Abstract
Danger-associated molecular patterns are released by damaged cells and trigger neuroinflammation through activation of non-specific pattern recognition receptors, e.g., toll-like receptors (TLRs). Since the role of TLR2 and 4 after traumatic brain injury (TBI) is still unclear, we examined the outcome and the expression of pro-inflammatory mediators after experimental TBI in Tlr2/4−/− and wild-type (WT) mice. Tlr2/4−/− and WT mice were subjected to controlled cortical injury and contusion volume and brain edema formation were assessed 24 h thereafter. Expression of inflammatory markers in brain tissue was measured by quantitative PCR 15 min, 3 h, 6 h, 12 h, and 24 h after controlled cortical impact (CCI). Contusion volume was significantly attenuated in Tlr2/4−/− mice (29.7 ± 0.7 mm3 as compared to 33.5 ± 0.8 mm3 in WT; p < 0.05) after CCI while brain edema was not affected. Only interleukin (IL)-1β gene expression was increased after CCI in the Tlr2/4−/− relative to WT mice. Inducible nitric oxide synthetase, TNF, IL-6, and COX-2 were similar in injured WT and Tlr2/4−/− mice, while the increase in high-mobility group box 1 was attenuated at 6 h. TLR2 and 4 are consequently shown to potentially promote secondary brain injury after experimental CCI via neuroinflammation and may therefore represent a novel therapeutic target for the treatment of TBI.
Highlights
Head injury is a major public health problem as it is the most frequent cause of death and disability in young adults and produces considerable demands on health services [1]
Brain Water Content In WT mice, traumatic brain injury (TBI) significantly increased BWC of the traumatized right hemisphere to 80.9 ± 0.5% (p < 0.001), while the BWC of the contralateral hemisphere did not change significantly compared to non-traumatized animals (78.5 ± 0.2%)
In Tlr2/4−/− animals, post-traumatic BWC was similar to WT mice in the traumatized (80.3 ± 0.2% in TLR2/4−/− versus 80.9 ± 0.5% in WT animals; p = 0.573) as well as in the non-traumatized contralateral hemisphere (78.3 ± 0.4% in TLR2/4−/− versus 78.5 ± 0.2% in WT animals; not significant)
Summary
Head injury is a major public health problem as it is the most frequent cause of death and disability in young adults and produces considerable demands on health services [1]. In the pathophysiology of TBI, primary and secondary brain damage needs to be differentiated. TLR2 and 4 Deficiency in TBI caused by molecular events initiated by the primary lesion leads to propagation of the tissue damage and is an important predictor of clinical outcome [2]. As a matter we are unable to reverse and reduce the instant primary brain damage, but delayed secondary loss of tissue is a target for the therapy of TBI and its sequelae for many years. Though several clinical management strategies to reduce secondary brain damage are summarized in guidelines for the treatment of traumatic brain injury (TBI), the efforts to directly target molecular events by neuroprotective drugs failed so far [3,4,5]
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