Abstracts

Rationale: Traumatic brain injury (TBI) is a major contributor to death and disability worldwide. Children are at particularly high risk of both sustaining a TBI and experiencing serious long-term consequences, such as cognitive deficits, mental health problems and post-traumatic epilepsy. Severe TBI patients are highly susceptible to nosocomial infections, which are mostly acquired within the first week of hospitalization post-TBI. Yet the potential chronic impact of such acute infections following pediatric TBI remains unclear. In this study, we hypothesized that a peripheral immune challenge, such as lipopolysaccharide (LPS)—mimicking a hospital-acquired infection—would worsen inflammatory, neurobehavioral, and seizure outcomes after experimental pediatric TBI.

Methods: To test this, three-week old male C57Bl/6J mice received a moderate controlled cortical impact or sham surgery, followed by 1 mg/kg i.p. LPS (or 0.9% saline vehicle) at 4 days TBI. Mice were randomized to four groups; sham-saline, sham-LPS, TBI-saline or TBI-LPS (n=15/group).

Results: Reduced general activity and increased anxiety-like behavior were observed within 24 h in LPS-treated mice, indicating a transient sickness response. LPS-treated mice also exhibited a reduction in body weights, which persisted chronically. From 2 months post-injury, mice underwent a battery of tests for sensorimotor, cognitive, and psychosocial behaviors. TBI resulted in hyperactivity and spatial memory deficits, independent of LPS; whereas LPS resulted in subtle deficits in spatial memory retention. At 5 months post-injury, video-electroencephalographic recordings were obtained to evaluate both spontaneous seizure activity as well as the evoked seizure response to pentylenetetrazol (PTZ). TBI increased susceptibility to PTZ-evoked seizures; whereas LPS appeared to increase the incidence of spontaneous seizures. Finally, post-mortem analyses found that TBI, but not LPS, resulted in robust glial reactivity and loss of cortical volume; while the combination of TBI + LPS appeared to influence hippocampal volume. Both TBI and LPS independently had modest effects on chronic hippocampal gene expression.

Conclusions: Together, contrary to our hypothesis, we observed minimal synergy between TBI and LPS. Instead, pediatric TBI and a subsequent transient immune challenge independently influenced chronic outcomes. These findings have implications for future preclinical modeling as well as acute post-injury patient management.

Funding: Please list any funding that was received in support of this abstract.: The authors are supported by grants from the National Health and Medical Research Council of Australia [APP1141347 to BDS; APP1176426 to TOB; APP1087172 to PCE], a Co-Funded Monash Graduate Scholarship [RS], Monash University Central Clinical School [BDS and SS], and the US Department of Defense [W81XWH2010848; BDS].