title: Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo.
abstract: Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, PO Box 9500, Morgantown, WV 26506, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Kaushal
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seminerio
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robson
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000009:adverse effects / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004357:Drug Synergism; D005334:Fever / Q000209:etiology / Q000517:prevention & control; D006146:Guanidines / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D011897:Random Allocation; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000737:chemistry / Q000378:metabolism; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism
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; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D006146:Guanidines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010879:Piperazines; D017480:Receptors, sigma; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493215:Slc6a3 protein, mouse; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D008694:Methamphetamine; C050232:1,3-ditolylguanidine; D004298:Dopamine