{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:17:28Z","timestamp":1787847448602,"version":"build-2784847793"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition. Although crocin has shown potential in reducing stress-related symptoms, its low bioavailability limits its effectiveness. Caffeine may enhance the bioavailability of various compounds by modulating liver enzymes. This study examined whether caffeine could improve crocin\u2019s efficacy in a rat model of PTSD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods:<\/jats:title>\n                    <jats:p>Male Wistar rats (8\u201310 weeks old) were divided into five groups: control, PTSD, crocin-treated, caffeine-treated, and crocin + caffeine-treated. PTSD was induced using repeated foot shocks, followed by 7 days of treatment. Behavioral assessments were performed using the elevated plus maze and shuttle box tests. Serum corticosterone levels were measured as a biochemical marker of anxiety, and histological evaluation of the hippocampus was conducted using Cresyl Violet and Golgi\u2013Cox staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The combination treatment significantly reduced serum corticosterone levels compared to either compound alone (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.01). Behavioral improvements\u2014including increased grooming, time spent in open arms, and reduced freezing latency\u2014were most pronounced in the crocin + caffeine group. Histological analysis also revealed reduced neuronal damage in this group.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>We concluded that a combination of crocin and caffeine could improve the efficacy of crocin given alone. These findings indicate that caffeine can help further enhance the neuroprotective efficacy of crocin in this model.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.4103\/abr.abr_464_25","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T11:00:17Z","timestamp":1780138817000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Investigating the Effect of Caffeine on the Effectiveness of Crocin in Improving Behavioral Symptoms and Brain Tissue Changes in the Hippocampus in the Post-Traumatic Stress Model in Rats"],"prefix":"10.4103","volume":"15","author":[{"given":"Mohammadmehdi","family":"Alfideh","sequence":"first","affiliation":[{"name":"Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gila","family":"Pirzad Jahromi","sequence":"additional","affiliation":[{"name":"Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gholam Reza","family":"Kaka","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Baqiyatallah University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Khodadadi","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, University of Lorestan, Lorestan, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Alimohamadi","sequence":"additional","affiliation":[{"name":"Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,3]]},"reference":[{"key":"R1-20260530","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nrdp.2015.57","article-title":"Post-traumatic stress disorder","volume":"1","author":"Yehuda","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"R2-20260530","first-page":"2","article-title":"Post-traumatic stress disorder","volume":"3","author":"Javidi","year":"2012","journal-title":"Int J Occup Environ Med"},{"key":"R3-20260530","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3325\/cmj.2010.51.209","article-title":"Patients with combat-related and war-related posttraumatic stress disorder 10 years after diagnosis","volume":"51","author":"Arbanas","year":"2010","journal-title":"Croat Med J"},{"key":"R4-20260530","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1080\/000486700271","article-title":"Prevalence and precipitants of aggression in psychiatric inpatient units","volume":"34","author":"Barlow","year":"2000","journal-title":"Aust N Z J Psychiatry"},{"key":"R5-20260530","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/s11920-018-0908-9","article-title":"Neurotransmitter, peptide, and steroid hormone abnormalities in PTSD: Biological endophenotypes relevant to treatment","volume":"20","author":"Rasmusson","year":"2018","journal-title":"Curr Psychiatry Rep"},{"key":"R6-20260530","first-page":"1003273","article-title":"Steroidogenesis of Corticosteroids, Genetic Mutation, and Endocrine Disruption Leading to Adrenal Insufficiency 2023","author":"Su","journal-title":"doi: 10.5772\/intechopen"},{"key":"R7-20260530","article-title":"The Hippocampus Book","author":"Morris","year":"2024","journal-title":"Oxford University Press"},{"key":"R8-20260530","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.jpsychires.2020.10.042","article-title":"The environment contributes more than genetics to smaller hippocampal volume in Posttraumatic Stress Disorder (PTSD)","volume":"137","author":"Bremner","year":"2021","journal-title":"J Psychiatr Res"},{"key":"R9-20260530","doi-asserted-by":"crossref","first-page":"909442","DOI":"10.3389\/fpsyt.2022.909442","article-title":"Impaired episodic memory in PTSD patients\u2014A meta-analysis of 47 studies","volume":"13","author":"Petzold","year":"2022","journal-title":"Front Psychiatry"},{"key":"R10-20260530","first-page":"281","article-title":"Crocin: An overview","volume":"1","author":"Singla","year":"2011","journal-title":"Indo