title: Fluoxetine protects against methamphetamine‑induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.
abstract: Methamphetamine (MA) abuse is a major public health and safety concern throughout the world and a growing burden on healthcare costs. The purpose of the present study was to investigate the protective effect of fluoxetine against MA‑induced chronic pulmonary inflammation and to evaluate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidative stress. Wistar rats were divided into control, MA and two fluoxetine‑treated groups. Rats in the MA and the two fluoxetine‑treated groups were treated daily with intraperitoneal injection of 10 mg/kg MA twice daily. Rats in the two fluoxetine‑treated groups were injected intragastrically with fluoxetine (2 and 10 mg/kg) once daily, respectively. After 5 weeks, the rats were euthanized and hematoxylin and eosin staining, immunohistochemistry, western blot analysis and redox assay were performed. It was demonstrated that chronic exposure to MA can induce pulmonary inflammation in rats, with the symptoms of inflammatory cell infiltration, crowded lung parenchyma, thickened septum and a reduced number of alveolar sacs. Fluoxetine attenuated pulmonary inflammation and the expression of interleukin‑6 and tumor necrosis factor‑α in rat lungs. Fluoxetine inhibited MA‑induced increases in the expression levels of serotonin transporter (SERT) and p‑p38 mitogen‑activated protein kinase (MAPK), and reversed the MA‑induced decrease in nuclear Nrf2 and human heme oxygenase‑1 in lungs. Fluoxetine at 10 mg/kg significantly reversed the reduced glutathione (GSH) level, the ratio of GSH/oxidized glutathione, and the reactive oxygen species level in rat lungs from the MA group. These findings suggested that fluoxetine, a SERT inhibitor, has a protective effect against MA‑induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Gu
authors.affiliation: Department of Drug Control, China Criminal Police University, Shenyang, Liaoning 110035, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
authors.forename: Huai-Liang
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005473:Fluoxetine / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005473:Fluoxetine; D005978:Glutathione; D051547:Heme Oxygenase-1; D015850:Interleukin-6; D008694:Methamphetamine; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases