racine score and delays latency to generalized tonic-clonic seizures onset with a significant decrease in hippocampal levels of pro-inflammatory cytokines, oxidative stress markers, and increase in reduced glutathione. In addition, celecoxib treatment either alone or in combination with VPA suppressed HMGB1translocation into peripheral circulation more than treatment with VPA alone. Furthermore, hippocampus, liver, lung, and kidney histopathological changes were improved in contrast to other epileptic groups. Celecoxib either alone or combined with VPA has antiepileptic and multiorgan protective effects on acute seizures and inflammatory models induced by PILO with LPS. It decreased histopathological findings, oxidative, and inflammatory effects induced by VPA and LPS. This might be due to its anti-oxidative, anti-inflammatory and anti-HMGB1 mediated effects.<\/jats:p>","DOI":"10.3390\/ph14040380","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T11:21:38Z","timestamp":1618831298000},"page":"380","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Celecoxib Decrease Seizures Susceptibility in a Rat Model of Inflammation by Inhibiting HMGB1 Translocation"],"prefix":"10.3390","volume":"14","author":[{"given":"Hadeel","family":"Alsaegh","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-8834","authenticated-orcid":false,"given":"Hala","family":"Eweis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemah","family":"Kamel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0978-5775","authenticated-orcid":false,"given":"Aziza","family":"Alrafiah","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Andres-Mach, M., Zagaja, M., Haratym-Maj, A., Rola, R., Maj, M., Haratym, J., Dudra-Jastrz\u0119bska, M., and \u0141uszczki, J.J. (2017). A long-term treatment with arachidonyl-2\u2032-chloroethylamide combined with valproate increases neurogenesis in a mouse pilocarpine model of Epilepsy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18050900"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/epi.13786","article-title":"Neurobehavioral comorbidities of epilepsy: Role of inflammation","volume":"58","author":"Mazarati","year":"2017","journal-title":"Epilepsia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s12974-018-1192-7","article-title":"The role of inflammation in the development of epilepsy","volume":"15","author":"Rana","year":"2018","journal-title":"J. Neuronflamm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"628","DOI":"10.3389\/fnins.2018.00628","article-title":"HMGB1: A common biomarker and potential target for TBI, neuroinflammation, epilepsy, and cognitive dysfunction","volume":"12","author":"Paudel","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/epi.13783","article-title":"Neuroinflammatory targets and treatments for epilepsy validated in experimental models","volume":"58","author":"Aronica","year":"2017","journal-title":"Epilepsia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.pbb.2018.05.007","article-title":"Immunomodulatory effect of Celecoxib on HMGB1\/TLR4 pathway in a recurrent seizures model in immature rats","volume":"170","year":"2018","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"219","DOI":"10.5603\/FHC.2011.0030","article-title":"Investigations of hippocampal astrocytes in lipopolysaccharide-preconditioned rats in the pilocarpine model of epilepsy","volume":"49","author":"Dmowska","year":"2011","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12929-015-0157-8","article-title":"Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus","volume":"22","author":"Ho","year":"2015","journal-title":"J. Biomed. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1111\/jnc.12784","article-title":"The anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1\u03b2 and TNF-\u03b1 expression in rat hippocampus","volume":"130","author":"Buijs","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_10","first-page":"319","article-title":"The effects of antiepileptic drug valproic acid on apoptosis of hippocampal neurons in epileptic rats","volume":"28","author":"Luo","year":"2015","journal-title":"Pak. J. Pharm. Sci."},{"key":"ref_11","first-page":"272","article-title":"Anticonvulsant effect of celecoxib in mice induced by PTZ","volume":"11","author":"Mirhadi","year":"2012","journal-title":"Middle East J. Sci. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-019-1592-3","article-title":"Cyclooxygenase-2 (COX-2) inhibitors: Future therapeutic strategies for epilepsy management","volume":"16","author":"Rawat","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"M\u00e9ndez-Armenta, M., Nava-Ru\u00edz, C., Ju\u00e1rez-Rebollar, D., Rodr\u00edguez-Mart\u00ednez, E., and Yescas G\u00f3mez, P. (2014). Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy. Oxidative Med. Cell. Longev., 2014.","DOI":"10.1155\/2014\/293689"},{"key":"ref_14","first-page":"2483","article-title":"Mitochondrial damage in hippocampal neurons of rats with epileptic protein expression of Fas and caspase-3","volume":"16","author":"Feng","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.pathophys.2011.04.002","article-title":"Efficacy of fish liver oil and propolis as neuroprotective agents in pilocarpine epileptic rats treated with valproate","volume":"18","author":"Mannaa","year":"2011","journal-title":"Pathophysiology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.3109\/13880209.2015.1010738","article-title":"Rosmarinic acid exerts a neuroprotective effect in the kainate rat model of temporal lobe epilepsy: Underlying mechanisms","volume":"53","author":"Khamse","year":"2015","journal-title":"Pharm. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.yebeh.2014.12.032","article-title":"Anticonvulsant activity of the cyclooxygenase-2 (COX-2) inhibitor etoricoxib in pentylenetetrazole-kindled rats is associated with memory impairment","volume":"44","author":"Katyal","year":"2015","journal-title":"Epilepsy Behav."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1007\/s11064-017-2347-0","article-title":"Anticonvulsant effect of Swertiamarin against Pilocarpine-induced seizures in adult male mice","volume":"42","author":"Deng","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/neu.2016.47","article-title":"Inflammatory aspects of epileptogenesis: Contribution of molecular inflammatory mechanisms","volume":"29","author":"Alyu","year":"2017","journal-title":"Acta Neuropsychiatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.vetimm.2015.06.012","article-title":"Valproic acid attenuates the expression of pro-inflammatory cytokines lipopolysaccharide-treated canine peripheral blood mononuclear cells (in vitro) and in a canine endotoxemia model (in vivo)","volume":"166","author":"Song","year":"2015","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbr.2014.03.029","article-title":"Valproic acid effects in the hippocampus and prefrontal cortex in an animal model of post-traumatic stress disorder","volume":"268","author":"Wilson","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lim, J.-A., Jung, K.-Y., Park, B., Kim, T.-J., Jun, J.-S., Kim, K.T., Yang, T.-W., Lee, S.-T., Jung, K.-H., and Chu, K. (2019). Impact of a selective cyclooxygenase-2 inhibitor, celecoxib, on cortical excitability and electrophysiological properties of the brain in healthy volunteers: A randomized, double-blind, placebo-controlled study. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212689"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ejphar.2017.05.013","article-title":"Cyclooxygenase-2 inhibitors differentially attenuate pentylenetetrazol-induced seizures and increase of pro-and anti-inflammatory cytokine levels in the cerebral cortex and hippocampus of mice","volume":"810","author":"Temp","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.neuroscience.2013.02.041","article-title":"Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats","volume":"240","author":"Fan","year":"2013","journal-title":"Neuroscience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.neuro.2018.07.006","article-title":"Molecular mechanisms of neuroprotective effect of adjuvant therapy with phenytoin in pentylenetetrazole-induced seizures: Impact on Sirt1\/NRF2 signaling pathways","volume":"68","author":"Nagib","year":"2018","journal-title":"Neurotoxicology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.3109\/13880209.2013.803128","article-title":"Antiepileptogenic effect of curcumin on kainate-induced model of temporal lobe epilepsy","volume":"51","author":"Kiasalari","year":"2013","journal-title":"Pharm. Biol."},{"key":"ref_27","first-page":"1","article-title":"Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice","volume":"7","author":"Fu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1111\/j.1365-2796.2011.02431.x","article-title":"Interleukin-1 type 1 receptor\/Toll-like receptor signalling in epilepsy: The importance of IL-1beta and high-mobility group box 1","volume":"270","author":"Maroso","year":"2011","journal-title":"J. