Contents lists available at ScienceDirect Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph Molybdenum bupropion combined neurotoxicity in rats A.M. Helaly a,b , Naglaa Mokhtar c,f , Alaa El-Din L. Firgany d,f , Noha M. Hazem c,f,* , E. El Morsi a,f , D. Ghorab e,f a Forensic and Clinical Toxicology Department, Egypt b Faculty of Medicine, Yarmouk University, Jordan c Medical Biochemistry Department, Egypt d Department of Histology and Cell Biology, Egypt e Pathology Department, Egypt f Faculty of Medicine, Mansoura University, Egypt ARTICLE INFO Keywords: Molybdenum Bupropion Brain Oxidative stress Nrf2 TNF-α Antidepressant Inflammatory response ABSTRACT Heavy metal toxicity is a common foodborne problem in Egypt, especially in combination. Molybdenum toxicity has been studied as a model of the heavy metal toxicity. Molybdenum could promote toxicity via oxidative- inflammatory mechanisms. Bupropion is a well-known antidepressant that has anti-oxidant mechanisms. It exerts a cytoprotective action against molybdenum induced metal toxicity. The aim of the study is to evaluate the effects of combined bupropion and molybdenum in a toxic animal model. The results showed that the combination of bupropion and high doses of molybdenum was extremely toxic with an evident animal fatality. Bupropion showed a clear anti-oxidant/anti-inflammatory profile detected by the ELISA assay of mal- ondialdehyde (MDA), reduced glutathione, and interleukin -6 (IL-6), and real-time gene expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and tumor necrosis factor-α (TNF-α). The immunohistochemistry of nuclear factor Kappa Beta (NF-κB) showed that bupropion reduced the inflammatory response induced by the molybdenum neurotoxicity. Despite the improved laboratory profile, the animals were extremely intoxicated with recorded fatalities raising the question about other pathways and mechanisms explaining the drug metal interaction. Furthermore, Bupropion even in normal doses was toxic to the animals. Choroid plexus hyperplasia was reported in the histological examination of the animal brain loaded with bupropion, and choroid plexus papilloma was recorded in the combined drug metal group. More wide-scale studies are needed to verify the safety of the current antidepressant medications for the long-term therapy. It is important to focus on drug metal interaction as a possible cause of neuropathology. 1. Introduction Molybdenum is a biological trace element that plays a structural role in the function of enzymes like sulfite oxidase, xanthine oxidase, and aldehyde oxidase (Kisker et al., 1997). Studies showed that mo- lybdenum in combination with other elements creates a load of toxicity on human organs like kidneys. The cytokine expression is increased, indicating an inflammatory mechanism behind molybdenum accumu- lation in the body (Xiao et al., 2016). The daily requirement of mo- lybdenum ranges from 1.4 to 4.3 μg/kg/day (Novotny and Turnlund, 2007). Patients may expose to high doses of combined Cobalt, Chromium and Molybdenum as a result of a hip replacement with a metal implant. They showed complex cytokine expression with increased expression of interleukin-10 (IL-10), and associated decrease in the expression of interleukin-6 (IL-6) (Pearson et al., 2015). Another study recorded that combined heavy metal toxicity, including molybdenum, induced splenic damage in ducks and produced an expression of inflammatory cytokines like nuclear factor-kappa B (NF-κB) and tumor necrosis factor-α (TNF- α)(Xiao et al., 2016; Zhang et al., 2006). TNF- α induces mitochondrial dysfunction resulting in further increases in oxidative stress, cytochrome c release, caspase 3 activity, and cell death leading to apoptosis in the brain (Zhuang et al., 2016). Oxidative stress markers were elevated in intoxicated livers of goats with high dose molybdenum. The mitochondria were swollen and the apoptosis cascade was activated. The results of molybdenum toxicity on spleen showed similar results (Xiao et al., 2016; Tangpong et al., 2006). Bupropion is a known antidepressant that has other uses including https://doi.org/10.1016/j.yrtph.2018.08.001 Received 27 April 2018; Received in revised form 31 July 2018; Accepted 2 August 2018 * Corresponding author. Medical Biochemistry Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt. E-mail address: nohadata@gmail.com (N.M. Hazem). Regulatory Toxicology and Pharmacology 98 (2018) 224–230 Available online 03 August 2018 0273-2300/ © 2018 Elsevier Inc. All rights reserved. T