Date of Award

1-1-2017

Embargo Period

1-1-2022

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Stephen Tomlinson

Second Advisor

Alejandro Spiotta

Third Advisor

Bärbel Rohrer

Fourth Advisor

Carl Atkinson

Fifth Advisor

DeAnna Adkins

Sixth Advisor

Naren Banik

Abstract

Ischemic and traumatic injuries to the brain are associated with a robust neuroinflammatory response that exacerbates the initial injury and limits the extent of recovery. The complement system is a central mediator of neuroinflammatory responses to neuronal injury, and contributes to the recognition of damage, activation and amplification of a multitude of inflammatory processes. This work utilizes two generation of complement inhibitors that are targeted specifically to the injured brain to provide local inhibition of complement activation for the aims of improving chronic outcomes and understanding the role of complement in the pathophysiology of cerebral injury. Findings from this work demonstrate that complement activation contributes to edema, hemorrhage, and neuronal loss acutely after brain injury, and to a sustained neurodegenerative inflammatory response that persists for months after initial insult. This work also demonstrates that injury-site targeted complement inhibitors can prevent early loss of neurons, in part, by limiting microglial phagocytosis of stressed neurons, and interrupts chronic neuroinflammation allowing for enhanced regeneration and re-modeling. Targeted complement inhibition worked synergistically with rehabilitation therapy to significantly ameliorate chronic gross and fine motor deficits as well as cognitive deficits, and, simultaneously, favorably improved the safety and efficacy profiles of thrombolytic therapy for stroke, the current standard of care, by limiting intracranial hemorrhage and enhancing efficacy. Finally, injury-site targeted inhibition of complement did not show systemic adverse effects, did not inhibit homeostatic complement activation in the brain, and did not increase the susceptibility to infection. Therefore, injury-site targeted inhibition of complement activation is a novel translational strategy for the treatment of ischemic stroke and traumatic brain injury that can work favorably with the standard of care.

Rights

All rights reserved. Copyright is held by the author.

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