Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Dr. Donald Peter Cain

Abstract

Traumatic brain injury is a global health concern with limited treatment options currently available. Concussion is the most common form of traumatic brain injury, and although a single concussion rarely results in long-term neurological dysfunction, repeated concussion can result in cumulative damage and chronic neurodegenerative disease. However, little is known about the factors and mechanisms of concussion involved in these detrimental effects. Animal models provide a means to examine the factors and mechanisms involved in traumatic brain injury, as well as potential treatments, in experiments that cannot be conducted using human participants. In the present thesis a fluid percussion model of traumatic brain injury was used to study single and repeated concussion in adult male Long-Evans rats. Anti-CD11d integrin antibody, a novel compound that reduces neuroinflammation by targeting the infiltration of peripheral leukocytes into the brain after traumatic brain injury, was evaluated as a potential treatment for concussion.

In Study 1 a single mild lateral fluid percussion injury (1.0-1.5 atm) caused short-term (24 hrs) behavioral impairments and neuropathological alterations indicative of neuroinflammation and axonal injury. In Study 2, three or five mild lateral fluid percussion injuries given at 5-day intervals caused cumulative short-term (24 hrs) and long-term (8 weeks) behavioral impairments and neuropathological alterations indicative of neuroinflammation and cortical loss. These results appear to validate the use of single and repeated mild lateral fluid percussion injuries to model important aspects of human concussion. In Study 3 anti-CD11d antibody administered after a single moderate lateral fluid percussion injury (2.5 - 3.0 atm) reduced cognitive, emotional, and motor impairments, and also reduced neuroinflammation and neuronal loss relative to injured rats treated with a control antibody. In Study 4 anti-CD11d antibody administered after each of three repeated mild lateral fluid percussion injuries similarly reduced cognitive, emotional, and motor impairments, and neuroinflammation and cortical loss relative to injured rats treated with a control antibody. These novel findings suggest the involvement of infiltrating peripheral leukocytes and neuroinflammation in both single and repeated concussion, and they support the further investigation of anti-CD11d antibody as a potential treatment for concussion.


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