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"The docosahexaenoic acid (DHA)-derived specialized pro-resolving mediator (SPM), 17-HDHA provides neuroprotective and anti-inflammatory properties in traumatic brain injury"

by
Courtney Rella
Infection, Immunity, and Inflammation (I3) Program
M.S. 2012, Fairleigh Dickinson University, Madison, NJ
B.S. 2005, Georgian Court University, Lakewood, NJ


Thesis Advisor: Frances Calderon. Ph.D.
Assistant Professor
Department of Pharmacology, Physiology, & Neuroscience

Monday, March 27, 2017
1:00 P.M., MSB Room C-555


Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability for children and young adults, though it spans across all ages. The primary injury triggers secondary events that result in chronic inflammation and long-term neurodegeneration. There is currently no effective treatment for TBI, and the long-term results of chronic neuroinflammation are detrimental to neuronal survival and repair. Several studies have shown that reducing neuroinflammation mitigates TBI-induced neurological dysfunction. In this work, we investigated the anti-inflammatory functions of an omega-3 polyunsaturated fatty acid (PUFA)-derived specialized pro-resolving mediator (SPMs) when administered after injury. SPMs are bioactive metabolites endogenously synthesized from PUFAs that have been recently isolated and characterized to mediate resolution of inflammation in peripheral systems. Using the controlled cortical impact (CCI) model of TBI in Sprague Dawley rats, we found that administration of 17-HDHA, the metabolic intermediate of docosahexaenoic acid-derived resolvins one hour after injury significantly reduced the overall volume and area of blood brain barrier leakage at 24 hours after injury. Furthermore, the cortex mRNA levels of several pro-inflammatory cytokines, including IL-1, TNF, and IL-6, were significantly reduced at 4 and 24 hrs post injury. Conversely, the anti-inflammatory cytokine, IL1-RA was significantly increased with treatment versus the vehicle at 3 days post injury. The reduction in pro-inflammatory cytokine levels correlated with a significant decrease in the expression of three TBI biomarkers at 24 hours whose elevations correlate with poor TBI prognosis. These markers include MMP-9, spectrin-II-, and the astrocyte marker, GFAP. One treatment of 17-HDHA significantly reduced MMP-9 and spectrin-II- levels 24 hours after injury. Examination of microglia expression levels showed that at 24 hours, the activated microglia marker, CD68 was significantly decreased by almost half of control levels. Investigation of the neutrophil marker myeloperoxidase (MPO) mRNA expression and area of infiltration showed significant reduction at 24 hours suggesting that 17-HDHA is possibly interacting with neutrophils and microglia to reduce neuroinflammation. Reduction of acute inflammation was accompanied with an overall decrease of brain injury lesion volume at 24 hours. Neurological function was analyzed using the rotarod assay. Comparison of control and 17-HDHA treated rats showed sustained improvement in the rotarod performance for motor behavior from day 3 post injury, specifically, in the latency to fall and distance travelled. Our results indicate that treatment with 17-HDHA decreases neuroinflammation and improves the neurological outcome following TBI.


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