title: The danger-associated molecular pattern HMGB1 mediates the neuroinflammatory effects of methamphetamine.
abstract: Methamphetamine (METH) induces neuroinflammatory effects, which may contribute to the neurotoxicity of METH. However, the mechanism by which METH induces neuroinflammation has yet to be clarified. A considerable body of evidence suggests that METH induces cellular damage and distress, particularly in dopaminergic neurons. Damaged neurons release danger-associated molecular patterns (DAMPs) such as high mobility group box-1 (HMGB1), which induces pro-inflammatory effects. Therefore, we explored the notion here that METH induces neuroinflammation indirectly through the release of HMGB1 from damaged neurons. Adult male Sprague-Dawley rats were injected IP with METH (10mg/kg) or vehicle (0.9% saline). Neuroinflammatory effects of METH were measured in nucleus accumbens (NAcc), ventral tegmental area (VTA) and prefrontal cortex (PFC) at 2h, 4h and 6h after injection. To assess whether METH directly induces pro-inflammatory effects in microglia, whole brain or striatal microglia were isolated using a Percoll density gradient and exposed to METH (0, 0.1, 1, 10, 100, or 1000μM) for 24h and pro-inflammatory cytokines measured. The effect of METH on HMGB1 and IL-1β in striatal tissue was then measured. To determine the role of HMGB1 in the neuroinflammatory effects of METH, animals were injected intra-cisterna magna with the HMGB1 antagonist box A (10μg) or vehicle (sterile water). 24h post-injection, animals were injected IP with METH (10mg/kg) or vehicle (0.9% saline) and 4h later neuroinflammatory effects measured in NAcc, VTA, and PFC. METH induced robust pro-inflammatory effects in NAcc, VTA, and PFC as a function of time and pro-inflammatory analyte measured. In particular, METH induced profound effects on IL-1β in NAcc (2h) and PFC (2h and 4h). Exposure of microglia to METH in vitro failed to induce a pro-inflammatory response, but rather induced significant cell death as well as a decrease in IL-1β. METH treatment increased HMGB1 in parallel with IL-1β in striatum. Pre-treatment with the HMGB1 antagonist box A blocked the neuroinflammatory effects (IL-1β) of METH in NAcc, VTA and PFC. The present results suggest that HMGB1 mediates, in part, the neuroinflammatory effects of METH and thus may alert CNS innate immune cells to the toxic effects of METH.
authors.affiliation: Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, USA. Electronic address: matt.frank@colorado.edu.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Frank
authors.affiliation: National Institute on Drug Abuse, National Institutes of Health, USA.
authors.forename: Sweta
authors.initials: S
authors.lastname: Adhikary
authors.affiliation: Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Sobesky
authors.affiliation: Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weber
authors.affiliation: Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.affiliation: Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018836:Inflammation Mediators; D008694:Methamphetamine
keywords: DAMP; HMGB1; Methamphetamine; Microglia; Neuroinflammation; Neurotoxicity