Intracerebral NMDA injection stimulates production of interleukin-1 beta in perinatal rat brain

Susceptibility to NMDA neurotoxicity peaks in the early postnatal period in rats. Although indirect evidence suggests that interleukin-1 beta is a mediator of NMDA neurotoxicity in perinatal rats, direct confirmation of NMDA-induced interleukin-1 beta production in the brain has not been reported previously. The primary goal of this study was to determine if intracerebral injection of a neurotoxic dose of NMDA stimulates interleukin-1 beta production acutely. We used a rat-specific interleukin-1 beta ELISA to quantify brain tissue homogenate interleukin-1 beta content, and an immunocytochemical assay with a monoclonal antirat interleukin-1 beta antibody to visualize its distribution. NMDA (10 nmol) was injected stereotaxically into 7-day-old rats, using coordinates that targeted the striatum and overlying dorsal hippocampus. Interleukin-1 beta concentrations were measured in samples from the injected and contralateral cerebral hemispheres 0-12 h later; In addition, the impact of treatment with the noncompetitive NMDA antagonist MK-801 on interleukin-1 beta production was assessed. We found marked increases in tissue content of interleukin-1 beta in the lesioned hemisphere; values peaked at 6 h post injection. Treatment with MK-801 (1 mg/kg) blocked NMDA-induced increases in interleukin-1 beta. Preliminary immunocytochemical analysis demonstrated high concentrations of interleukin-1 beta-immunoreactive cells in the lesioned hippocampus, and concurrent increases in interleukin-1 beta immunoreactivity diffusely in the ependyma at 6 h after NMDA administration. Our data provide the first direct evidence that NMDA-induced excitotoxic injury stimulates interleukin-1 beta production in vivo.