title: Vascular-directed responses of microglia produced by methamphetamine exposure: indirect evidence that microglia are involved in vascular repair?
abstract: BACKGROUND
  Brain microglial activations and damage responses are most commonly associated with neurodegeneration or systemic innate immune system activation. Here, we used histological methods to focus on microglial responses that are directed towards brain vasculature, previously undescribed, after a neurotoxic exposure to methamphetamine.
  
  
  METHODS
  Male rats were given doses of methamphetamine that produce pronounced hyperthermia, hypertension, and toxicity. Identification of microglia and microglia-like cells (pericytes and possibly perivascular cells) was done using immunoreactivity to allograft inflammatory factor 1 (Aif1 a.k.a Iba1) and alpha M integrin (Itgam a.k.a. Cd11b) while vasculature endothelium was identified using rat endothelial cell antigen 1 (RECA-1). Regions of neuronal, axonal, and nerve terminal degeneration were determined using Fluoro-Jade C.
  
  
  RESULTS
  Dual labeling of vasculature (RECA-1) and microglia (Iba1) showed a strong association of hypertrophied cells surrounding and juxtaposed to vasculature in the septum, medial dorsal hippocampus, piriform cortex, and thalamus. The Iba1 labeling was more pronounced in the cell body while Cd11b more so in the processes of activated microglia. These regions have been previously identified to have vascular leakage after neurotoxic methamphetamine exposure. Dual labeling with Fluoro-Jade C and Iba1 indicated that there was minimal or no evidence of neuronal damage in the septum and hippocampus where many hypertrophied Iba1-labeled cells were found to be associated with vasculature. Although microglial activation around the prominent neurodegeneration was found in the thalamus, there were also many examples of activated microglia associated with vasculature.
  
  
  CONCLUSIONS
  The data implicate microglia, and possibly related cell types, in playing a major role in responding to methamphetamine-induced vascular damage, and possibly repair, in the absence of neurodegeneration. Identifying brain regions with hypertrophied/activated microglial-like cells associated with vasculature has the potential for identifying regions of more subtle examples of vascular damage and BBB compromise.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicology/FDA, Jefferson, AR, 72079, USA. John.Bowyer@fda.hhs.gov.|National Center for Toxicological Research/FDA, 3900 NCTR Road, HFT-132, Jefferson, AR, 72079, USA. John.Bowyer@fda.hhs.gov.
authors.forename: John F
authors.initials: JF
authors.lastname: Bowyer
authors.affiliation: Division of Neurotoxicology, National Center for Toxicology/FDA, Jefferson, AR, 72079, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Division of Neurotoxicology, National Center for Toxicology/FDA, Jefferson, AR, 72079, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Tranter
authors.affiliation: Center for Drug Evaluation and Research/FDA, Silver Spring, MD, 20993, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
authors.affiliation: Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA.
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.affiliation: Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001808:Blood Vessels / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C100745:Aif1 protein, rat; D000954:Antigens, Surface; D039481:CD11b Antigen; D002135:Calcium-Binding Proteins; D000697:Central Nervous System Stimulants; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; C055591:endothelial cell-monocyte antigens; D008694:Methamphetamine
keywords: Amphetamine; Hypertension; Hyperthermia; Methamphetamine; Microglia; Neurotoxicity; Vascular damage