{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T14:18:19Z","timestamp":1777126699400,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,27]],"date-time":"2025-07-27T00:00:00Z","timestamp":1753574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005716","name":"Babol University of Medical Sciences","doi-asserted-by":"publisher","award":["724132146"],"award-info":[{"award-number":["724132146"]}],"id":[{"id":"10.13039\/501100005716","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: The hippocampus is an essential part of the central nervous system (CNS); it plays a significant role in social\u2013cognitive memory processing. Prenatal exposure to valproic acid (VPA) can lead to impaired hippocampal functions. In this study, we evaluated the effect of plumbagin (PLB) as a natural product on spatial learning and memory, neuro-morphological changes, and inflammation levels in a VPA-induced autism model during adolescence. Methods: Pregnant Wistar rats received a single intraperitoneal (i.p.) injection of VPA (600 mg\/kg) or saline on gestational day 12.5. The male offspring were then categorized and assigned to five groups: Saline+DMSO-, VPA+DMSO-, and VPA+PLB-treated groups at doses of 0.25, 0.5, or 1 mg\/kg. Spatial learning and memory were evaluated using the Morris water maze. Histopathological evaluations of the hippocampus were performed using Nissl and hematoxylin\u2013eosin staining, as well as immunofluorescence. The pro-inflammatory cytokine levels were also quantified by quantitative real-time PCR. Results: The findings revealed that a VPA injection on gestational day 12.5 is associated with cognitive impairments in male pups, including a longer escape latency and traveled distance, as well as decreased time spent in the target quadrant. Treatment with PLB significantly enhanced the cognitive function, reduced dark cells, and ameliorated neuronal\u2013morphological alterations in the hippocampus of VPA-exposed rats. Moreover, PLB was found to reduce astrocyte activation and the expression levels of pro-inflammatory cytokines. Conclusions: These findings suggest that PLB partly mitigates VPA-induced cognitive deficits by ameliorating hippocampal inflammation levels.<\/jats:p>","DOI":"10.3390\/brainsci15080798","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T10:51:14Z","timestamp":1753699874000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Plumbagin Improves Cognitive Function via Attenuating Hippocampal Inflammation in Valproic Acid-Induced Autism Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1828-3809","authenticated-orcid":false,"given":"Nasrin","family":"Nosratiyan","sequence":"first","affiliation":[{"name":"Student Research Committee, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"},{"name":"Department of Anatomy, Embryology and Histology, Faculty of Medicine, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5014-5166","authenticated-orcid":false,"given":"Maryam","family":"Ghasemi-Kasman","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"},{"name":"Department of Physiology, School of Medicine, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohsen","family":"Pourghasem","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Histology, Faculty of Medicine, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"},{"name":"Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farideh","family":"Feizi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Histology, Faculty of Medicine, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"},{"name":"Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farzin","family":"Sadeghi","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"},{"name":"Department of Medical Virology and Biotechnology, Faculty of Medicine, Babol University of Medical Sciences, Babol P.O. Box 4136747176, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association Autism Spectrum Disorder (2013). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Publishing. [5th ed.]. (DSM-5).","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.tins.2021.08.005","article-title":"Hippocampal contributions to social and cognitive deficits in autism spectrum disorder","volume":"44","author":"Banker","year":"2021","journal-title":"Trends Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Siniscalco, D., Schultz, S., Brigida, A.L., and Antonucci, N. (2018). Inflammation and Neuro-Immune Dysregulations in Autism Spectrum Disorders. Pharmaceuticals, 11.","DOI":"10.3390\/ph11020056"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1159\/000492225","article-title":"Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy","volume":"25","author":"Marchezan","year":"2018","journal-title":"Neuroimmunomodulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.pediatrneurol.2007.01.012","article-title":"Elevation of Tumor Necrosis Factor-Alpha in Cerebrospinal Fluid of Autistic Children","volume":"36","author":"Chez","year":"2007","journal-title":"Pediatr. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kuo, H.-Y., and Liu, F.