Glob J Pharm Sci"},{"key":"R11-20260530","first-page":"879","article-title":"Crocin nano-chitosan-coated compound improves anxiety disorders, learning, and spatial memory in Alzheimer's model induced by beta-amyloid in rats","volume":"27","author":"Meftahi","year":"2024","journal-title":"Iran J Basic Med Sci"},{"key":"R12-20260530","doi-asserted-by":"crossref","DOI":"10.3390\/molecules27072076","article-title":"Anti-depressant properties of crocin molecules in saffron","volume":"27","author":"Siddiqui","year":"2022","journal-title":"Molecules"},{"key":"R14-20260530","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12944-018-0955-6","article-title":"Crocin ameliorates hepatic steatosis through activation of AMPK signaling in db\/db mice","volume":"18","author":"Luo","year":"2019","journal-title":"Lipids Health Dis"},{"key":"R15-20260530","doi-asserted-by":"crossref","first-page":"745683","DOI":"10.3389\/fphar.2021.745683","article-title":"Crocetin: A systematic review","volume":"12","author":"Guo","year":"2022","journal-title":"Front Pharmacol"},{"key":"R16-20260530","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.bbr.2010.01.037","article-title":"Dose-dependent effects of caffeine on behavior and thermoregulation in a chronic unpredictable stress model of depression in rats","volume":"209","author":"Pechlivanova","year":"2010","journal-title":"Behav. Brain Res"},{"key":"R17-20260530","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nutres.2020.05.005","article-title":"Caffeine effects on systemic metabolism, oxidative-inflammatory pathways, and exercise performance","volume":"80","author":"Barcelos","year":"2020","journal-title":"Nutr Res"},{"key":"R18-20260530","doi-asserted-by":"crossref","first-page":"110995","DOI":"10.1016\/j.biopha.2020.110995","article-title":"Association between chronic stress and Alzheimer's disease: Therapeutic effects of Saffron","volume":"133","author":"Saeedi","year":"2021","journal-title":"Biomed Pharmacother"},{"key":"R19-20260530","doi-asserted-by":"crossref","first-page":"e22278","DOI":"10.1002\/syn.22278","article-title":"Date palm spathe extract reverses chronic stress-induced changes in dendritic arborization in the amygdala and impairment of hippocampal long-term potentiation","volume":"77","author":"Hadipour","year":"2023","journal-title":"Synapse"},{"key":"R20-20260530","doi-asserted-by":"crossref","first-page":"730","DOI":"10.3390\/ph16050730","article-title":"Synergistic effects of caffeine in combination with conventional drugs: Perspectives of a drug that never ages","volume":"16","author":"Ialongo","year":"2023","journal-title":"Pharmaceuticals"},{"key":"R21-20260530","first-page":"370","article-title":"Deep brain stimulation in a rat model of post-traumatic stress disorder modifies forebrain neuronal activity and serum corticosterone","volume":"21","author":"Hashtjini","year":"2018","journal-title":"Iran J Basic Med Sci"},{"key":"R22-20260530","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.psyneuen.2012.02.007","article-title":"Psychosocial animal model of PTSD produces a long-lasting traumatic memory, an increase in general anxiety and PTSD-like glucocorticoid abnormalities","volume":"37","author":"Zoladz","year":"2012","journal-title":"Psychoneuroendocrinology"},{"key":"R23-20260530","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nprot.2007.44","article-title":"The use of the elevated plus maze as an assay of anxiety-related behavior in rodents","volume":"2","author":"Walf","year":"2007","journal-title":"Nat Protoc"},{"key":"R24-20260530","doi-asserted-by":"crossref","first-page":"87","DOI":"10.4103\/0976-500X.72350","article-title":"Blood sample collection in small laboratory animals","volume":"1","author":"Parasuraman","year":"2010","journal-title":"J Pharmacol Pharmacother"},{"key":"R25-20260530","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jneumeth.2004.04.029","article-title":"Infarct volume quantification in mouse focal cerebral ischemia: A comparison of triphenyltetrazolium chloride and cresyl violet staining techniques","volume":"139","author":"T\u00fcreyen","year":"2004","journal-title":"J Neurosci Methods"},{"key":"R26-20260530","doi-asserted-by":"crossref","first-page":"695","DOI":"10.5530\/ijper.53.4.133","article-title":"Neuroprotective and antiapoptotic effects of N-acetylcystein and Crocus sativus aqueous extract on arsenic-induced neurotoxicity in SH-SY5Y human dopaminergic neuroblastoma cells","volume":"53","author":"Jahromi","year":"2019","journal-title":"Indian J Pharm Educ Res"},{"key":"R27-20260530","doi-asserted-by":"crossref","first-page":"34","DOI":"10.30699\/jambs.26.119.34","article-title":"The effect of saffron aqueous extract and crocin on PTSD rat models: The focus on learning and spatial memory","volume":"26","author":"Asalgoo","year":"2018","journal-title":"J Adv Med Biomed Res"},{"key":"R28-20260530","doi-asserted-by":"crossref","first-page":"136912","DOI":"10.1016\/j.neulet.2022.136912","article-title":"Crocin, the main active saffron (Crocus sativus L.) constituent, as a potential candidate to prevent anxiety and depressive-like behaviors induced by unpredictable chronic mild stress","volume":"791","author":"Abbaszade-Cheragheali","year":"2022","journal-title":"Neurosci Lett"},{"key":"R29-20260530","doi-asserted-by":"crossref","first-page":"101099","DOI":"10.1016\/j.cofs.2023.101099","article-title":"Crocin-loaded