Corrected Proof Jundishapur J Nat Pharm Prod. 2022 February; 17(1):e112160. Published online 2021 September 6. doi: 10.5812/jjnpp.112160. Research Article The Effect of Crude Extract and Fractions of Teucrium polium L. on the Brain, Liver, and Kidney of Male Rats Seyed Noureddin Nematollahi-Mahani 1, 2, 3 , Sepideh Ganjalikhan-Hakemi 1 and Zahra Abdi 4, * 1 Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran 2 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran 3 Afzal Research Institute (NGO), Kerman, Iran 4 Department of Anatomical Sciences, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran * Corresponding author: Department of Anatomical Sciences, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran. Email: zabdi@zums.ac.ir Received 2020 December 14; Revised 2021 May 02; Accepted 2021 May 03. Abstract Background: Teucrium polium (TP) is a medicinal plant with a long history of consumption as a folk remedy for curing many dis- eases, including diabetes, common cold, obesity, anxiety, etc. Objectives: The present study aimed at investigating the effects of TP crude extracts (TPCE), as well as its diethyl ether (DE) and petroleum ether (PE) fractions, on the brain, kidney, and liver tissue of male rats in the subchronic phase. Methods: In the study, 45 adult male Wistar rats were randomly assigned to five groups as the PBS (receiving phosphate buffer saline), vehicle (receiving dimethyl sulfoxide), as well as CE, PE, and DE receiving 3 mg/kg (100 μL) TPCE, PE, and DE, respectively, for six weeks. Histopathological examinations by hematoxylin and eosin staining investigated morphological changes in all specimens. Also, the brain samples were stained by the immunohistochemistry (IHC) technique with Ki-67, CD31, p53, Nestin, and GFAP markers. Results: The findings showed that the prolonged consumption of TP caused the formation of histological lesions as apoptosis, degeneration, cytoplasmic vacuolization of neurons, and foamy cells in the brain. The liver, displayed cytoplasmic vacuolization, apoptosis, degeneration, and dilated sinusoids. Moreover, TP led to atrophy, vacuolization, and necrosis in renal cells. IHC studies evidenced an increase in the expression of P53, whereas the expression of Ki67 and CD31 decreased. It should be noted that TP crude extract and fractions were toxic; however, the PE fraction was more cytotoxic than others. Conclusions: The study findings indicated that long-term administration of a sublethal dose of TP impairs cellular integrity in vital orangs, including the liver, brain, and kidney, through triggering the cell death mechanisms. Keywords: Teucrium polium, Toxicity, Brain, Kidney, Liver 1. Background Nowadays, demand for medicinal plants is consider- ably increasing in developing and developed countries. The use of herbal medicines, known as folk remedies, is common worldwide, with a growing trend, to treat known diseases and problems, such as diabetes, common cold, obesity, anxiety, eczema, parasitic, and microbial infec- tions (1-3). Teucrium L.(Teucrium polium L, Teucrium capitatum L, ger- mander) resides in the Lamiaceae family and has a long his- tory of consumption among medicinal plants. Teucrium L. is a traditional remedy and native to South-Western Asia, North Africa, Europe, and Iran. This genus with 12 species is identified in various regions of Iran. Teucrium polium L (T. polium) is one of the most common species with global spread (4-6). Teucrium polium is a perennial shrub with linear and oblong leaves and small flowers ranging from white to pink. It contains terpenoids, glycosides, iridoids, saponins, polyphenols, flavonoids, and furano neoclerodane diter- penoids. Its brew is usually consumed to treat common cold, abdominal colic, indigestion, type 2 diabetes, and wounds. Because of the various usage of T. polium in folk medicine, it is one of the most widely used plants (7-10). Despite the wide medicinal use of T. polium, some stud- ies claimed its toxicity, especially after chronic consump- tion; for example, hepatotoxicity, neurotoxicity, and even carcinogenicity (11-15). A recent study on the effect of T. polium revealed significant changes in the kidney tissue of mice treated with this herb; disturbance in the kidney function was also reported (14). Another study by Laliberte and Villeneuve (11), demonstrated that chronic consump- tion of T. polium led to hepatitis. Moreover, Al-Ashban et al. (15), reported that long-term use of T. polium in mice could Copyright © 2021, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.