Chronic exposure to glucocorticoids primes the CNS proinflammatory response in methamphetamine neurotoxicity

Details

• Personal Author:
  James OP ; Kelly KA ; Miller DB
• Description:
  Upregulation of proinflammatory cytokines and chemokines in the brain ("neuroinflammation") accompanies brain injury and disease as well as systemic infections. Previously we documented a neuroinflammatory response associated with the neurotoxic effects of the dopaminergic neurotoxicants, MPTP and METH. These elevations in a variety of proinflammatory mediators may serve as modulators or mediators of astroglial and microglial activation, cellular responses associated with all types of brain injury. Activated glia may have neuroprotective roles or may exacerbate neural damage. Our prior genetic and pharmacological interventions have resulted in partial suppression of neuroinflammatory responses associated with exposure to MPTP and METH without affecting neurotoxicity and gliosis. Because glucocorticoids are regarded as potent anti-inflammatory agents, we pretreated mice with corticosterone (CORT) prior to administration of MPTP or METH and assessed a variety of cytokines/chemokines by qPCR and examined dopaminergic terminal damage and astrogliosis by tyrosine hydroxylase (TH) and GFAP immunoassay, respectively. Acute CORT (20 mg/kg, s.c.) 30 minutes prior to MPTP or METH reduced, but did not completely suppress the expression of LIF, CCL2, IL-1B induced neurotoxicity, whereas the decrease in TH and increase in GFAP remained unaffected. A chronic (1 week) CORT pretreatment in the drinking water was employed to achieve a longer and higher level of anti-inflammatory therapy on METH. Surprisingly, this CORT regimen appeared to prime the neuroinflammatory response to METH as most proinflammatory mediators showed exacerbated responses. In contrast to acute pretreatment with CORT, the effect of METH on TH and GFAP was exacerbated by chronic CORT. As the levels of chronic CORT approached or exceeded those associated with high physiological stress levels, our data suggest chronic CORT therapy or sustained physiological stress sensitizes CNS neuroinflammatory and neurotoxicity responses to METH. [Description provided by NIOSH]
• Subjects:
  Chemistry Cytotoxins Hazardous Substances Histocytochemistry Laboratories Microbiology Nervous System Occupational Health Safety Toxicology
• Keywords:
  Biological-effects Cell-biology Cellular-reactions Chemical-reactions Cytochemistry Cytotoxic-effects Laboratory-animals Laboratory-testing Microscopic-analysis Neuropharmacology Neurophysiological-effects Neurotoxic-effects Pharmacodynamics Physiological-effects Quantitative-analysis Statistical-analysis Toxic-dose Toxic-effects

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  District of Columbia ; OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  37-38
• Volume:
  120
• NIOSHTIC Number:
  nn:20038443
• Citation:
  Toxicologist 2011 Mar; 120(Suppl 2):37-38
• CAS Registry Number:
  1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (CAS RN 28289-54-5) ; Methamphetamine (CAS RN 537-46-2)
• Federal Fiscal Year:
  2011
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC
• Supplement:
  2
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:f828f9aae72dd32ab77568adcfe7336f89b73ab6e3ecc1b9a487dd0b8483ac6a080ab80498a17cd626debfb847cba159ccb7255ed47e147296054b3659b01359
• Download URL:
  https://stacks.cdc.gov/view/cdc/192154/cdc_192154_DS1.pdf
• File Type:
  [PDF - 1.11 MB ]