Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus.
Limbic status epilepticus was induced in rats by unilateral 60-min electrical stimulation of the CA3 region of the ventral hippocampus. As assessed by RT-PCR followed by Southern blot analysis, transcripts of interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist and inducible nitric oxide synthase were significantly increased 2 h after status epilepticus in the stimulated hippocampus. Induction was maximal at 6 h for interleukin-1beta (445%), interleukin-6 (405%) and tumour necrosis factor-alpha (264%) and at 24 h for interleukin-1 receptor antagonist (494%) and inducible nitric oxide synthase (432%). In rats with spontaneous seizures (60 days after status epilepticus), interleukin-1beta mRNA was still higher than controls (241%). Immunocytochemical staining of interleukin-1beta, interleukin-6 and tumour necrosis factor-alpha was enhanced in glia with a time-course similar to that of the respective transcripts. Sixty days after status epilepticus, interleukin-1beta immunoreactivity was increased exclusively in neurons in one third of the animals. Multiple intracerebroventricular injections of interleukin-1 receptor antagonist (0.5 microg/3 microL) significantly decreased the severity of behavioural convulsions during electrical stimulation and selectively reduced tumour necrosis factor-alpha content in the hippocampus measured 18 h after status epilepticus. Thus, the induction of spontaneously recurring seizures in rats involves the activation of inflammatory cytokines and related pro- and anti-inflammatory genes in the hippocampus. These changes may play an active role in hyperexcitability of the epileptic tissue.
De Simoni
M G
MG
Laboratory of Inflammation and Nervous System Diseases and Laboratory of Experimental Neurology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano, Italy. de_simoni@irfmn.mnegri.it
Perego
C
C
Ravizza
T
T
Moneta
D
D
Conti
M
M
Marchesi
F
F
De Luigi
A
A
Garattini
S
S
Vezzani
A
A
D000818:Animals; D016375:Antisense Elements (Genetics); D001522:Behavior, Animal / Q000502:physiology; D015139:Blotting, Southern; D016207:Cytokines / Q000235:genetics* / Q000276:immunology*; D004569:Electroencephalography / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000032:analysis / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics / Q000276:immunology; D008297:Male; D017628:Microglia / Q000737:chemistry / Q000276:immunology; D008845:Microinjections; D009474:Neurons / Q000737:chemistry / Q000201:enzymology / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D013226:Status Epilepticus / Q000276:immunology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000276:immunology
D016375:Antisense Elements (Genetics); D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat