Adenovirus-mediated over-expression of Interleukin-1 receptor antagonist reduces susceptibility to excitotoxic brain injury in perinatal rats

• Published in: Neuroscience 1996-12, Vol.75 (4), p.1033-1045
• Main Authors: Hagan, P, Barks, J.D.E, Yabut, M, Davidson, B.L, Roessler, B, Silverstein, F.S
• Format: Article
• Language: English
• Subjects: adenovirus; Adenoviruses, Human; Animals; Animals, Newborn; beta-Galactosidase - biosynthesis; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Injuries - pathology; Brain Injuries - prevention & control; Cerebral Ventricles - drug effects; Cerebral Ventricles - physiology; Corpus Striatum - drug effects; Corpus Striatum - pathology; cytokine; Excitatory Amino Acid Antagonists - administration & dosage; Excitatory Amino Acid Antagonists - toxicity; excitotoxicity; Genetic Vectors; Humans; Injections, Intraventricular; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Medical sciences; Microinjections; N-Methylaspartate - administration & dosage; N-Methylaspartate - toxicity; Neuropharmacology; neuroprotection; Neuroprotective agent; NMDA; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Recombinant Proteins - biosynthesis; Sialoglycoproteins - biosynthesis
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/0306-4522(96)00225-4

In seven-day-old rats, intracerebral injection of N-methyl- d-aspartate transiently stimulates expression of Interleukin-1β messenger RNA. To evaluate the role of Interleukin-1β in the pathogenesis of excitotoxic injury, we sought to determine if Interleukin-1 receptor antagonist, an endogenous competitive inhibitor of Interleukin-1β, could attenuate N-methyl- d-aspartate-induced injury. To induce sustained over-expression of Interleukin-1 receptor antagonist in the brain, a recombinant adenovirus encoding Interleukin-1 receptor antagonist was administered by intracerebroventricular injection into three-day-old rats. Increased brain concentrations of Interleukin-1 receptor antagonist two to six days later were documented by assays of tissue homogenates and by immunocytochemistry. To evaluate the impact of Interleukin-1 receptor antagonist on N-methyl- d-aspartate neurotoxicity, three-day-old animals received intracerebroventricular injections of either adenovirus encoding Interleukin-1 receptor antagonist or a control adenovirus encoding β-galactosidase, followed four days later by right intrastriatal injections of N-methyl- d-aspartate (10 nmol/0.5 μl), a dose that typically elicits excitotoxic injury in the ipsilateral striatum and adjacent hippocampus, or saline. Animals were killed five days later, and brain damage was quantitated by measurement of bilateral cross-sectional areas of the striatum and anterior hippocampus. In three independent experiments, in N-methyl- d-aspartate-lesioned animals, both striatal and hippocampal injuries were reduced in animals that had been infected with adenovirus that encoded Interleukin-1 receptor antagonist, in comparison with littermates infected with the control adenovirus (right striatal volume loss ranged from 16 to 24%, compared with 54–65% volume loss in controls). There was no striatal atrophy in adenovirus-infected saline-injected animals. These results provide strong support for the hypothesis that Interleukin-1β is a mediator of excitotoxic brain injury in perinatal rats.