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However, the incidence of its abuse is increasing. Rosmarinic acid (RA) is a natural flavonoid known for its antioxidant, anti-inflammatory, and neuroprotective properties. In this study, we determined the ameliorative effects of RA against TRM-induced neurotoxicity. Thirty\u200b\u200b\u200b\u200b\u200b\u200b\u200b five rats were divided into 5 groups; control, RA, TRM, TRM\u2009+\u2009RA25 and TRM\u2009+\u2009RA50. TRM 50\u00a0mg\/kg was administered intraperitoneally, and RA 25 and 50\u00a0mg\/kg doses were administered by oral gavage for 14\u00a0days. Water Maze Test (WMT) was performed to assess cognitive function. Oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis damage pathways, glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF) activities were determined in brain and hippocampus tissues. The structural and functional integrity of the tissues were also analyzed. RA decreased TRM-induced increased \u200b\u200b\u200b\u200b\u200b\u200b\u200boxidative stress, inflammation, ER stress, and apoptotic damage levels. In addition, it improved neuronal survival and activity by bringing BDNF and GFAP activities closer to normal in brain tissue. RA restored the structural properties of brain and hippocampus tissues disrupted by tramadol. These findings were also demonstrated using WMT, which improved the arrival time to the quadrant in which the platform was located and the time spent in the quadrant. RA reduces TRM-induced neurotoxicity by reducing inflammation, oxidative stress, ER stress, and apoptotic damage and increases neuronal survival and activity.<\/jats:p>","DOI":"10.1007\/s12035-025-04892-8","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:40:57Z","timestamp":1743986457000},"page":"10245-10263","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Potent Ameliorative Effects of Rosmarinic Acid on Tramadol-Induced Neurotoxicity in the Brain and Hippocampus; by Suppressing Oxidative stress, Apoptosis, ER stress, and Regulating Cognitive Functions"],"prefix":"10.1007","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3339-4195","authenticated-orcid":false,"given":"Onur","family":"Karaca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan","family":"\u015eim\u015fek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurhan","family":"Akaras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cihan","family":"G\u00fcr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"\u0130lerit\u00fcrk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zge","family":"Kandemir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sefa","family":"K\u00fc\u00e7\u00fckler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u015eeyda \u00d6te","family":"Karaca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih Mehmet","family":"Kandemir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"key":"4892_CR1","doi-asserted-by":"publisher","first-page":"101893","DOI":"10.1016\/J.JCHEMNEU.2020.101893","volume":"112","author":"GA Kader","year":"2021","unstructured":"Kader GA, Ibrahim MA, Khalifa AM, Mirza U, Rashwan EK, Abdel-Hady Z (2021) Evaluation of vitamin C protective effect on the cerebrocortical antioxidant defense, histopathological, pro-apoptotic p53 and anti-apoptotic Bcl2 expressions against tramadol neurotoxicity in rats. 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