Protein Phosphorylation Cascades Associated with Methamphetamine-Induced Glial Activation

Details

• Personal Author:
  Hebert MA ; O'Callaghan JP ; Hebert MA ; O'Callaghan JP
• Description:
  Reactive gliosis is the most prominent response to diverse forms of central nervous system (CNS) injury. The signaling events that mediate this characteristic response to neural injury are under intense investigation. Several studies have demonstrated the activation of phosphoproteins within the mitogen-activated protein kinase (MAPK) and Janus kinase (JAK) pathways following neural insult. These signaling pathways may be involved or responsible for the glial response following injury, by virtue of their ability to phosphorylate and dynamically regulate the activity of various transcription factors. This study sought to delineate, in vivo, the relative contribution of MAPK- and JAK-signaling components to reactive gliosis as measured by induction of glial-fibrillary acidic protein (GFAP), following chemical-induced neural damage. At time points (6, 24, and 48 h) following methamphetamine (METH, 10 mg/kg x 4, s.c.) administration, female C57BL/6J mice were sacrificed by focused microwave irradiation, a technique that preserves steady-state phosphorylation. Striatal (target) and nontarget (hippocampus) homogenates were assayed for METH-induced changes in markers of dopamine (DA) neuron integrity as well as differences in the levels of activated phosphoproteins. GFAP upregulation occurred as early as 6 h, reaching a threefold induction 48 h following METH exposure. Neurotoxicant-induced reductions in striatal levels of DA and tyrosine hydroxylase (TH) paralleled the temporal profile of GFAP induction. Blots of striatal homogenates, probed with phosphorylation-state specific antibodies, demonstrated significant changes in activated forms of extracellular-regulated kinase 1/2 (ERK 1/2), c-jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), MAPK/ERK kinase (MEK1/2), 70-kDa ribosomal S6 kinase (p70 S6), cAMP responsive element binding protein (CREB), and signal transducer and activator of transcription 3 (STAT3). MAPK-related phosphoproteins exhibited an activation profile that peaked at 6 h, remained significantly increased at 24, and fell to baseline levels 48 h following neurotoxicant treatment. The ribosomal S6 kinase was enhanced over 60% for all time points examined. Immunoreactivity profiles for the transcription factors CREB and STAT3 indicated maximal increases in phosphorylation occurring at 24 h, and measuring greater than 2- or 17-fold, respectively. Specific signaling events were found to occur with a time course suggestive of their involvement in the gliotic response. The toxicant-induced activation of these growth-associated signaling cascades suggests that these pathways could be obligatory for the triggering and/or persistence of reactive gliosis and may therefore serve as potential targets for modulation of glial response to neural damage. [Description provided by NIOSH]
• Subjects:
  Animals Environmental Exposure Laboratories Nervous System Occupational Health Safety
• Keywords:
  Animal Studies Central Nervous System Disorders Exposure Levels Injuries In Vivo Studies Laboratory Animals Neurotoxic Effects Neurotoxicity Neurotoxins
• ISBN:
  9781573312806
• ISSN:
  0077-8923
• Document Type:
  Text
• Genre:
  Journal Article ; Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH) ; National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division ; HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health ; Workplace Safety & Health
• Location:
  North America ; North America
• Pages in Document:
  238-262
• Volume:
  914
• NIOSHTIC Number:
  nn:20020692
• Citation:
  Ann NY Acad Sci 2000 Sep; 914:238-262
• Contact Point Address:
  James P. O'Callaghan, Ph.D., Centers for Disease Control and Prevention, NIOSH, 1095 Willowdale Road, Morgantown, WV 26505-2888
• Email:
  jdo5@cdc.gov
• Federal Fiscal Year:
  2000
• Peer Reviewed:
  True
• Source Full Name:
  Annals of the New York Academy of Sciences
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:0bf46d590826a69748c6a22b28f85320061b487aefd434f08ead9e2b0a4cfe7f21697973db6d12adcd6a1a5b94bee93bcf9d3da9defee70e333810bc7a6ff7ea
• Download URL:
  https://stacks.cdc.gov/view/cdc/198372/cdc_198372_DS1.pdf
• File Type:
  [PDF - 7.20 MB ]