title: Neurodegenerative actions of interleukin-1 in the rat brain are mediated through increases in seizure activity.
abstract: The cytokine interleukin-1 (IL-1) is an established and important mediator of diverse forms of neuronal injury in experimental animals. However, its mechanisms of action remain largely unknown. We have reported previously that IL-1 markedly enhances excitotoxic injury induced in the rat by striatal administration of the excitotoxin alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), leading to widespread neuronal loss throughout the ipsilateral cortex. Here we tested the hypothesis that IL-1 causes this injury through induction and/or enhancement of seizure activity in the rat. Consistently with this hypothesis, intrastriatal injection of AMPA or AMPA with IL-1 in the rat brain increased c-Fos expression in regions similar to those in which c-Fos has been reported previously in response to seizures. A significant increase in cortical neuronal activity (number of c-Fos positive cells) was observed in response to AMPA with IL-1 compared with AMPA (8 hr after injection). Increased seizure duration [3,522 +/- 660 sec (SEM) vs. 1,415 +/- 301 sec; P < 0.001] and cell death volume (140 +/- 20 mm3 vs. 52 +/- 6 mm3; P < 0.001) were seen in response to coinfusion of AMPA with IL-1 vs. AMPA alone. In addition, the anticonvulsant diazepam (intraperitoneal) significantly reduced cell death (P < 0.001) and seizure duration (P < 0.001) induced by AMPA with IL-1, and a significant correlation was found between seizure duration and cell death volume. These findings support our hypothesis that IL-1 enhances excitotoxic injury by enhancement of seizures, which may be of relevance to IL-1 actions in other forms of neuronal injury, including cerebral ischemia.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: H C
authors.initials: HC
authors.lastname: Patel
authors.forename: F M
authors.initials: FM
authors.lastname: Ross
authors.forename: L E
authors.initials: LE
authors.lastname: Heenan
authors.forename: R E
authors.initials: RE
authors.lastname: Davies
authors.forename: N J
authors.initials: NJ
authors.lastname: Rothwell
authors.forename: S M
authors.initials: SM
authors.lastname: Allan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003975:Diazepam / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004347:Drug Interactions; D004569:Electroencephalography / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D007375:Interleukin-1 / Q000633:toxicity*; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000150:complications* / Q000188:drug therapy; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
chemical_list: D000927:Anticonvulsants; D007375:Interleukin-1; D016760:Proto-Oncogene Proteins c-fos; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003975:Diazepam