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: Matthew J Robson, Ryan C Turner, Zachary J Naser, Christopher R McCurdy, James P O'Callaghan, Jason D Huber, Rae R Matsumoto
• Journal: Experimental neurology (Exp Neurol) Vol. 254 Pg. 180-9 (Apr 2014) ISSN: 1090-2430 [Electronic] United States
• PMID: 24508558 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo(d)oxazol-2(3H)-one
• Benzoxazoles
• Central Nervous System Stimulants
• Glial Fibrillary Acidic Protein
• Il6st protein, mouse
• Oncostatin M Receptor beta Subunit
• Osmr protein, mouse
• Piperazines
• Receptors, sigma
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Cytokine Receptor gp130
• Methamphetamine

Topics

• Animals
• Astrocytes (drug effects, pathology)
• Benzoxazoles (pharmacology)
• Central Nervous System Stimulants (toxicity)
• Corpus Striatum (pathology)
• Cytokine Receptor gp130 (metabolism)
• Dopaminergic Neurons (drug effects, pathology)
• Drug Interactions
• Fever (chemically induced, drug therapy)
• Glial Fibrillary Acidic Protein (genetics, metabolism)
• Gliosis (chemically induced, drug therapy)
• Male
• Methamphetamine (toxicity)
• Mice
• Oncostatin M Receptor beta Subunit (genetics, metabolism)
• Phosphorylation (drug effects, physiology)
• Piperazines (pharmacology)
• Receptors, sigma (antagonists & inhibitors)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects, physiology)