Delayed treatment with interleukin-1 receptor antagonist protects cortical neurons from injury after transient MCA occlusion
Background and Purpose:Inhibiting interleukin-1 action with its receptor antagonist (IL-1ra) following permanent middle cerebral artery occlusion (MCA-O) reduces the volume of brain infarction and improves neurological function in Wistar rats. We varied the times of IL-1ra administration and tested if IL-1ra treatment reduces the lesion produced by transient MCA-O (tMCA-O). Methods: One MCA was transiently occluded for 1hr in 49 adult male Wistar rats. These animals were grouped according to time of starting IL-1ra treatment (100 mg/Kg, 3 times/day): A) before MCA occlusion; B) at time of reperfusion); C) after 1hr of reperfusion; and D) controls, i.e., placebo given at time of reperfusion. Neurological function and body weight were measured on the day of tMCA-O and daily thereafter. After 7 days of reperfusion, fixed brain sections were obtained and either stained with H&E or immunostained for NeuN, GFAP, and ED-I (neuronal, astroglial, and microglial proteins, respectively). Cellular damage was assessed using quantitative image analysis. Results: Body weight and neurological function were not significantly different among groups A-D. Most rats of groups A-D had small, focal areas of pannecrosis in the striatum at 7 days, but selective neuronal necrosis was the predominant change in the cortex. In the striatum, the area of focal infarction was less in IL-1ra treated groups than in placebo group, but the difference was not statistically significant because of the variability (i.e., large SD). The frequency (mean number/mm2) of surviving neurons in the cortex (showing strong positive nuclear staining with NeuN) was significantly greater (p < 0.001) in the treated groups (A = 532 ± 32; B = 556 ± 33; and C = 588 ± 31) than the untreated group (D = 276 ± 14). Conclusion: The neuroprotective effects derived from reopening the artery after 1 hr of MCA-O were enhanced by administering IL-1ra even when treatment was started 1hr after beginning reperfusion. The protection induced by treatment with IL-1ra seems to be more effective in cortex than striatum.