Systemic Inflammation Exacerbates Behavioral and Histopathological Consequences of Isolated Traumatic Brain Injury in Rats

The proinflammatory cytokine interleukin-1beta (IL-1beta) is induced rapidly after traumatic brain injury (TBI) and contributes to the inflammatory events that lead to neuronal loss. Although an important source of IL-1beta is from the injured brain itself, in patients with multiple organ trauma (polytrauma) IL-1beta is also released into the bloodstream which may potentially influence brain vulnerability. The purpose of this study was to determine the effects of systemic inflammation induced by peripheral administration of IL-1beta on histopathological and behavioral outcome after moderate fluid percussion (FP) brain injury in rats. At 30 min or 24 h after TBI, saline, 20 mug/kg or 40 mug/kg of IL-1beta was injected (n=4-9/group) intraperitoneally (IP). Sham operated animals (n=9) received either saline or IL-1beta (20 or 40 mug/kg) injections. The somatosensory tactile placing test was administered at 1, 2 and 3 days posttrauma. IL-1beta-treated animals showed significant placing deficits compared to vehicle-treated TBI animals. Three days after injection, contusion areas and volumes were significantly increased (p<0.05) with both IL-1beta doses and at both treatment times compared to vehicle-treated animals. IL-1beta-treated rats showed more contusion injury and hippocampal neuronal damage as well as enhanced perivascular neutrophil accumulation. Cortical IL-1r1 mRNA increased as early as 1 h following TBI, peaking at 24 h and remained elevated 3 days posttrauma. These data show that the posttraumatic administration of IL-1beta significantly aggravates behavioral outcome and increases overall contusion volume after TBI. Increased systemic inflammatory processes, including extravasation of activated leukocytes and proinflammatory cytokines could participate in this detrimental outcome. Because peripherally circulating cytokines and other neurotoxic factors may be increased following multi-organ trauma, these findings may be important in targeting therapeutic interventions in this patient population.