Tibial Fracture Exacerbates Traumatic Brain Injury Outcomes and Neuroinflammation in a Novel Mouse Model of Multitrauma

Abstract

Multitrauma is a common medical problem worldwide, and often involves concurrent traumatic brain injury (TBI) and bone fracture. Despite the high incidence of combined TBI and fracture, preclinical TBI research commonly employs independent injury models that fail to incorporate the pathophysiologic interactions occurring in multitrauma. Here, we developed a novel mouse model of multitrauma, and investigated whether bone fracture worsened TBI outcomes. Male mice were assigned into four groups: sham-TBI +sham-fracture (SHAM); sham-TBI+fracture (FX); TBI+sham-fracture (TBI); and TBI+fracture (MULTI). The injury methods included a closed-skull weight-drop TBI model and a closed tibial fracture. After a 35-day recovery, mice underwent behavioral testing and magnetic resonance imaging (MRI). MULTI mice displayed abnormal behaviors in the open-field compared with all other groups. On MRI, MULTI mice had enlarged ventricles and diffusion abnormalities compared with all other groups. These changes occurred in the presence of heightened neuroinflammation in MULTI mice at 24 hours and 35 days after injury, and elevated edema and bloodbrain barrier disruption at 24 hours after injury. Together, these findings indicate that tibial fracture worsens TBI outcomes, and that exacerbated neuroinflammation may be an important factor that contributes to these effects, which warrants further investigation.

Activation of Alpha-7 Nicotinic Acetylcholine Receptor Reduces Brain Edema in Mice with Ischemic Stroke and Bone Fracture

“…The expression of claudin-5 significantly decreased in a pMCAO rodent model [45, 46], which was responsible for increased BBB permeability and secondary brain edema. Recent studies have shown that tibia fracture exacerbates traumatic brain BBB disruption and edema [32, 33]. However, our study showed that tibia fracture post-stroke did not reduce claudin-5 expression further when compared with stroke-only mice.…”

“…We showed in this study that tibia fracture after ischemic stroke increases brain edema, which has been observed to occur as early as three hours after MCA occlusion in a rat MCAO model, reaching the maximum level on the third day and then gradually diminishing thereafter [31]. Bone fracture has also been shown to exacerbate brain edema and worsen the outcomes of traumatic brain injury in a multitrauma mouse model [32, 33]. Brain edema plays a critical role in neuronal damage, and clinical deterioration is often associated with brain ischemia.…”

Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers

“…Additionally, TBI, whether associated with a fall, motor vehicle accident, sports injury, or assault, often occurs concomitantly with other injuries. While studies have begun to investigate combined injuries such as TBI and bone fractures 87–89 , future opportunities exist to expand this research and study combined injuries that often occur in the clinical setting, such as TBI with hypoxia, and TBI with hypoglycemia. Furthermore, future opportunities exist to expand the mFPI model to repetitive head injury studies.…”

Sodium selenate, a protein phosphatase 2A activator, mitigates hyperphosphorylated tau and improves repeated mild traumatic brain injury outcomes

“…As previously described (Shultz et al, 2014b(Shultz et al, , 2015b(Shultz et al, , 2015c, MRI scanning was performed after the completion of behavioral testing (n ¼ 6e8 rats/group) using a 4.7 T Bruker Avance III scanner with 30 cm horizontal bore and fitted with a BGA12S2 actively shielded gradient set capable of 440 mT/m and actively decoupled volume transmit and 4-chanel surface receive coils. Anaesthetized animals were positioned supinely on an animal cradle with stereotactic fixation and a nose cone positioned over the rat's snout to maintain anesthesia.…”

“…All volumetric analysis procedures followed those previously described (Johnstone et al, 2015;Shultz et al, 2015bShultz et al, , 2015cShultz et al, , 2014aShultz et al, , 2014b. Volumes of eight manually drawn regions of interest (ROI), including the cortex, hippocampus, corpus callosum, and lateral ventricles from both hemispheres, were quantified using the T 2 -weighted MRI images (FSL, Analysis Group, Oxford, UK).…”