title: Neuroprotective targets through which 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a sigma receptor ligand, mitigates the effects of methamphetamine in vitro.
abstract: Exposure to high or repeated doses of methamphetamine can cause hyperthermia and neurotoxicity, which are thought to increase the risk of developing a variety of neurological conditions. Sigma receptor antagonism can prevent methamphetamine-induced hyperthermia and neurotoxicity, but the underlying cellular targets through which the neuroprotection is conveyed remain unknown. Differentiated NG108-15 cells were thus used as a model system to begin elucidating the neuroprotective mechanisms targeted by sigma receptor antagonists to mitigate the effects of methamphetamine. In differentiated NG108-15 cells, methamphetamine caused the generation of reactive oxygen/nitrogen species, an increase in PERK-mediated endoplasmic reticulum stress and the activation of caspase-3, -8 and -9, ultimately resulting in apoptosis at micromolar concentrations, and necrotic cell death at higher concentrations. The sigma receptor antagonist, 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), attenuated methamphetamine-induced increases in reactive oxygen/nitrogen species, activation of caspase-3, -8 and -9 and accompanying cellular toxicity. In contrast, 1,3-di(2-tolyl)-guanidine (DTG), a sigma receptor agonist, shifted the dose response curve of methamphetamine-induced cell death towards the left. To probe the effect of temperature on neurotoxicity, NG108-15 cells maintained at an elevated temperature (40 °C) exhibited a significant and synergistic increase in cell death in response to methamphetamine, compared to cells maintained at a normal cell culture temperature (37 °C). SN79 attenuated the enhanced cell death observed in the methamphetamine-treated cells at 40 °C. Together, the data demonstrate that SN79 reduces methamphetamine-induced reactive oxygen/nitrogen species generation and caspase activation, thereby conveying neuroprotective effects against methamphetamine under regular and elevated temperature conditions.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Kaushal
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robson
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Abagail
authors.initials: A
authors.lastname: Rosen
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA. Electronic address: rmatsumoto@hsc.wvu.edu.
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D005334:Fever / Q000378:metabolism; D008024:Ligands; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D009336:Necrosis / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D001583:Benzoxazoles; D020169:Caspases; D008024:Ligands; D008694:Methamphetamine; D018696:Neuroprotective Agents; D010879:Piperazines; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D019892:eIF-2 Kinase; C557789:6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo(d)oxazol-2(3H)-one
keywords: Apoptosis; Caspase; Methamphetamine; Necrosis; Reactive oxygen species; Sigma receptors