-C. (2018). Molecular Pathology and Pharmacological Treatment of Autism Spectrum Disorder-Like Phenotypes Using Rodent Models. Front. Cell. Neurosci., 12.","DOI":"10.3389\/fncel.2018.00422"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"703675","DOI":"10.6064\/2012\/703675","article-title":"The Neuropathology of Autism","volume":"2012","author":"Blatt","year":"2012","journal-title":"Scientifica"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Shnayder, N.A., Grechkina, V.V., Khasanova, A.K., Bochanova, E.N., Dontceva, E.A., Petrova, M.M., Asadullin, A.R., Shipulin, G.A., Altynbekov, K.S., and Al-Zamil, M. (2023). Therapeutic and Toxic Effects of Valproic Acid Metabolites. Metabolites, 13.","DOI":"10.3390\/metabo13010134"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107477","DOI":"10.1016\/j.neuropharm.2018.12.024","article-title":"Prenatal valproate in rodents as a tool to understand the neural underpinnings of social dysfunctions in autism spectrum disorder","volume":"159","author":"Tartaglione","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_10","first-page":"8863256","article-title":"A Need for Consistency in Behavioral Phenotyping for ASD: Analysis of the Valproic Acid Model","volume":"2021","author":"Larner","year":"2021","journal-title":"Autism Res. Treat."},{"key":"ref_11","first-page":"114","article-title":"Naphthoquinones and their pharmacological properties","volume":"56","author":"Babula","year":"2007","journal-title":"Ceska Slov. Farm."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Petrocelli, G., Marrazzo, P., Bonsi, L., Facchin, F., Alviano, F., and Canaider, S. (2023). Plumbagin, a Natural Compound with Several Biological Effects and Anti-Inflammatory Properties. Life, 13.","DOI":"10.3390\/life13061303"},{"key":"ref_13","first-page":"250","article-title":"Plumbago zeylinica Linn. (Chitrak)-Review as Rasayan (Rejuvenator\/Antiaging)","volume":"3","author":"Datta","year":"2012","journal-title":"Int. J. Res. Pharm. Biomed. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Cores, \u00c1., Carmona-Zafra, N., Clerigu\u00e9, J., Villacampa, M., and Men\u00e9ndez, J.C. (2023). Quinones as Neuroprotective Agents. Antioxidants, 12.","DOI":"10.3390\/antiox12071464"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1837278","DOI":"10.1155\/2022\/1837278","article-title":"Inhibition of the TLR\/NF-\u03baB Signaling Pathway and Improvement of Autophagy Mediates Neuroprotective Effects of Plumbagin in Parkinson\u2019s Disease","volume":"2022","author":"Su","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.biopha.2018.02.052","article-title":"Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer\u2019s disease via activation of Nrf2\/ARE pathway and inhibition of \u03b2-secretase","volume":"101","author":"Nakhate","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"497","DOI":"10.22159\/ajpcr.2018.v11i7.27028","article-title":"Bioactivity-guided isolation of memory-enhancing compound from chloroform extract of roots of Plumbago zeylanica Linn","volume":"11","author":"Uplanchiwar","year":"2018","journal-title":"Asian J. Pharm. Clin. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kumar Arora, M., Ratra, A., Asdaq, S.M.B., Alshamrani, A.A., Alsalman, A.J., Kamal, M., Tomar, R., Sahoo, J., Ashok, J., and Imran, M. (2022). Plumbagin Alleviates Intracerebroventricular-Quinolinic Acid Induced Depression-like Behavior and Memory Deficits in Wistar Rats. Molecules, 27.","DOI":"10.3390\/molecules27061834"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100060","DOI":"10.1016\/j.crbeha.2021.100060","article-title":"Neuroprotective and acetylcholinesterase inhibitory activity of plumbagin in ICV-LPS induced behavioral deficits in rats","volume":"2","author":"Jangra","year":"2021","journal-title":"Curr. Res. Behav. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1007\/s11064-025-04425-8","article-title":"Plumbagin Alleviates Social Behavior Deficits in a Valproic Acid Model of Autism by Reducing Glial Activation and Oxidative Stress in the Cerebellum","volume":"50","author":"Nosratiyan","year":"2025","journal-title":"Neurochem. Res."},{"key":"ref_21","first-page":"13","article-title":"Determination of the estrous cycle phases of rats: Some helpful considerations","volume":"62","author":"Lange","year":"2015","journal-title":"3rd BIOACIDII Meet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.brainresbull.2021.08.006","article-title":"Acute administration of sulfur-doped g-C3N4 induces cognitive deficits and exacerbates the levels of glial activation in mouse hippocampus","volume":"176","author":"Ramezani","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.ijbiomac.2017.09.073","article-title":"Piperine-loaded chitosan-STPP nanoparticles reduce neuronal loss and astrocytes activation in chemical kindling model of epilepsy","volume":"107","author":"Anissian","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_24","first-page":"404","article-title":"Oxidative Stress, GFAP and NFT Activities in Prefrontal Cortex of Rats Treated with Musangacecropioides (Urticaceae) Stem-Bark Extract in Sodium Valproate toxicity","volume":"7","author":"Nwidu","year":"2019","journal-title":"EC Pharmacol. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1159\/000375489","article-title":"Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism","volume":"37","author":"Codagnone","year":"2015","journal-title":"Dev. