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 damage. The aim of the present study was to investigate the influence of a non-competitive (dizocilpine maleate, MK-801) and a competitive ((R)-CPP) NMDA receptor antagonist on the transient cytokine expression in the rat brain induced by systemic kainic acid administration. Peripheral administration 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 neurodegeneration such as the hippocampus, thalamus, amygdala, and certain cortical regions. In addition, a few neurons expressing IL-1ra mRNA were observed in the piriform cortex and amygdala following kainic acid injection. Administration of MK-801 (i.p.) 1 h prior to kainic acid injection reduced cytokine expression in all of these regions. MK-801 at 3.0 mg/kg decreased the IL-1 beta mRNA expression, blocked or decreased the IL-1ra mRNA expression, depending on the brain region. MK-801 at 5.0 mg/kg abolished IL-1ra mRNA expression in all of the regions, whereas the IL-1 beta mRNA expression was decreased or blocked, depending on the brain region, or the time point investigated. Peripheral administration of (R)-CPP (15 mg/kg, i.p.) 15 min prior to the kainic acid injection abolished the IL-1 beta mRNA expression. The IL-1ra mRNA expression was abolished in all regions except for a few neurons in the piriform cortex. The finding that NMDA receptor antagonists inhibit the IL-1 beta and IL-1ra mRNA synthesis induced by kainic acid suggests that NMDA receptor activation may be involved in triggering cytokine synthesis following excitotoxic brain damage.
Eriksson
C
C
Division of Geriatric Medicine, NEUROTEC, Karolinska Institute, Huddinge Hospital, Novum, S-141 86 Huddinge, Sweden.
Zou
L P
LP
Ahlenius
S
S
Winblad
B
B
Schultzberg
M
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004831:Epilepsies, Myoclonic / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D017403:In Situ Hybridization; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000235:genetics*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D010879:Piperazines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D012795:Sialoglycoproteins; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D007608:Kainic Acid