HYPOXIC-ISCHEMIC INJURY INDUCES MONOCYTE CHEMOATTRACTANT PROTEIN-1 EXPRESSION IN NEONATAL RAT-BRAIN

Monocyte chemoattractant protein-1 (MCP-I) regulates monocyte accumula tion in several macrophage-dependent experimental disease models. In t he neonatal brain, activated microglia accumulate rapidly after hypoxi c-ischemic injury. These cells produce potentially neurotoxic factors that may contribute to the progression of injury. To determine whether MCP-I could be one of the molecular signals that influences the micro glial response to hypoxic-ischemic injury in the neonatal brain, we ex amined the impact of acute hypoxic-ischemic injury on MCP-I mRNA and p rotein expression. Seven-day-old rats underwent right carotid artery l igation, followed by 3 hours of 8% oxygen exposure, to elicit ipsilate ral forebrain hypoxic-ischemic injury. To detect MCP-T mRNA in situ hy bridization assays were performed using S-35-labeled antisense ribopro bes generated from rat MCP-1 cDNA. Animals were evaluated 0, I, 2, 4, 8, 16, 24, 48, and 120 hours after hypoxic exposure (N greater than or equal to 3/group). Immunocytochemistry (with a polyclonal rabbit anti rat MCP-1 antibody) was used to determine the anatomic and temporal di stribution of MCP-I, in samples obtained 10 minutes to 5 days after hy poxic exposure (N greater than or equal to 3/group). Monocyte chemoatt ractant protein-1 mRNA was first detected in periventricular regions o f the lesioned hemisphere 1 hour after hypoxia-ischemia; periependymal and intraparenchymal MCP-I mRNA expression were detected at 4 hours; hybridization signal peaked at 8 to 24 hours; and no MCP-I mRNA was de tected at 48 and 120 hours. In lesioned forebrain, MCP-I protein expre ssion were consistently detected at 2.5 to 48 hours after hypoxia-isch emia. Many immunoreactive cells appeared to be neurons. These results suggest that in the developing brain, MCP-1 could represent a function ally important molecular signal for the microglial response to hypoxic -ischemic injury.