Inhibition of kainic acid induced expression of interleukin-1 beta and interleukin-1 receptor antagonist mRNA in the rat brain by NMDA receptor antagonists

The cytokines interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist ( IL-1ra) are rapidly induced in response to excitotoxic and ischemic brain d amage. The aim of the present study was to investigate the influence of a n on-competitive (dizocilpine maleate, (MK-801) and a competitive ((R)-CPP) N MDA receptor antagonist on the transient cytokine expression in the rat bra in induced by systemic kainic acid administration. Peripheral administratio n of kainic acid (10 mg/kg, i.p.) results in a transient expression of IL-1 beta and IL-1ra mRNA, mainly in microglia, in regions showing neurodegener ation such as the hippocampus, thalamus, amygdala, and certain cortical reg ions. In addition, a few neurons expressing IL-1ra mRNA were observed in th e piriform cortex and amygdala following kainic acid injection. Administrat ion of MK-801 (i.p.) 1 h prior to kainic acid injection reduced cytokine ex pression in all of these regions. MK-801 at 3.0 mg/kg decreased the IL-1 be ta mRNA expression, blocked or decreased the IL-1ra mRNA expression, depend ing on the brain region. MK-801 at 5.0 mg/kg abolished IL-1ra mRNA expressi on in all of the regions, whereas the IL-1 beta mRNA expression was decreas ed or blocked, depending on the brain region, or the time point investigate d. Peripheral administration of (R)-CPP (15 mg/kg, i.p.) 15 min prior to th e kainic acid injection abolished the LL-1 beta mRNA expression. The IL 1ra mRNA expression was abolished in all regions except for a few neurons in t he piriform cortex. The finding that NMDA receptor antagonists inhibit the IL-1 beta and IL-1ra mRNA synthesis induced by kainic acid suggests that NM DA receptor activation may be involved in triggering cytokine synthesis fol lowing excitotoxic brain damage. (C) 2000 Elsevier Science B.V. All rights reserved.