Abstract

Surgical brain injury (SBI) is the inadvertent injury to brain tissue at the perisurgical site which occurs due to neurosurgical maneuvers such as incision, retraction, and electrocoagulation that can result in post-operative complications. Blood brain barrier (BBB) disruption and neuroinflammation are major pathophysiological consequences after neurosurgical injury. Blood brain barrier dysfunction leads to increased influx of water and plasma proteins as well as peripheral immune cell infiltration into the brain parenchyma that further potentiates brain edema and worsens post-operative neurological function. Activated resident immune cells and infiltrated peripheral immune cells release inflammatory mediators and promote oxidative stress and cell death which contributes to neuroinflammation and progression of injury.

In this project we have identified Slit2, an extracellular matrix protein expressed endogenously in the brain, as a potential therapeutic target for reducing SBI-induced complications. Our central hypothesis was that Slit2 will increase after SBI as an endogenous protective mechanism, and recombinant Slit2 pretreatment will reduce neuroinflammation and stabilize the BBB via Robo receptor signaling pathway. The dual effects of Slit2— anti-migratory and anti- permeability—were explored under three aims using the rat SBI model. The first aim evaluated the role of Slit2 in reducing neuroinflammation and BBB permeability after SBI. The second aim investigated the role of Slit2 and its receptor Robo1 in reducing neuroinflammation after SBI. Lastly, the third aim investigated the role of Slit2 and its receptor Robo4 in stabilizing the BBB after SBI.

Our findings showed that endogenous Slit2 increased in the perisurgical site in response to injury and had a protective function after SBI. Exogenous recombinant Slit2 pretreatment attenuated brain edema and neuroinflammation and thereby improved neurological function after SBI. Furthermore, we observed that recombinant Slit2 reduced neuroinflammation after SBI by inhibiting peripheral immune cell infiltration to the injury site possibly through Robo1-srGAP1 pathway mediated Cdc42 inactivation. Lastly, we elucidated that recombinant Slit2 reduced BBB permeability by stabilizing endothelial tight junction after experimental SBI possibly via Robo4-paxillin dependent Rac1 activation.

These observations suggest that Slit2 may be beneficial to reduce neurosurgical injury and improve post-operative outcomes in neurosurgical patients.

LLU Discipline

Physiology

Department

Basic Sciences

School

School of Medicine

First Advisor

Zhang, John H.

Second Advisor

Gridley, Daila

Third Advisor

Hartman, Richard E.

Fourth Advisor

Obenaus, Andre

Fifth Advisor

Tang, Jiping

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2016

Date (Title Page)

3-2016

Language

English

Library of Congress/MESH Subject Headings

Brain Injuries - Physiopathology; Brain - Surgery; Postoperative Complications; Brain Edema; Neurogenic Inflammation; Blood-Brain Barrier

Subject - Local

Surgical Brain Injury; Neurosurgical maneuvers; Post-operative neurological function; Brain parenchyma; Slit2; Extracellular Matrix Protein

Type

Dissertation

Page Count

131

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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