Intercellular Adhesion Molecule-1-Induced Posttraumatic Brain Injury Neuropathology in the Prefrontal Cortex and Hippocampus Leads to Sensorimotor Function Deficits and Psychological Stress.

Intercellular adhesion molecule-1 (ICAM-1) promotes adhesion and transmigration of circulating leukocytes across the blood-brain barrier (BBB). Traumatic brain injury (TBI) causes transmigrated immunocompetent cells to release mediators [function-associated antigen (LFA)-1 and macrophage-1 antigen (Mac-1)] that stimulate glial and endothelial cells to express ICAM-1 and release cytokines, sustaining neuroinflammation and neurodegeneration. Although a strong correlation exists between TBI-mediated inflammation and impairment in functional outcome following brain trauma, the role of ICAM-1 in impairing functional outcome by inducing neuroinflammation and neurodegeneration after TBI remains inconclusive. The experimental TBI was induced in vivo by fluid percussion injury (FPI; 10 and 20 psi) in wild-type (WT) and ICAM-1-/- mice and in vitro by stretch injury (3 psi) in brain endothelial cells. We manipulate ICAM-1 pharmacologically and genetically and conducted several biochemical analyses to gain insight into the mechanisms underlying ICAM-1-mediated neuroinflammation and performed rotarod, grid-walk, sucrose preference, and light-dark tests to assess functional outcome. TBI-induced ICAM-1-mediated neuroinflammation and cell death occur via LFA-1 or Mac-1 signaling pathways that rely on oxidative stress, matrix metalloproteinase (MMP), and vascular endothelial growth factor (VEGF) pathways. The deletion or blocking of ICAM-1 resulted in a better outcome in attenuating neuroinflammation and cell death as marked by the markers such as NF-kB, IL-1ß, TNF-α, cleaved-caspase-3 (cl-caspase-3), Annexin V, and by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and Trypan blue staining. ICAM-1 deletion in TBI improves sensorimotor, depression, and anxiety-like behavior with significant upregulation of norepinephrine (NE), dopamine (DA) D1 receptor (DAD1R), serotonin (5-HT)1AR, and neuropeptide Y (NPY). This study could establish the significance of ICAM-1 as a novel therapeutic target against the pathophysiology to establish functional recovery after TBI.

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

Traumatic brain injury (TBI) can result in persistent sensorimotor and cognitive deficits, which occur through a cascade of deleterious pathophysiological events over time. In this study, we investigated the hypothesis that neurodegeneration caused by TBI leads to impairments in sensorimotor function. TBI induces the activation of the caspase-3 enzyme, which triggers cell apoptosis in an in vivo model of fluid percussion injury (FPI). We analyzed caspase-3 mediated apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and poly (ADP-ribose) polymerase (PARP) and annexin V western blotting. We correlated the neurodegeneration with sensorimotor deficits by conducting the animal behavioral tests including grid walk, balance beam, the inverted screen test, and the climb test. Our study demonstrated that the excess cell death or neurodegeneration correlated with the neuronal dysfunction and sensorimotor impairments associated with TBI.