Influence of Isoflurane on the Integrity of the Blood Brain Barrier in Rats

Treatment of massive orthopedic and soft tissue trauma has evolved over the last 15 years of military conflicts. Damage control surgery, or repeated brief surgical exposures has become standard practice. Each of these brief operations requires exposure to some form of anesthesia, usually with a volatile anesthetic. Prolonged exposure to anesthesia has been shown to cause alterations in the structure and function of the blood brain barrier (BBB). The effects of multiple brief exposures to isoflurane on the structure and function of the BBB have not yet been studied. 

The objective of this proposal is to evaluate the expression and location of tight junction proteins as well as the permeability of BBB following multiple brief exposures to isoflurane. 

DESIGN: A randomized, posttest only, comparison group design will be employed.  Adult male Sprague Dawley Rats will be divided into one of three groups: control group, prolonged exposure (4 hr), and multiple brief (2 hr) exposure. The brief exposure group will increase by one until no change between groups is noted or five exposures is achieved. 

The central HYPOTHESIS of this study is that multiple brief exposures to isoflurane will decrease the expression of occludin and alter the distribution of ZO-1 thereby increasing the paracellular permeability of the BBB to hydrophilic substance.  

To test our hypotheses and accomplish the objective of this application, I will accomplish this SPECIFIC AIM: To identify changes in the expression and location of tight junction proteins and to evaluate the permeability of the BBB following a single prolonged or multiple brief exposures to isoflurane. 

H1:  Animals exposed to a single prolonged or multiple brief exposures to isoflurane will demonstrate a reduction in the expression of occludin and ZO-1 at 4 and 24 hours following exposure. 

H2:  Animals exposed to a single prolonged or multiple brief exposures to isoflurane will display alterations in the location of occludin and ZO-1 4 and 24 hours following exposure.  

H3:  Animals exposed to a single prolonged or multiple brief exposures to isoflurane will exhibit increased BBB permeability to high molecular weight dextrans 4 and 24 hours following exposure.

Final Report is available on NTRL: https://www.usuhs.edu/tsnrp/funded-study/influence-isoflurane-integrity-...