Upregulation of proinflammatory cytokines and chemokines in the brain ("neuroinflammation") accompanies CNS injury as well as, e.g., systemic infections, depression, pain and sleep disorders. Previously, we documented neuroinflammatory responses following nerve terminal damage due to acute exposure to the dopaminergic neurotoxicants, MPTP and METH. Elevations in these varied proinflammatory mediators may serve as modulators glial activation, i.e., cell responses associated with all types of brain injury. Activated glia may have neuroprotective roles or may exacerbate neural damage. As such, glia are potential targets for manipulation in order to effect neuroprotection. Our prior genetic (knockouts) and pharmacological (minocycline) interventions resulted in partial suppression of MPTP- and METH-induced neuroinflammatory responses without affecting neurotoxicity and gliosis. Because glucocorticoids are widely regarded as potent anti-inflammatory agents, we pretreated mice with corticosterone (CORT) prior to administration of MPTP or METH and then assessed striatal content of a variety of cytokines/chemokines by qPCR, and examined dopaminergic terminal damage and astrogliosis by tyrosine hydroxylase (TH) and GFAP immunoassay, respectively. Acute CORT pretreatment (20 mg/kg, s.c.) 30 minutes prior to MPTP or METH reduced, but did not completely suppress the expression of LIF, CCL2, or IL-1beta in striatum, whereas decreases in TH and increases in GFAP remained unaffected. Chronic (1 week) CORT pretreatment then was employed to achieve a protracted level of anti-inflammatory therapy. Surprisingly, this CORT regimen appeared to prime the neuroinflammatory response to MPTP and METH, as all proinflammatory mediators showed highly exacerbated (e.g., >200-fold for LIF) responses. As with acute pretreatment with CORT, TH and GFAP remained unaffected. Because the levels of chronic CORT approached or exceeded those associated with high physiological stress levels, our data suggest that chronic CORT therapy or sustained physiological stress primes the CNS neuroinflammatory response to injury.
Biological-effects; Biological-monitoring; Cell-biology; Cellular-reactions; Exposure-assessment; Exposure-levels; Exposure-methods; Laboratory-animals; Laboratory-testing; Microscopic-analysis; Nanotechnology; Neurological-reactions; Neurological-system; Neurotoxic-effects; Particulates; Pharmacodynamics; Physical-reactions; Physiological-effects; Physiological-response; Physiological-stress; Toxic-effects; Toxic-materials
The Toxicologist. Society of Toxicology 49th Annual Meeting and ToxExpo, March 7-11, 2010, Salt Lake City, Utah