International Journal of Preventive Medicine (Int J Prev Med)2008-78021592024112029372937Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran1Faculty of Veterinary Medicine, Tehran University, Tehran2 Faculty of Veterinary Medicine, Semnan University, Semnan3Life Sciences Institute, University of Michigan, Ann Arbor, MIChronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, TehranChronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran4Department of Comparative Bioscience, Faculty of Veterinary Medicine, University of Tehran, Tehran5Division of Toxicology, Department of Comparative Bioscience, Faculty of Veterinary Medicine, University of Tehran, Tehran20241120Background: Previous evidence indicates that tramadol (TRA) can lead to neurodegenerative events and minocycline (MIN) has neuroprotective properties. Aim of the Study: The current research evaluated the neuroprotective effects of MIN for TRA‑promoted neurodegeneration. Methods: Sixty adult male rats were placed into the following groups: 1 (received 0.7 ml/rat of normal saline, IP), 2 (received 50 mg/kg of TRA, i.p.), 3, 4, 5 (administered TRA as 50 mg/kg simultaneously with MIN at 20, 40, and 60 mg/kg, IP, respectively), and 6 (received MIN alone as 60 mg/kg, IP). The treatment procedure was 21 days. An open field test (OFT) was used to measure motor activity and anxiety‑related behavior. Furthermore, oxidative stress; hippocampal inflammation; apoptotic parameters as well as activity of mitochondrial complexes I, II, III, and IV; ATP levels; and mitochondrial membrane potential (MMP) were evaluated. In addition, histomorphological alteration was assessed in two regions of the hippocampus: Cornu Ammonis (CA1) and dentate gyrus (DG). Results: MIN treatment could inhibit TRA‑induced anxiety and motor activity disturbances (P < 0.05). In addition, MIN could attenuate reactive oxygen species (ROS), H2 O2 , oxidized glutathione (GSSG), and malondialdehyde (MDA) level (P < 0.05), while there was increased reduced glutathione (GSH), total antioxidant capacity (TAC), ATP, MMP, and BCL2 levels (P < 0.05) and also elevation of SOD, GPX, GSR (P < 0.05), and mitochondrial complexes I, II, III, and IV activity (P < 0.05) in TRA‑treated rats. In consistence with these findings, MIN could reduce TNF/TNF‑α, IL1B/IL1‑β, BAX, and CASP3 levels (P < 0.05) in TRA‑treated rats. MIN also restored the quantitative (P < 0.05) and qualitative histomorphological sequels of TRA in both CA1 and DG areas of the hippocampus. Conclusions: MIN probably has repositioning capability for inhibition of TRA‑induced neurodegeneration via modulation of inflammation, oxidative stress, apoptosis, and mitochondrial disorders.http://ijpm.mui.ac.ir/index.php/ijpm/article/view/2937http://ijpm.mui.ac.ir/index.php/ijpm/article/download/2937/717718778