Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain

Abstract

Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize post-traumatic epilepsy in a mouse model of pediatric brain injury, and to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by magnetic resonance imaging. At 2 weeks and 3 months post-injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1β and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra-TBI mice showed improved spatial memory at 4 months post-injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model's utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility. Epilepsy is a common cause of morbidity after traumatic brain injury in early childhood. However, a limited understanding of how epilepsy develops, particularly in the immature brain, likely contributes to the lack of efficacious treatments. In this preclinical study, we first demonstrate that a mouse model of traumatic injury to the pediatric brain reproduces many neuropathological and seizure-like hallmarks characteristic of epilepsy. Second, we demonstrate that targeting the acute inflammatory response reduces cognitive impairments, the degree of neuropathology, and seizure susceptibility, after pediatric brain injury in mice. These findings provide evidence that inflammatory cytokine signaling is a key process underlying epilepsy development after an acquired brain insult, which represents a feasible therapeutic target to improve quality of life for survivors.

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…39 Pharmacologic targeting of IL1-b using IL-1Ra in an experimental model of pediatric traumatic brain injury (TBI) in mice, reduced seizure susceptibility to pentylenetetrazol and the number of evoked seizures, and improved spatial memory. 46 This set of data suggests that the IL-1b signaling pathway is involved in the mechanisms underlying seizures and comorbidity development.…”

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…47,48,51 For instance, treating mice with an IL-1R antagonist for 1 week after pediatric TBI resulted in reduced susceptibility to provoked seizures in adulthood. 52 Similarly, inhibiting proinflammatory signaling using HMGB1 and Toll-like receptor 4 antagonists reduced established epileptic seizures in a model of temporal lobe epilepsy. 48 Therefore, it would seem that suppressing proinflammatory responses may be beneficial, but caution should be taken, because these are also associated with triggering repair mechanisms, so complete suppression of such processes may not be an ideal strategy.…”

“…Finally, blocking these M1 cytokines or their biosynthesis is known to reduce epileptogenesis in both genetic and acquired models of epilepsy . For instance, treating mice with an IL‐1R antagonist for 1 week after pediatric TBI resulted in reduced susceptibility to provoked seizures in adulthood . Similarly, inhibiting proinflammatory signaling using HMGB1 and Toll‐like receptor 4 antagonists reduced established epileptic seizures in a model of temporal lobe epilepsy .…”

Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid–induced temporal lobe epilepsy in rats

“…Many studies have uncovered a connection between epilepsy and neuroinflammation. 2,11,12 Prolyl oligopeptidase (PREP), a proline-specific endooligopeptidase, has been proposed to be involved in neurodegeneration, cell proliferation, differentiation, and neuroinflammation. 1,2 A proinflammatory response can contribute to cell death, 3,4 network excitability, 5,6 and synaptic reorganization.…”

“…9,10 Moreover, antiinflammatory approaches during epileptogenesis in animal models of acquired epilepsy can affect seizure development. 2,11,12 Prolyl oligopeptidase (PREP), a proline-specific endooligopeptidase, has been proposed to be involved in neurodegeneration, cell proliferation, differentiation, and neuroinflammation. [13][14][15] The proposed underlying mechanisms include modification of neuropeptides and alteration of inositol triphosphate, an intracellular signaling molecule, to control gene expression, although no clear role has been established to date.…”