Neurodegenerative actions of interleukin‐1 in the rat brain are mediated through increases in seizure activity

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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 α‐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.