Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat.
The cytokine IL-1 mediates diverse forms of neurodegeneration, but its mechanism of action is unknown. We have demonstrated previously that exogenous and endogenous IL-1 acts specifically in the rat striatum to dramatically enhance ischemic and excitotoxic brain damage and cause extensive cortical injury. Here we tested the hypothesis that this distant effect of IL-1 is mediated through polysynaptic striatal outputs to the cortex via the hypothalamus. We show that IL-1beta injected into the rat striatum with the excitotoxin alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1beta (mRNA and protein) mainly in the cortex where maximum injury occurs. Marked increases in IL-1beta mRNA and protein were also observed in the hypothalamus. S-AMPA, injected alone into the striatum, caused only localized damage, but administration of IL-1beta into either the striatum or the lateral hypothalamus immediately after striatal S-AMPA resulted in widespread cell loss throughout the ipsilateral cortex. Finally we showed that the cortical cell death produced by striatal coinjection of S-AMPA and IL-1beta was significantly reduced by administration of the IL-1 receptor antagonist into the lateral hypothalamus. These data suggest that IL-1beta can act in the hypothalamus to modify cell viability in the cortex. We conclude that IL-1-dependent pathways project from the striatum to the cortex via the hypothalamus and lead to cortical injury, and that these may contribute to a number of human neurological conditions including stroke and head trauma.
Allan
S M
SM
School of Biological Sciences, 1.124 Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom.
Parker
L C
LC
Collins
B
B
Davies
R
R
Luheshi
G N
GN
Rothwell
N J
NJ
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics* / Q000633:toxicity*; D007700:Kinetics; D008297:Male; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000633:toxicity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000494:pharmacology; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity*
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid