Minocycline Acts as a Neuroprotective Agent Against Tramadol‑Induced Neurodegeneration: Behavioral and Molecular Evidence

Mina Gholami, Zahra Ghelichkhani, Reza Aghakhani, Daniel J. Klionsky, Ozra Motaghinejad, Majid Motaghinejad, Mohammad Kazem Koohi, Jalal Hassan

Abstract


Background: 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.

Keywords


Anxiety; minocycline; neurodegeneration; stress; tramadol

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References


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