Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study

Abstract

The cytokine interleukin-1beta (IL-1beta) is implicated in a broad spectrum of CNS pathologies, in which it is thought to exacerbate neuronal loss. Here, the effects of injecting recombinant rat IL-1beta into the striatum of 3-week-old rats were followed noninvasively from 2 to 123 hr using magnetic resonance imaging and spectroscopy. Four hours after injection of IL-1beta (1 ng in 1 microliter), cerebral blood volume was significantly increased, the blood-brain barrier (BBB) became permeable to intravenously administered contrast agent between 4.5 and 5 hr, and the apparent diffusion coefficient (ADC) of brain water fell by 6 hr (5.42 +/- 0. 35 x 10(-4) mm(2)/sec treated, 7.35 +/- 0.77 x 10(-)(4) mm(2)/sec control; p < 0.001). At 24 hr the BBB was again intact, but the ADC, although partially recovered, remained depressed at both 24 and 123 hr (p < 0.03). Depleting the animals of neutrophils before IL-1beta injection prevented the BBB permeability at all time points, but the ADC was still depressed at 6 hr (6.64 +/- 0.34 x 10(-4) mm(2)/sec treated, 7.49 +/- 0.38 x 10(-4) mm(2)/sec control; p < 0.005). No changes were seen in brain metabolites using proton spectroscopy at 6 hr after IL-1beta. Intraparenchymal injection of IL-1beta caused a neutrophil-dependent transient increase in BBB permeability. The presence of neutrophils within the brain parenchyma significantly contributed to the IL-1beta-induced changes in cerebral blood volume and the ADC of brain water. However, IL-1beta apparently had a direct effect on the resident cell populations, which persisted well after all recruited leukocytes had disappeared. Thus the action of IL-1beta alone can give rise to magnetic resonance imaging-visible changes that are normally attributed to alterations to cellular homeostasis.

Figures

Fig. 1.

Typical imaging data set acquired 6 hr after injection of IL-1β. a, T1-weighted axial image; b, T2-weighted axial image;c, ADC map calculated from the diffusion-weighted images; d, image showing the area of BBB breakdown (bright) obtained by dividing the 10 min postcontrast T1-weighted image by the preinjection image. IL-1β injection was into the left hemisphere (top in each image). Note the focal area of decreased ADC, which corresponds to the area of BBB breakdown. Images are in radiological representation with the left side being the right side of the brain and vice versa.

Fig. 2.

Time course of the ADC of brain water after striatal injection of IL-1β. Data shown are the mean ADC (error bars indicate 1 SD) within a region of interest encompassing either the left (IL-1β treatment) or the right (control) striatum of the animals.Asterisks indicate a significant difference between treated and untreated (control) hemispheres: ***p< 0.001; **p < 0.01; *p < 0.03.

Fig. 3.

Comparison of the mean ADC (error bars indicate 1 SD) in the left and right striatum 6 hr after IL-1β injection. Data are presented for the three animal groups: control (injection of vehicle only), depleted (pretreatment with anti-neutrophil serum to deplete neutrophils and then injection of IL-1β), and nondepleted (IL-1β injection only). Asterisks indicate a significant difference between treated and untreated (control) hemispheres: **p < 0.001; * p< 0.005.

Fig. 4.

Comparison of the mean ratio of rCBV in the treated and untreated striatum at 2 and 4 hr after injection (error bars indicate 1 SD). Data are presented for the three animal groups: control (injection of vehicle only), depleted (pretreatment with anti-neutrophil serum to deplete neutrophils and then injection of IL-1β), and nondepleted (IL-1β injection only).Asterisks indicate a significant difference between treated and control hemispheres: *p = 0.004.