title: SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation.
abstract: Methamphetamine (METH) exposure results in dopaminergic neurotoxicity in striatal regions of the brain, an effect that has been linked to an increased risk of Parkinson's disease. Various aspects of neuroinflammation, including astrogliosis, are believed to be contributory factors in METH neurotoxicity. METH interacts with sigma receptors at physiologically relevant concentrations and treatment with sigma receptor antagonists has been shown to mitigate METH-induced neurotoxicity in rodent models. Whether these compounds alter the responses of glial cells within the central nervous system to METH however has yet to be determined. Therefore, the purpose of the current study was to determine whether the sigma receptor antagonist, SN79, mitigates METH-induced striatal reactive astrogliosis. Male, Swiss Webster mice treated with a neurotoxic regimen of METH exhibited time-dependent increases in striatal gfap mRNA and concomitant increases in GFAP protein, indicative of astrogliosis. This is the first report that similar to other neurotoxicants that induce astrogliosis through the activation of JAK2/STAT3 signaling by stimulating gp-130-linked cytokine signaling resulting from neuroinflammation, METH treatment also increases astrocytic oncostatin m receptor (OSMR) expression and the phosphorylation of STAT3 (Tyr-705) in vivo. Pretreatment with SN79 blocked METH-induced increases in OSMR, STAT3 phosphorylation and astrocyte activation within the striatum. Additionally, METH treatment resulted in striatal cellular degeneration as measured by Fluoro-Jade B, an effect that was mitigated by SN79. The current study provides evidence that sigma receptor antagonists attenuate METH-induced astrocyte activation through a pathway believed to be shared by various neurotoxicants.
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA; Department of Pharmacology, School of Medicine, Vanderbilt University, 1161 21st Ave S., Nashville, TN 37232, USA.
authors: Matthew J
authors: MJ
authors: Robson
authors: Department of Neurosurgery, School of Medicine, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA; Center for Neuroscience, School of Medicine, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA.
authors: Ryan C
authors: RC
authors: Turner
authors: Department of Neurosurgery, School of Medicine, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA.
authors: Zachary J
authors: ZJ
authors: Naser
authors: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, P.O. Box 1848, University, MS 38677-1848, USA; Department of Pharmacology, School of Pharmacy, University of Mississippi, P.O. Box 1848, University, MS 38677-1848, USA.
authors: Christopher R
authors: CR
authors: McCurdy
authors: Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health, 1095 Willowdale Rd., Morgantown, WV 26505, USA.
authors: James P
authors: JP
authors: O'Callaghan
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA; Center for Neuroscience, School of Medicine, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA.
authors: Jason D
authors: JD
authors: Huber
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA; Center for Neuroscience, School of Medicine, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA. Electronic address: rmatsumoto@hsc.wvu.edu.
authors: Rae R
authors: RR
authors: Matsumoto
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001583:Benzoxazoles / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000633:toxicity; D003342:Corpus Striatum / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D004347:Drug Interactions; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: C557789:6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo(d)oxazol-2(3H)-one; D001583:Benzoxazoles; D000697:Central Nervous System Stimulants; D005904:Glial Fibrillary Acidic Protein; C494200:Il6st protein, mouse; D053681:Oncostatin M Receptor beta Subunit; C508349:Osmr protein, mouse; D010879:Piperazines; D017480:Receptors, sigma; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; D008694:Methamphetamine
keywords: Astrocyte; Glia; Methamphetamine neurotoxicity; Neuroinflammation; Sigma receptor