Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis.
OBJECTIVE
We investigated the changes in the expression of proinflammatory cytokines and related molecules in the rodent hippocampus after the induction of limbic seizures. We then studied the effects of pharmacologic intervention on the interleukin (IL)-1 system on limbic seizures and the susceptibility to seizures of transgenic mice overexpressing the naturally occurring antagonist of IL-1 (IL-1Ra) in astrocytes.


METHODS
Limbic seizures were induced in rodents by intrahippocampal injection of kainic acid or bicuculline methiodide or by electrical stimulation of the hippocampus causing status epilepticus (SE). Seizure activity was recorded by EEG analysis and behavioral observation according to Racine's scale. Cytokine expression in the hippocampus was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by Southern blot quantification of the various messenger RNAs (mRNAs) and by immunocytochemistry.


RESULTS
We found that limbic seizures rapidly and transiently enhanced IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha mRNA in the hippocampus with a peak effect at 6 h after SE. Immunoreactivity of the various cytokines was increased in glia. The increase of IL-1Ra was delayed because the peak effect was observed at 24 h after SE. Moreover, IL-1Ra was not produced in large excess, as during peripheral inflammation but in a molar ratio to IL-1beta of 1:1. Intrahippocampal injection of IL-1beta worsened seizure activity, whereas IL-1Ra was a powerful anticonvulsant in various models of limbic seizures. Transgenic mice overexpressing IL-1Ra in astrocytes were less sensitive to bicuculline-induced seizures.


CONCLUSIONS
This study shows that limbic seizures in rodents rapidly and reversibly induce proinflammatory cytokines in glia and suggests that changes in the IL-1Ra/IL-1beta ratio in brain may represent an effective physiopathologic mechanism to control seizures.
Vezzani
Annamaria
A
Department of Neuroscience, Mario Negri Institute of Pharmacological Research, Via Eritrea 62, 20157 Milan, Italy. vezzani@marionegri.it
Moneta
Daniela
D
Richichi
Cristina
C
Aliprandi
Marisa
M
Burrows
Stephanie J
SJ
Ravizza
Teresa
T
Perego
Carlo
C
De Simoni
M Grazia
MG
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004827:Epilepsy / Q000209:etiology* / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D008032:Limbic System / Q000503:physiopathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000503:physiopathology*; D012795:Sialoglycoproteins / Q000494:pharmacology
D016207:Cytokines; C507764:Il1rn protein, mouse; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins