{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:43:35Z","timestamp":1791920615388,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yuan-Shan Branch of Taipei Veterans General Hospital","award":["YSVH111-01"],"award-info":[{"award-number":["YSVH111-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Geraniin (GRN), an ellagitannin from Phyllanthus urinaria, shows antioxidant, anti-inflammatory, and neuroprotective effects. This study evaluated GRN\u2019s potential against haloperidol (HPD)-induced orofacial dyskinesia (OD). Rats treated with HPD (1 mg\/kg i.p.) for 21 days exhibited dopamine D2 receptor blockade, neurotoxicity, and OD, characterized by vacuous chewing movements (VCM) and tongue protrusion (TP). Then, 60 min post-HPD, GRN was administered i.p. daily for 21 days. OD behaviors were assessed, and on Day 21, striatal tissues were analyzed for oxidative stress, mitochondrial function, inflammation, and apoptosis. GRN alone did not cause OD but significantly reduced HPD-induced VCM and TP. It also reduced oxidative stress, improved antioxidant defense, preserved mitochondrial function, and decreased neuroinflammation and apoptosis. These effects were blocked by ML385, a nuclear factor erythroid-2-related factor 2 (Nrf2) pathway inhibitor. GRN protects against HPD-induced OD, likely via Nrf2 activation. It may be a promising candidate for TD therapy, pending further clinical investigation.<\/jats:p>","DOI":"10.3390\/ijms26125458","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T11:08:31Z","timestamp":1749208111000},"page":"5458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Geraniin Ameliorates Haloperidol-Induced Orofacial Dyskinesia in Rats Through Mitigating Neuronal Oxidative Stress, Neuroinflammation, and Apoptosis via Modulation of the Nrf2 Signaling Pathway"],"prefix":"10.3390","volume":"26","author":[{"given":"Chih-Pei","family":"Hsu","sequence":"first","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, Hsinchu Branch of Mackay Memorial Hospital, Hsinchu City 30071, Taiwan"},{"name":"Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei 11260, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiang-Chien","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan"},{"name":"School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7797-6584","authenticated-orcid":false,"given":"Chih-Hsiang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Wen","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Sheng","family":"Soung","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yuan-Shan Branch of Taipei Veteran General Hospital, Yilan 26604, Taiwan"},{"name":"Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14335","DOI":"10.4088\/JCP.19r12798","article-title":"Pharmacologic Treatment of Tardive Dyskinesia: A Meta-Analysis and Systematic Review","volume":"81","author":"Artukoglu","year":"2020","journal-title":"J. Clin. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ncl.2020.01.004","article-title":"Treatment of Tardive Dyskinesia","volume":"38","author":"Bashir","year":"2020","journal-title":"Neurol. Clin."},{"key":"ref_3","unstructured":"Vasan, S., and Padhy, R.K. (2025). Tardive Dyskinesia. StatPearls, Ineligible Companies. Disclosure: Ranjit Padhy Declares No Relevant Financial Relationships with Ineligible Companies."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e68","DOI":"10.1002\/cpns.68","article-title":"Haloperidol-Induced Preclinical Tardive Dyskinesia Model in Rats","volume":"88","author":"Guzen","year":"2019","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.pbb.2008.08.021","article-title":"Co-administration of nitric oxide (NO) donors prevents haloperidol-induced orofacial dyskinesia, oxidative damage and change in striatal dopamine levels","volume":"91","author":"Bishnoi","year":"2009","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.4077\/CJP.2018.BAG529","article-title":"Protective Effect of L-Theanine on Haloperidol-Induced Orofacial","volume":"61","author":"Chen","year":"2018","journal-title":"Chin. J. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ejphar.2015.12.032","article-title":"Beneficial effects of lycopene against haloperidol induced orofacial dyskinesia in rats: Possible neurotransmitters and neuroinflammation modulation","volume":"771","author":"Datta","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1080\/1028415X.2017.1338549","article-title":"Protective effect of hesperetin against haloperidol-induced orofacial dyskinesia and catalepsy in rats","volume":"21","author":"Dhingra","year":"2018","journal-title":"Nutr. Neurosci."},{"key":"ref_9","first-page":"1070","article-title":"Crocin prevents haloperidol-induced orofacial dyskinesia: Possible an antioxidant mechanism","volume":"19","author":"Kamyar","year":"2016","journal-title":"Iran. J. Basic. Med. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.4103\/CJP.CJP_8_19","article-title":"Possible nitric oxide mechanism involved in the protective effect of L-theanine on haloperidol-induced orofacial dyskinesia","volume":"62","author":"Tsai","year":"2019","journal-title":"Chin. J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1007\/s11064-008-9660-6","article-title":"Protective effect of L-type calcium channel blockers against haloperidol-induced orofacial dyskinesia: A behavioural, biochemical and neurochemical study","volume":"33","author":"Bishnoi","year":"2008","journal-title":"Neurochem. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jep.2016.04.020","article-title":"Anti-inflammatory activity of aqueous leaf extract of Phyllanthus muellerianus (Kuntze) Exell. and its major constituent, geraniin","volume":"187","author":"Boakye","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.3109\/13880209.2014.1003356","article-title":"The physicochemical properties of geraniin, a potential antihyperglycemic agent","volume":"53","author":"Elendran","year":"2015","journal-title":"Pharm. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1016\/j.bmcl.2015.06.093","article-title":"Geraniin inhibits TGF-beta1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration, invasion and anoikis resistance","volume":"25","author":"Ko","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.cbi.2016.05.014","article-title":"Inhibitory effects of geraniin on LPS-induced inflammation via regulating NF-kappaB and Nrf2 pathways in RAW 264.7 cells","volume":"253","author":"Wang","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1089\/jmf.2019.4613","article-title":"Geraniin Protects PC12 Cells Against Abeta(25\u201335)-Mediated Neuronal Damage: Involvement of NF-kappaB and MAPK Signaling Pathways","volume":"23","author":"Youn","year":"2020","journal-title":"J. Med. Food"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"813","DOI":"10.3109\/10715762.2016.1173206","article-title":"Geraniin ameliorates cisplatin-induced nephrotoxicity in mice","volume":"50","author":"Jiang","year":"2016","journal-title":"Free Radic. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1016\/j.bbagen.2015.04.010","article-title":"Geraniin exerts cytoprotective effect against cellular oxidative stress by upregulation of Nrf2-mediated antioxidant enzyme expression via PI3K\/AKT and ERK1\/2 pathway","volume":"1850","author":"Wang","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10079","DOI":"10.1021\/acs.jafc.9b03977","article-title":"Geraniin Attenuates Lipopolysaccharide-Induced Cognitive Impairment in Mice by Inhibiting Toll-Like Receptor 4 Activation","volume":"67","author":"Wang","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2152746","DOI":"10.1155\/2022\/2152746","article-title":"Geraniin Protects against Cerebral Ischemia\/Reperfusion Injury by Suppressing Oxidative Stress and Neuronal Apoptosis via Regulation of the Nrf2\/HO-1 Pathway","volume":"2022","author":"Yang","year":"2022","journal-title":"Oxidative Med. Cell Longev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.ejphar.2008.06.033","article-title":"Activation of striatal inflammatory mediators and caspase-3 is central to haloperidol-induced orofacial dyskinesia","volume":"590","author":"Bishnoi","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.pbb.2005.05.002","article-title":"Ebselen attenuates haloperidol-induced orofacial dyskinesia and oxidative stress in rat brain","volume":"81","author":"Burger","year":"2005","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/978-1-61779-458-2_12","article-title":"An animal model to study the molecular basis of tardive dyskinesia","volume":"829","author":"Bishnoi","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.pnpbp.2012.10.018","article-title":"Oxidative stress and tardive dyskinesia: Pharmacogenetic evidence","volume":"46","author":"Cho","year":"2013","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.2174\/13895575113136660100","article-title":"Haloperidol cytotoxicity and its relation to oxidative stress","volume":"13","author":"Raudenska","year":"2013","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chen, S.-M., Wang, M.-H., Chang, K.-C., Fang, C.-H., Lin, Y.-W., and Tseng, H.-C. (2024). Vitexin Mitigates Haloperidol-Induced Orofacial Dyskinesia in Rats through Activation of the Nrf2 Pathway. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251810206"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1007\/s00210-019-01665-8","article-title":"In vitro effects of antipsychotics on mitochondrial respiration","volume":"392","author":"Cikankova","year":"2019","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.neuro.2021.10.007","article-title":"Resveratrol prevents haloperidol-induced mitochondria dysfunction through the induction of autophagy in SH-SY5Y cells","volume":"87","author":"Hu","year":"2021","journal-title":"Neurotoxicology"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tseng, H.C., Wang, M.H., Fang, C.H., Lin, Y.W., and Soung, H.S. (2023). Involvement of Antioxidant and Prevention of Mitochondrial Dysfunction, Anti-Neuroinflammatory Effect and Anti-Apoptotic Effect: Betaine Ameliorates Haloperidol-Induced Orofacial Dyskinesia in Rats. Brain Sci., 13.","DOI":"10.3390\/brainsci13071064"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1023\/A:1025682611389","article-title":"Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: Implications for the pathogenesis of neurodegenerative diseases","volume":"28","author":"Rego","year":"2003","journal-title":"Neurochem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1046\/j.1471-4159.2003.02211.x","article-title":"The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: Exemplified with toxic effects on cerebellar granule cells","volume":"88","author":"Fonnum","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1007\/s12640-021-00333-1","article-title":"Naringin Ameliorates Haloperidol-Induced Neurotoxicity and Orofacial Dyskinesia in a Rat Model of Human Tardive Dyskinesia","volume":"39","author":"Wang","year":"2021","journal-title":"Neurotox. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s12640-018-9897-z","article-title":"L-Theanine Decreases Orofacial Dyskinesia Induced by Reserpine in Rats","volume":"34","author":"Soung","year":"2018","journal-title":"Neurotox. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5156","DOI":"10.1007\/s12035-024-04566-x","article-title":"Molecular and Behavioral Neuroprotective Effects of Clavulanic Acid and Crocin in Haloperidol-Induced Tardive Dyskinesia in Rats","volume":"62","author":"Razavi","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yedke, N.G., Upadhayay, S., Singh, R., Jamwal, S., Ahmad, S.F., and Kumar, P. (2023). Bacillus Calmette-Guerin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats. Biomolecules, 13.","DOI":"10.3390\/biom13111667"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0021-9258(19)50881-X","article-title":"A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase","volume":"195","author":"Beers","year":"1952","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1007\/s11064-022-03829-0","article-title":"Vitexin Improves Cerebral ischemia-reperfusion Injury by Attenuating Oxidative Injury and Ferroptosis via Keap1\/Nrf2\/HO-1signaling","volume":"48","author":"Guo","year":"2023","journal-title":"Neurochem. Res."},{"key":"ref_38","first-page":"1045","article-title":"The brain in stereotaxic coordinates (a textbook for colleges)","volume":"43","author":"Kisliuk","year":"1993","journal-title":"Zhurnal Vyss. Nervn. Deiatelnosti Im. IP Pavlova"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1042\/bj0990667","article-title":"Mechanisms of lipid peroxide formation in animal tissues","volume":"99","author":"Wills","year":"1966","journal-title":"Biochem. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/0003-9861(59)90090-6","article-title":"Tissue sulfhydryl groups","volume":"82","author":"Ellman","year":"1959","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1016\/S0021-9258(19)45228-9","article-title":"The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase","volume":"247","author":"Misra","year":"1972","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/0003-2697(84)90098-8","article-title":"Isolation of mitochondria from ascites tumor cells permeabilized with digitonin","volume":"137","author":"Moreadith","year":"1984","journal-title":"Anal. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1042\/bj0800649","article-title":"Biochemistry of dystrophic muscle. Mitochondrial succinate-tetrazolium reductase and adenosine triphosphatase","volume":"80","author":"Pennington","year":"1961","journal-title":"Biochem. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1007\/s11064-012-0924-9","article-title":"Neuroprotective efficacy of eugenol and isoeugenol in acrylamide-induced neuropathy in rats: Behavioral and biochemical evidence","volume":"38","author":"Prasad","year":"2013","journal-title":"Neurochem. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"R505","DOI":"10.1152\/ajpregu.00208.2003","article-title":"Beneficial effects of moderate exercise on mice aging: Survival, behavior, oxidative stress, and mitochondrial electron transfer","volume":"286","author":"Navarro","year":"2004","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the Folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5458\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:47:57Z","timestamp":1760032077000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,6]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26125458"],"URL":"https:\/\/doi.org\/10.3390\/ijms26125458","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,6]]}}}