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tousson, E., Keshta, A.T., Hussein, Y., Fekry, R.M., and Abo-Ghaneima, W.K. (2019). Renal protective effect of ginkgo biloba and l-carnitine extracts against pentylenetetrazol induced toxicity, oxidative stress, injury and proliferation alternation in epileptic rats. Annu. Res. Rev. Biol., 1\u201313.","DOI":"10.9734\/arrb\/2019\/v32i230076"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1165\/rcmb.2013-0087OC","article-title":"The NLRP3 inflammasome is required for the development of hypoxemia in LPS\/mechanical ventilation acute lung injury","volume":"50","author":"Jones","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e00130","DOI":"10.1016\/j.heliyon.2016.e00130","article-title":"Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: Role of inflammation and apoptosis","volume":"2","author":"Katary","year":"2016","journal-title":"Heliyon"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.pediatrneurol.2017.09.013","article-title":"Antiepileptic drugs and liver disease","volume":"77","author":"Vidaurre","year":"2017","journal-title":"Pediatric Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e135","DOI":"10.4172\/2161-1025.1000e135","article-title":"PCSK9 Inhibition in Acute Myocardial Infarction: A Novel Opportunity","volume":"6","author":"Trankle","year":"2016","journal-title":"Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"White, L.E., and Hassoun, H.T. (2012). Inflammatory mechanisms of organ crosstalk during ischemic acute kidney injury. Int. J. Nephrol., 2012.","DOI":"10.4061\/2012\/505197"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"130","DOI":"10.5935\/0103-507X.20130024","article-title":"Acute kidney injury in critically ill patients with lung disease: Kidney-lung crosstalk","volume":"25","author":"Muniz","year":"2013","journal-title":"Rev. Bras. Ter. Intensiva"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"145","DOI":"10.4046\/trd.2014.77.3.145","article-title":"A case of drug-induced interstitial pneumonitis caused by valproic acid for the treatment of seizure disorders","volume":"77","author":"Kim","year":"2014","journal-title":"Tuberc. Respir. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.intimp.2012.07.020","article-title":"Role of M3 mAChR in in vivo and in vitro models of LPS-induced inflammatory response","volume":"14","author":"Xu","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Costalonga, E.C., Silva, F.M., and Noronha, I.L. (2016). Valproic acid prevents renal dysfunction and inflammation in the ischemia-reperfusion injury model. BioMed Res. Int., 2016.","DOI":"10.1155\/2016\/5985903"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2146\/ajhp110049","article-title":"Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy","volume":"69","author":"Mock","year":"2012","journal-title":"Am. J. Health Syst. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"228","DOI":"10.3389\/fped.2019.00228","article-title":"Celecoxib protects hyperoxia-induced lung injury via NF-\u03baB and AQP1","volume":"7","author":"Wang","year":"2019","journal-title":"Front. Pediatrics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"L184","DOI":"10.1152\/ajplung.00303.2009","article-title":"Anti-inflammatory effects of celecoxib in rat lungs with smoke-induced emphysema","volume":"299","author":"Roh","year":"2010","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.hepres.2005.11.003","article-title":"The effect of celecoxib, a selective COX-2 inhibitor, on liver ischemia\/reperfusion-induced oxidative stress in rats","volume":"34","author":"Ozturk","year":"2006","journal-title":"Hepatol. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.eplepsyres.2017.05.012","article-title":"Increase in seizure susceptibility in sepsis like condition explained by spiking cytokines and altered adhesion molecules level with impaired blood brain barrier integrity in experimental model of rats treated with lipopolysaccharides","volume":"135","author":"Sewal","year":"2017","journal-title":"Epilepsy Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.brainres.2016.07.046","article-title":"The effect of some immunomodulatory and anti-inflammatory drugs on Li-pilocarpine-induced epileptic disorders in Wistar rats","volume":"1648","author":"Borham","year":"2016","journal-title":"Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0013-4694(72)90177-0","article-title":"Modification of seizure activity by electrical stimulation: II. Motor seizure","volume":"32","author":"Racine","year":"1972","journal-title":"Electroencephalogr. Clin. Neurophysiol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/4\/380\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:49:45Z","timestamp":1760161785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/4\/380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,19]]},"references-count":45,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ph14040380"],"URL":"https:\/\/doi.org\/10.3390\/ph14040380","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,19]]}}}