title: Magnolol protects against trimethyltin-induced neuronal damage and glial activation in vitro and in vivo.
abstract: Trimethyltin (TMT), an organotin with potent neurotoxic effects by selectively damaging to hippocampus, is used as a tool for creating an experimental model of neurodegeneration. In the present study, we investigated the protective effects of magnolol, a natural biphenolic compound, on TMT-induced neurodegeneration and glial activation in vitro and in vivo. In HT22 murine neuroblastoma cells, TMT induced necrotic/apoptotic cell death and oxidative stress, including intracellular reactive oxygen species (ROS), protein carbonylation, induction of heme oxygenase-1 (HO-1), and activation of all mitogen-activated protein kinases (MAPKs) family proteins. However, magnolol treatment significantly suppressed neuronal cell death by inhibiting TMT-mediated ROS generation and activation of JNK and p38 MAPKs. In BV-2 microglial cells, magnolol efficiently attenuated TMT-induced microglial activation via suppression of ROS generation and activation of JNK, p38 MAPKs, and nuclear factor-κB (NF-κB) signaling. In an in vivo mouse study, TMT induced massive neuronal damage and enhanced oxidative stress at day 2. We also observed a concomitant increase in glial cells and inducible nitric oxide synthase (iNOS) expression on the same day. These features of TMT toxicity were reversed by treatment of magnolol. We observed that p-JNK and p-p38 MAPK levels were increased in the mouse hippocampus at day 1 after TMT treatment and that magnolol blocked TMT-induced JNK and p38 MAPK activation. Magnolol administration prevented TMT-induced hippocampal neurodegeneration and glial activation, possibly through the regulation of TMT-mediated ROS generation and MAPK activation.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, 103 Daehakno, Jongno-Gu, Seoul 110-799, Republic of Korea. Electronic address: dkim3193@hotmail.com.
authors.forename: Da Jung
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, 103 Daehakno, Jongno-Gu, Seoul 110-799, Republic of Korea. Electronic address: kimysu@snu.ac.kr.
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009457:Neuroglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D009573:Nitrites / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014298:Trimethyltin Compounds / Q000633:toxicity*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D016207:Cytokines; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D017705:Lignans; D009573:Nitrites; D017382:Reactive Oxygen Species; D014298:Trimethyltin Compounds; C005498:magnolol; C046488:trimethyltin
keywords: Glial activation; Magnolol; Mitogen-activated Protein kinases; Neuronal death; Oxidative stress; Trimethyltin