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Chronic exposure to glucocorticoids primes the CNS proinflammatory response in methamphetamine neurotoxicity.
Kelly KA; Miller DB; James OP
Toxicologist 2011 Mar; 120(Suppl 2):37-38
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.
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; Toxicology
The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC