A CD11d Monoclonal Antibody Treatment Reduces Tissue Injury and Improves Neurological Outcome after Fluid Percussion Brain Injury in Rats

Abstract

Traumatic brain injury (TBI) is an international health concern often resulting in chronic neurological abnormalities, including cognitive deficits, emotional disturbances, and motor impairments. An anti-CD11d monoclonal antibody that blocks the CD11d/CD18 integrin and vascular cell adhesion molecule (VCAM)-1 interaction following experimental spinal cord injury improves functional recovery, while reducing the intraspinal number of neutrophils and macrophages, oxidative activity, and tissue damage. Since the mechanisms of secondary injury in the brain and spinal cord are similar, we designed a study to evaluate fully the effects of antiCD11d treatment after a moderate lateral fluid percussion TBI in the rat. Rats were treated at 2 h after TBI with either the anti-CD11d antibody or an isotype-matched control antibody 1B7, and both short (24-to 72-h) and long (4-week) recovery periods were examined. The anti-CD11d integrin treatment reduced neutrophil and macrophage levels in the injured brain, with concomitant reductions in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss. The reduced neuroinflammation seen in anti-CD11d-treated rats correlated with improved performance on a number of behavioral tests. At 24 h, the anti-CD11d group performed significantly better than the 1B7 controls on several water maze measures of spatial cognition. At 4 weeks post-injury the anti-CD11d-treated rats had better sensorimotor function as assessed by the beam task, and reduced anxiety-like behaviors, as evidenced by elevated-plus maze testing, compared to 1B7 controls. These findings suggest that neuroinflammation is associated with behavioral deficits after TBI, and that anti-CD11d antibody treatment is a viable strategy to improve neurological outcomes after TBI.

Neurodegeneration and Sensorimotor Deficits in the Mouse Model of Traumatic Brain Injury

“…Traumatic brain injury is frequently associated with secondary neurodegeneration that leads to impairment in sensory motor functions [35][36][37]. Our result agrees with previous studies that demonstrates progressive brain atrophy and sensorimotor deficits in rodent model of traumatic brain injury [38][39][40][41].…”

Granulocyte-Macrophage Colony-Stimulating Factor Is Neuroprotective in Experimental Traumatic Brain Injury

“…The neuroimaging findings that all mice given LFP injury displayed significant damage to the cortex and corpus callosum, as well as morphological changes and neuronal loss in the hippocampus, may have each contributed to the motor and cognitive deficits observed post-LFP injury. 30,33,39,40 The GM -/-+ LFP mice made significantly fewer entries into the novel arm of the Y-maze compared with the WT + LFP mice, indicating worsened cognitive deficits. The GM -/-+ LFP mice also displayed abnormal behavior in the elevated-plus maze, spending significantly more time in the open arm compared with the sham-injured groups.…”

“…As previously described, 38,39 for semi-quantitative analysis of reactive astrogliosis (GFAP) and neuronal loss (NeuN), FOVs (20 · ) were captured from coronal sections at the level of injury by a researcher that was blinded to the experimental conditions. Using ImageJ software (National Institutes of Health), color thresholds were adjusted to detect immunopositive cells.…”

“…GFAP immunoreactivity was assessed using photomicrographs captured from tissue adjacent to the lesion that included the area of highest immunoreactivity, and was measured as the percent of immunoreactive area within the FOV. 38,39 Neuronal counts were conducted within an area of interest that included the end of the CA2 and beginning of CA3 regions of the ipsilateral hippocampus.…”

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

“…20,21 In doing so, neutrophils can further damage the BBB, contribute to edema formation, increase oxidative stress, and exacerbate neuroinflammation through the further production of pro-inflammatory mediators, including IL-1β, all of which may contribute to secondary brain injury. [20][21][22][23] Reactive astrocytes are also capable of producing pro-inflammatory cytokines, including IL-1β, and may be linked to the accompanying increase in neutrophils at 24 hours after injury, and IL-1β levels at 24 hours and 35 days after injury. 20,21 We also found increased levels of IL-6, albeit nonsignificant, in the plasma of multitrauma mice at 24 hours and 35 days.…”