nanocarriers;approaches and applications","volume":"54","author":"Tavasoli","year":"2023","journal-title":"Curr Opin Food Sci"},{"key":"R30-20260530","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/0006-2952(93)90526-3","article-title":"Interaction of caffeine with acetaminophen: 1. Correlation of the effect of caffeine on acetaminophen hepatotoxicity and acetaminophen bioactivation following treatment of mice with various cytochrome P450 inducing agents","volume":"46","author":"Jaw","year":"1993","journal-title":"Biochem Pharmacol"},{"key":"R31-20260530","doi-asserted-by":"crossref","first-page":"40","DOI":"10.2174\/18755453MTEyCOTgcx","article-title":"Metabolism and mechanism of human cytochrome P450 enzyme 1A2","volume":"22","author":"Guo","year":"2021","journal-title":"Curr Drug Metab"},{"key":"R32-20260530","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/tops.12537","article-title":"When fear shrinks the brain: A computational model of the effects of posttraumatic stress on hippocampal volume","volume":"13","author":"Smith","year":"2021","journal-title":"Top Cogn Sci"},{"key":"R33-20260530","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1152\/physrev.00041.2006","article-title":"Physiology and neurobiology of stress and adaptation: Central role of the brain","volume":"87","author":"McEwen","year":"2007","journal-title":"Physiol Rev"},{"key":"R34-20260530","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1196\/annals.1314.014","article-title":"An animal model of posttraumatic stress disorder: The use of cut-off behavioral criteria","author":"Cohen","year":"2004","journal-title":"Ann N Y Acad Sci"},{"key":"R35-20260530","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.neuroscience.2020.02.026","article-title":"Mechanisms of memory impairment induced by orexin-A via orexin 1 and orexin 2 receptors in post-traumatic stress disorder rats","volume":"432","author":"Han","year":"2020","journal-title":"Neuroscience"},{"key":"R36-20260530","doi-asserted-by":"crossref","first-page":"e39203","DOI":"10.1016\/j.heliyon.2024.e39203","article-title":"Protective effects of crocin nano-chitosan-coated compound on hippocampal cerebral blood-brain barrier, anxiety, memory, and learning in a chronic immobilization stress-induced rat model","volume":"10","author":"Khodadadi","year":"2024","journal-title":"Heliyon"},{"key":"R37-20260530","doi-asserted-by":"crossref","first-page":"5462","DOI":"10.3390\/molecules27175462","article-title":"Antidepressant effect of Crocin in mice with chronic mild stress","volume":"27","author":"Alsanie","year":"2022","journal-title":"Molecules"},{"key":"R38-20260530","doi-asserted-by":"crossref","first-page":"100346","DOI":"10.1016\/j.ynstr.2021.100346","article-title":"Variations in response to trauma and hippocampal subfield changes","volume":"15","author":"Postel","year":"2021","journal-title":"Neurobiol Stress"},{"key":"R39-20260530","doi-asserted-by":"crossref","first-page":"5804","DOI":"10.1007\/s12035-024-04638-y","article-title":"Crocin improves cognitive impairment in LPS-treated rats through anti-apoptotic, anti-inflammatory, and antioxidant activities","volume":"62","author":"Dastan","year":"2025","journal-title":"Mol Neurobiol"},{"key":"R40-20260530","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s11033-023-09197-4","article-title":"Interaction of aerobic exercise and crocin improves memory, learning and hypocampic tau and neurotrophins gene expression in rats treated with trimethytin as a model of Alzheimer's disease","volume":"51","author":"Moghadasi","year":"2024","journal-title":"Mol Biol Rep"},{"key":"R41-20260530","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1111\/1440-1681.13494","article-title":"Administering crocin ameliorates anxiety-like behaviours and reduces the inflammatory response in amyloid-beta induced neurotoxicity in rat","volume":"48","author":"Hadipour","year":"2021","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"R42-20260530","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/S0006-8993(02)04162-8","article-title":"Effects of chronic stress on dendritic arborization in the central and extended amygdala","volume":"965","author":"Vyas","year":"2003","journal-title":"Brain Res"},{"key":"R43-20260530","first-page":"43","article-title":"Anxiety and fear in PTSD\u2606. Emotion in posttraumatic stress disorder","author":"Zoellner","year":"2020","journal-title":"Elsevier"},{"key":"R44-20260530","doi-asserted-by":"crossref","first-page":"668","DOI":"10.3389\/fnins.2017.00668","article-title":"The psychoactive agent crocin can regulate hypothalamic-pituitary-adrenal axis activity","volume":"11","author":"Asalgoo","year":"2017","journal-title":"Front Neurosci"}],"container-title":["Advanced Biomedical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/abr.abr_464_25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:18:30Z","timestamp":1787843910000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/abr.abr_464_25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.4103\/abr.abr_464_25","relation":{},"ISSN":["2277-9175"],"issn-type":[{"value":"2277-9175","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2025-08-11","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-18","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}