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Investigations on Alterations of Hippocampal Circuit Function Following Mild Traumatic Brain Injury
Published on: November 19, 2012
Intercellular Adhesion Molecule-1-Induced Posttraumatic Brain Injury Neuropathology in the Prefrontal Cortex and
Saurav Bhowmick1, Anitha Malat1, Danielle Caruso1
1Laboratory of CNS injury and Molecular Therapy, JFK Neuroscience Institute, Hackensack Meridian Health JFK University Medical Center, Edison, NJ 08820.
Insights
Blocking Intercellular Adhesion Molecule-1 (ICAM-1) reduces neuroinflammation and cell death after traumatic brain injury (TBI). ICAM-1 deletion improves functional outcomes and behavior, suggesting it as a therapeutic target for TBI recovery.
Area of Science:
- Neuroscience
- Immunology
- Trauma Research
Background:
- Intercellular Adhesion Molecule-1 (ICAM-1) facilitates leukocyte adhesion and transmigration across the blood-brain barrier (BBB).
- Traumatic brain injury (TBI) triggers immunocompetent cells to release mediators, stimulating ICAM-1 expression and cytokine release, perpetuating neuroinflammation and neurodegeneration.
- The precise role of ICAM-1 in TBI-induced functional deficits remains unclear despite its correlation with inflammation.
Purpose of the Study:
- To investigate the role of ICAM-1 in TBI-induced neuroinflammation, neurodegeneration, and functional impairment.
- To elucidate the molecular mechanisms underlying ICAM-1-mediated pathology post-TBI.
- To evaluate ICAM-1 as a potential therapeutic target for improving functional recovery after TBI.
Main Methods:
- Experimental TBI induced via fluid percussion injury (FPI) in wild-type and ICAM-1 knockout mice, and stretch injury in brain endothelial cells.
- Pharmacological and genetic manipulation of ICAM-1.
- Assessment of neuroinflammation markers (NF-kB, IL-1β, TNF-α), cell death (cleaved-caspase-3, Annexin V, TUNEL, Trypan blue), and functional outcomes (rotarod, grid-walk, sucrose preference, light-dark tests).
Main Results:
- TBI-induced neuroinflammation and cell death involve ICAM-1 acting through LFA-1/Mac-1 pathways, oxidative stress, MMP, and VEGF.
- ICAM-1 deletion or blockade significantly attenuated neuroinflammation and cell death markers.
- ICAM-1 knockout mice exhibited improved sensorimotor function, reduced depression, and anxiety-like behaviors, with altered neurotransmitter levels (NE, DA, 5-HT, NPY).
Conclusions:
- ICAM-1 plays a critical role in TBI-induced neuroinflammation, cell death, and functional deficits.
- Targeting ICAM-1 via genetic deletion or pharmacological blockade ameliorates TBI pathophysiology and improves functional recovery.
- ICAM-1 represents a promising therapeutic target for mitigating TBI consequences and promoting brain repair.
Abstract:
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-1β, 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.
