Monocyte chemoattractant protein (MCP)-1, a proinflammatory chemokine, recently has been reported to be up-regulated in many models of neuronal damage, including infection, axotomy, Alzheimer's (mouse model), excitotoxicity, and traumatic brain injury. A role for this chemokine in toxic injuries of the CNS has not been established, therefore, we evaluated the expression of MCP-1 following neuronal damage resulting from exposure to the prototypical hippocampal toxicant, TMT. Althought mediators of inflammation (TNF, IL-1, etc) are linked to neurological disease states, they are not, in general, associated with hippocampal damage and gliosis resulting from exposure to TMT. In the present study, however, we found a marked increase in the expression of MCP-1 after exposure of rats to TMT (8 mg/kg, i.p.). MCP-1 mRNA (assessed by RT-PCR) was elevated as early as 3 days post TMT, with peak increases (450%) observed at 21 days; the last timepoint studied. These effects of TMT on MCP-1 mRNA were confirmed by real-time Taqman analysis and were associated with increases in MCP-1 assessed by immunoblot and ELISA. Glucocorticoids (drinking water) suppressed the expression of MCP-1 without affecting TMT-induced gliosis; therefore, MCP-1 does not appear to mediate TMT-induced damage. Although the blood-brain barrier remained intact after TMT and blood could be ruled out as a source of MCP-1 expression in the brain, a source in the periphery for induction of brain MCP-1 cannot be excluded. This latter view is supported by the fact that systematic LPS (0.5 mg/kg) increases hippocampal MCP-1 mRNA in the absence of neuronal damage. MCP-1 may be a sensitive biomarker of neural injury but signals from peripheral target organs cannot be ruled out as sources of signals including brain expression of this chemokine.
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California