Lack of Benefit on Brain Edema, Blood-Brain Barrier Permeability, or Cognitive Outcome in Global Inducible High Mobility Group Box 1 Knockout Mice Despite Tissue Sparing after Experimental Traumatic Brain Injury.

High mobility group box 1 (HMGB1) is a prototypical danger-associated molecular pattern molecule that is considered a late mediator of neuro-inflammation after traumatic brain injury (TBI). Prior studies have suggested that targeting HMGB1 may lead to neuroprotective effects, but none of these studies have reported cognitive outcomes. We hypothesized that loss of HMGB1 before and after TBI would markedly attenuate post-traumatic brain edema, blood-brain barrier (BBB) permeability, improve functional deficits and long-term neuropathology versus control mice. Using the controlled cortical impact model and conditional global HMGB1 knockout (HMGB1 KO) mice, we demonstrate that there was a neuroprotective effect seen in the HMGB1 KO versus wild-type control evidenced by a significant reduction in contusion volume. However, two surprising findings were 1) the lack of benefit on either post-traumatic brain edema or BBB permeability, and 2) that spatial memory performance was impaired in HMGB1 KO naïve mice such that the behavioral effects of HMGB1 deletion in uninjured naïve mice were similar to those observed after TBI. Our data suggest the possibility that the role of HMGB1 in TBI is a "double-edged sword"; that is, despite the benefits on selected aspects of secondary injury, the sustained absence of HMGB1 may impair cognitive function, even in naïve mice. Given the pleiotropic actions of extracellular and intracellular HMGB1, when evaluating the potential use of therapies targeting HMGB1, effects on long-term cognitive outcome should be carefully evaluated. It also may be prudent in future studies to examine cell-specific effects of manipulating the HMGB1 pathway.