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.pnpbp.2017.07.025","article-title":"Curcumin-loaded chitosan-alginate-STPP nanoparticles ameliorate memory deficits and reduce glial activation in pentylenetetrazol-induced kindling model of epilepsy","volume":"79","author":"Hashemian","year":"2017","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14515","DOI":"10.1073\/pnas.0406344101","article-title":"Spatial memory, recognition memory, and the hippocampus","volume":"101","author":"Broadbent","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.expneurol.2017.04.017","article-title":"The valproic acid-induced rodent model of autism","volume":"299","author":"Nicolini","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Long, J., Li, H., Liu, Y., Liao, X., Tang, Z., Han, K., Chen, J., and Zhang, H. (2024). Insights into the Structure and Function of the Hippocampus: Implications for the Pathophysiology and Treatment of Autism Spectrum Disorder. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1364858"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1037\/bne0000027","article-title":"Persistent hyperactivity and distinctive strategy features in the Morris water maze in 3xTg-AD mice at advanced stages of disease","volume":"129","year":"2015","journal-title":"Behav. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.pharmthera.2018.05.007","article-title":"Pharmacology & Therapeutics Autism Spectrum Disorder : Classification, diagnosis and therapy","volume":"190","author":"Sharma","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.brainres.2011.06.015","article-title":"Animal model of autism induced by prenatal exposure to valproate: Behavioral changes and liver parameters","volume":"1408","author":"Rodrigues","year":"2011","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.brainres.2013.06.024","article-title":"Increased hippocampal cell density and enhanced spatial memory in the valproic acid rat model of autism","volume":"1526","author":"Edalatmanesh","year":"2013","journal-title":"Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chaddad, A., Desrosiers, C., Hassan, L., and Tanougast, C. (2017). Hippocampus and amygdala radiomic biomarkers for the study of autism spectrum disorder. BMC Neurosci., 18.","DOI":"10.1186\/s12868-017-0373-0"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/j.jaac.2019.08.008","article-title":"Understanding Hippocampal Development in Young Children With Autism Spectrum Disorder","volume":"59","author":"Reinhardt","year":"2020","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Elnahas, E.M., Abuelezz, S.A., Mohamad, M.I., Nabil, M.M., Abdelraouf, S.M., Bahaa, N., Hassan, G.A., Ibrahim, E.A., Ahmed, A.I., and Aboul-Fotouh, S. (2021). Validation of prenatal versus postnatal valproic acid rat models of autism: A behavioral and neurobiological study. Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 108.","DOI":"10.1016\/j.pnpbp.2020.110185"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/02646830500381930","article-title":"Immunity, neuroglia and neuroinflammation in autism","volume":"17","author":"Pardo","year":"2005","journal-title":"Int. Rev. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1111\/jphp.12681","article-title":"Neuroprotection by plumbagin involves BDNF-TrkB-PI3K\/Akt and ERK1\/2\/JNK pathways in isoflurane-induced neonatal rats","volume":"69","author":"Yuan","year":"2017","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1111\/j.1471-4159.2009.06552.x","article-title":"Plumbagin, a novel Nrf2\/ARE activator, protects against cerebral ischemia","volume":"112","author":"Son","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Petrelli, F., Pucci, L., and Bezzi, P. (2016). Astrocytes and Microglia and Their Potential Link with Autism Spectrum Disorders. Front. Cell. Neurosci., 10.","DOI":"10.3389\/fncel.2016.00021"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"841","DOI":"10.2147\/NDT.S390053","article-title":"Pathology and Astrocytes in Autism","volume":"19","author":"Vakilzadeh","year":"2023","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.4103\/1673-5374.306064","article-title":"Astrocytes: A double-edged sword in neurodegenerative diseases","volume":"16","author":"Ding","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100646","DOI":"10.1016\/j.bbih.2023.100646","article-title":"Autistic spectrum disorder (ASD)\u2013Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment","volume":"30","author":"Gevezova","year":"2023","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13229-018-0254-0","article-title":"Neuroglia in the autistic brain: Evidence from a preclinical model","volume":"9","author":"Bronzuoli","year":"2018","journal-title":"Mol. Autism"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrn.2015.22","article-title":"Rediscovering area CA2: Unique properties and functions","volume":"17","author":"Dudek","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100351","DOI":"10.1016\/j.prmcm.2023.100351","article-title":"Unravelling the Potent Anti-Oxidant and Anti-Inflammatory Actions of Plumbagin: A Review of Preclinical Discoveries","volume":"10","author":"Verma","year":"2023","journal-title":"Pharmacol. Res. Mod. Chin. Med."},{"key":"ref_47","first-page":"1250","article-title":"Plumbagin Mediates Cardioprotection Against Myocardial Ischemia\/Reperfusion Injury Through Nrf-2 Signaling. Medical science monitor","volume":"22","author":"Wang","year":"2016","journal-title":"Int. J. Exp. Clin. Res."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/8\/798\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:16:54Z","timestamp":1760033814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/8\/798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,27]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["brainsci15080798"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15080798","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,27]]}}}