Abstract
Upregulation of proinflammatory cytokines/chemokines in brain ("neuroinflammation") accompanies brain injury/disease and systemic infections. Following nerve terminal damage after acute exposure to dopaminergic neurotoxicant, methamphetamine (METH), we documented elevated neuroinflammation, which may serve as a modulator or mediator of astroglial/microglial activation. Activated glia (associated with all types of brain injury) may be neuroprotective or exacerbate neural damage. Our prior genetic and pharmacological interventions have resulted in partial suppression of METH induced neuroinflammation without affecting neurotoxicity/astrogliosis. Here, mice were pretreated with the stress hormone corticosterone (CORT;400 mg/L drinking water) for 1 week or repeated in vivo stress for 5d, consisting of social reorganization and cage shaking. METH administration alone (20mg/kg,s.c.) caused significant increases in proinflammatory cytokine (TNFalpha,IL6,CCL2,IL1beta,LIF,OSM) mRNA expression in striatum at 12h. By 72h marked astrocytic hypertrophy (GFAP protein/immunohistochemistry(IHC)), microglial activation (isolectin IHC) and dopaminergic nerve terminal damage (TH protein /IHC) was observed in striatum. Chronic CORT pretreatment caused exacerbated inflammation, astrocyte hypertrophy and microglial activation after METH exposure in the striatum, hippocampus and cortex. Of note, chronic CORT pretreatment exacerbated METH-induced decreases in TH protein (to 10% of control) in striatum. However, repeated in vivo stress exposure completely blocked striatal dopaminergic neurotoxicity and reduced the neuroinflammatory response to METH. As the levels of chronic CORT approached or exceeded those associated with high physiological stress, our data suggest that chronic CORT therapy or sustained physiological stress sensitizes the CNS neuroinflammatory and neurotoxic responses to METH. Also, more severe or prolonged in vivo stressor application may be required to produce priming of the CNS similar to exogenous CORT.
Keywords
Brain-function; Brain-matter; Immune-reaction; Immunochemistry; Cytochemistry; Neurological-reactions; Neurophysiological-effects; Drug-abuse; Nerve-damage; Neurotoxins; In-vivo-study; Corticoids; Laboratory-animals; Laboratory-testing; Corticosteroids; Stress; Hormone-activity; Hormones; Proteins; Histochemical-analysis; Exposure-assessment; Exposure-levels; Chronic-exposure; Chronic-inflammation; Pharmacodynamics
Source Name
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California
