IL-1β Antibody Protects Brain from Neuropathology of Hypoperfusion

Abstract

Chronic brain hypoperfusion is the primary cause of vascular dementia and has been implicated in the development of white matter disease and lacunar infarcts. Cerebral hypoperfusion leads to a chronic state of brain inflammation with immune cell activation and production of pro-inflammatory cytokines, including IL-1β. In the present study, we induced chronic, progressive brain hypoperfusion in mice using ameroid constrictor, arterial stenosis (ACAS) surgery and tested the efficacy of an IL-1β antibody on the resulting brain damage. We observed that ACAS surgery causes a reduction in cerebral blood flow (CBF) of about 30% and grey and white matter damage in and around the hippocampus. The IL-1β antibody treatment did not significantly affect CBF but largely eliminated grey matter damage and reduced white matter damage caused by ACAS surgery. Over the course of hypoperfusion/injury, grip strength, coordination, and memory-related behavior were not significantly affected by ACAS surgery or antibody treatment. We conclude that antibody neutralization of IL-1β is protective from the brain damage caused by chronic, progressive brain hypoperfusion.

Keywords: IL-1β; IL-1β antibody; canakinumab; cerebral hypoperfusion; white matter damage and grey matter damage.

Figure 1

Schematic of the experimental design for the assessment of the effects of hypoperfusion and an IL-1β antibody on behavior and neuropathology in mice.

Figure 2

Effects of ameroid constrictor, arterial stenosis (ACAS) surgery and IL-1β on cerebral blood flow 36 days after ACAS or sham surgery and the initiation of IL-1β antibody or IgG treatment. N = 9 mice/group; *** p < 0.001 vs. sham IgG; ^### p < 0.001 vs. sham IL-1β Ab. n.s. = not significantly different.

Figure 3

Grey matter pathology at 42 days after ACAS or sham surgery and the initiation of IL-1β antibody or IgG treatment. Depicted are the four treatment groups: sham + IgG, sham + IL-1β Ab, ACAS = IgG, and ACAS + IL-1β Ab for the following brain regions: SSCTX = somatosensory cortex; ECTCTX = entorhinocortex; CA1 and CA3 = regions of the hippocampus, and DG = dentate gyrus of the hippocampus. Areas shown with dotted lines or arrows are examples of lesions that were quantified as shown in Table 1. Dashed lines in the SSCTX outline a degenerative lesion; the arrow in the ECT CTX indicates a condensed lesion; the arrows in the CA1, CA2, and DG show cell loss, Bar graphs shown in (A–C) are mean ± SEM for lesion severity scores for each of the four treatment groups. N = 9 mice/group. ** p < 0.01 vs. the sham + IgG group or the ACAS + IgG group. *** p < 0.001 vs. sham + IgG group or the ACAS + IL1-β Ab group.

Figure 4

White matter pathology at 42 days after ACAS or sham surgery and the initiation of IL-1β antibody or IgG treatment. Depicted are the four treatment groups: sham = IgG, Sham + IL-1β Ab, ACAS = IgG and ACAS + IL-1β Ab for the following brain regions: globus pallidus and corpus callosum. The arrow in the ACAS IgG globus pallidus slide shows disorganized axons; the arrow in the ACAS IgG corpus callosum medial slide shows axonal loss; and the dashed line in the ACAS IgG corpus callosum lateral slide shows axonal disorganization. Bar graphs shown in (A–D) are mean ± SEM for lesion severity scores for each of the four treatment groups: n = 9 mice/group; * p < 0.05 between the connected groups; *** p < 0.001 vs. sham + IgG group or the ACAS + IL1-β Ab group.