The Role of IL-1 Signaling in Neurodegeneration, Neuroinflammation, and Behavior after Soman-Induced Status Epilepticus
Abstract
Soman (GD) is a nerve agent that blocks acetylcholinesterase, resulting in a buildup of acetylcholine in the synaptic cleft that induces a cholinergic crisis. GD exposure induces status epilepticus, that results in brain damage to the piriform cortex, amygdala, thalamus, and hippocampus. This brain injury stimulates peripheral macrophages and leukocytes, and microglia and astrocytes to overexpress neurotoxic cytokines, including Interleukin-1 (IL-1), resulting in a neuroinflammatory response. IL-1 binds to the IL-1 receptor (IL-1R1) to initiate IL-1 signaling by activating various kinase pathways, which activate the expression of other pro-inflammatory cytokines in response to injury (111). The IL-1R1 is inhibited by the IL-1 receptor antagonist (IL-1Ra), which competes with IL-1 for binding to the IL-1R1 (99). IL-1R1 and IL-1Ra knockout (KO) mice have been utilized to study various forms of CNS injury such as cerebral ischemia, Beta-amyloid infusion, and kainic acid induced seizures (9; 27; 120; 122). However, the role of IL-1 signaling after GD exposure has never been investigated with these KO strains. The purpose of these studies was to determine the role of IL-1 signaling after GD induced SE on neurodegeneration, neuroinflammation, and behavioral function. Wild type (WT), IL-1Ra KO, and IL-1R1 KO mice were exposed to GD, after which behavior was assessed with the Open Field, Zero Maze, and Barnes Maze (102). The neuroinflammatory response was examined using multiplex bead immunoassays (54). Anakinra, the human recombinant IL-1Ra (43) therapeutic, was studied to assess its neuroprotective effect after GD exposure. Results showed that WT and IL-1Ra KO mice sustain brain injury after GD-induced SE, whereas IL-1R1 KO mice show less brain damage 24 hours after convulsion onset that does not extend up to 18 days post exposure. IL-1R1 KO mice were less anxious than the WT mice after GD exposure, but IL-1Ra KO mice showed impaired learning over time.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 18, 2016
- Accession Number
- AD1127776
Entities
People
- Teresa M. Ferrara-bowens
Organizations
- Uniformed Services University of the Health Sciences