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Recently, HIS is an understudied neurotransmitter in the central nervous system, and its potential role in neuroinflammation and neurodegeneration is a critical area of research. So, the study's goal is to investigate the consequences of repeated oral intake of HIS\u00a0on the rat's brain and explore the mechanistic way of its neurotoxicity. Thirty male rats were divided into three groups (<jats:italic>n<\/jats:italic>\u2009=\u200910). The following treatments were administered orally to all rats every day for 14 days. Group (1) was given distilled water, whereas groups (2 &amp; 3) were given HIS at dosage levels 250\u00a0and 500\u2009mg\/kg body weight (BWT), respectively. Brain tissue samples were collected at 7\u2010 and 14\u2010days from the beginning of the experiment. Our results revealed that continuous oral administration of HIS at both doses for 14 days significantly reduced the BWT and induced severe neurobehavioral changes, including depression, dullness, lethargy, tremors, abnormal walking, and loss of spatial learning and memory in rats. In all HIS receiving groups, HPLC data showed a considerable raise in the HIS contents of the brain. Additionally, the daily consumption of HIS causes oxidative stress that is dose\u2010 and time\u2010dependent which is characterized by elevation of malondialdehyde levels along with reduction of catalase activity and reduced glutathione levels. The neuropathological lesions were commonly observed in the cerebrum, striatum, and cerebellum and confirmed by the immunohistochemistry staining that demonstrating moderate to strong caspase\u20103 and inducible nitric oxide synthase\u00a0expressions in all HIS receiving groups, mainly those receiving 500\u2009mg\/kg HIS. NF\u2010\u03baB, TNF\u2010\u03b1, and IL\u20101\u03b2 gene levels were also upregulated at 7\u2010 and 14\u2010days in all HIS groups, particularly in those getting 500\u2009mg\/kg. We concluded that ROS\u2010induced apoptosis and inflammation was the essential mechanism involved in HIS\u2010mediated neurobehavioral toxicity and histopathology.<\/jats:p>","DOI":"10.1002\/jbt.23653","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T07:05:16Z","timestamp":1705907116000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel insights on the probable mechanism associated with histamine oral model\u2010inducing neuropathological and behavioral toxicity in rats"],"prefix":"10.1002","volume":"38","author":[{"given":"Wafaa A.","family":"Mohamed","sequence":"first","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine Cairo University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3670-6841","authenticated-orcid":false,"given":"Eman I.","family":"Hassanen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine Cairo University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayam A.","family":"Mansour","sequence":"additional","affiliation":[{"name":"Department of Food Hygiene and Control, Faculty of Veterinary Medicine Cairo University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa A.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine Cairo University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehab A.","family":"Azouz","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Forensic Medicine, Faculty of Veterinary Medicine Cairo University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9385-2549","authenticated-orcid":false,"given":"Mahmoud A.","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine Cairo University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aller.2015.05.001"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9524075"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/gtc.12774"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2021.08.013"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/foods9121795"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-323-03453-1.10048-3"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2010.02.006"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3126\/jfstn.v8i0.11720"},{"key":"e_1_2_10_10_1","unstructured":"C. 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