NNS 2015 Program & Abstract Book

animals that had received impacts to the medial frontal cortex and not

in the parasagittal injury model. In the elevated plus maze, lesions to

the medial frontal cortex increased the time the rats spent in the open

arms which may indicate decreased anxiety and greater risk-taking

behavior. This behavior was not attenuated by progesterone. The in-

crease in the open arm time was modest in parasagittal injuries.

Nonetheless, progesterone attenuated this modest increase back to

levels similar to that of sham surgical controls. These data illustrate

that the efficacy of post-traumatic progesterone treatment may depend

on the brain region injured. Hence, the clinical translation of pro-

gesterone might benefit from additional stratification of patients ac-

counting for the position of the brain lesions.

Keywords: progesterone, controlled cortical impact, medial frontal

cortex, parasagittal cortex, neurobehavior

D8-11

TBI-INDUCED METABOLOMIC PROFILES IN ENERGETIC,

OXIDATIVE STRESS AND INFLAMMATORY PATHWAYS

ARE IMPROVED BY ETHYL PYRUVATE TREATMENT

Richard Sutton

, Nobuo Kutsuna, Sima Ghavim, David Hovda, Neil

Harris

UCLA, Neurosurgery, Los Angeles, USA

This study examined metabolomic changes after traumatic brain

injury (TBI) and ethyl pyruvate (EP) treatments. Adult male Spra-

gue-Dawley rats were injected (IP) with EP (40 mg/kg) or vehicle

(Veh; 0.1M PBS) at 0, 1, 3 and 6 h after sham injury (n

6/group) or

TBI (contusion; n

9/group) to the left parietal cortex. At 24 h post-

injury left cortical tissue was harvested and frozen samples were

processed for global metabolic profiles using ultrahigh performance

liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS)

or gas chromatography-MS at Metabolon, Inc. (Durham, NC). Two-

way ANOVA on the dataset of 503 identified biochemicals revealed

significant (p’s

0.05) main effects of Injury for 364 compounds, of

Drug for 19 compounds and a significant interaction for 56 bio-

chemicals. ANOVA contrasts (TBI-Veh vs. Sham-Veh) indicated

220 biochemicals increased after TBI and 98 were decreased by

injury. In TBI-EP vs. TBI-Veh comparisons, 48 biochemicals were

increased and 13 were decreased by the EP treatments. Principle

component analysis showed Sham-injured rats formed an over-

lapping population, while TBI-Veh and TBI-EP generated two

separate but partially overlapping populations. Random forest yiel-

ded a predictive accuracy of 77% for group classifications (random

segregation would yield a predictive accuracy of 25%). The top 30

metabolites separating treatment groups indicated key differences in

carbohydrate metabolism, amino acid metabolism, lipid metabolism

and peptides after TBI and/or EP treatments. Overall, the results

indicated significant TBI-induced alterations in pathways related to

energetics, oxidative stress and inflammation. Glycolytic function

was decreased, with increased use of branched-chain amino acids

and fatty acid beta-oxidation for energy production after TBI. Gly-

cogen synthesis was decreased, with an increase in glycogenolysis

and increased glucose levels post-TBI. EP treatment after TBI in-

creased acetyl CoA and decreased glycogenolysis, consistent with

EP use in the TCA cycle and decreased energy demand. More subtle

changes in TBI-EP rats were consistent with an anti-oxidant and

anti-inflammatory function for EP.

Support: UCLA Brain Injury Research Center, P01NS058489 and

SUMITOMO Life Social Welfare Services Foundation.

Keywords: bioenergetics, controlled cortical impact, cerebral cor-

tex, inflammation, metabolomics, oxidative stress

D8-12

SELENIUM DEFICIENCY IS DETRIMENTAL TO MI-

TOCHONDRIAL RESPIRATION FOLLOWING TRAUMATIC

BRAIN INJURY

Carolyn Meyer

, Ronan Power

James Geddes

University of Kentucky, SCoBIRC, Lexington, USA

Alltech Inc., Nutrigenomics, Nicholasville, USA

Traumatic brain injury continues to be a substantial clinical problem

with few available treatment strategies. Individuals who are at a

greater risk for sustaining a brain injury, such as professional athletes

and military personnel, may benefit from a prophylactic supplement

that would intervene in the neurodegenerative pathways immediately

following injury. Different dietary levels of selenium, a cofactor for

antioxidant enzymes, were supplemented in the diets of male Sprague-

Dawley rats. Included in this study were diets deficient in selenium,

equivalent levels to normal rat chow, and two levels of enriched se-

lenium. Animals received diets for 4 weeks prior to receiving a severe

(2.2 mm) controlled cortical impact brain injury or sham craniotomy.

Naı¨ve animals maintained on these diets showed a decrease or in-

crease in central nervous system tissue levels relative to the amount of

selenium present in the diet. Twenty-four hours following impact, a

cortical punch directly surrounding the injury epicenter was isolated

for mitochondrial respiration assays. Respiration was measured using

oxygen consumption rates (Seahorse Bioscience

) in response to

mitochondrial substrates, mimicking various stages of the electron

transport chain. These studies showed that selenium deficiency is

detrimental to mitochondrial respiration and exacerbated the observed

injury effect. This effect was seen in State III, State V (complex I),

and State V (complex II) driven respiration, as measured through

injection with endogenous substrates pyruvate/malate and ADP,

FCCP, and rotenone and succinate, respectively. Additionally, ani-

mals on the selenium deficient diet had a decrease in glutathione

peroxidase activation following injury. Animals given diets enriched

in selenium did not show significant improvements over animals re-

ceiving control diets, suggesting a possible ceiling effect with sele-

nium supplementation. The exacerbated injury outcomes with

selenium deficiency suggests that there are critical levels of dietary

selenium for maintenance of mitochondrial function following injury.

Supplementation with selenium above normal dietary levels, however,

may not enhance protection of mitochondria after TBI.

Keywords: Mitochondria

D8-13

INSULIN-LIKE GROWTH FACTOR-1 OVEREXPRESSION

PROMOTES SURVIVAL OF ADULT-BORN NEURONS

AFTER TRAUMATIC BRAIN INJURY

Erica Littlejohn

, Sindhu Kizhakke Madathil

, Travis Stewart

Jinhui Chen

, Kathryn Saatman

University of Kentucky, SCoBIRC, Physiology, Lexington, USA

Walter Reed Institute, Center for Neuroscience, Bethesda, USA

Indiana University, Stark Neurosciences Research Institute, School

of Medicine, Indianapolis, USA

The pathology associated with traumatic brain injury (TBI) manifests

in motor and cognitive dysfunction following injury. Immature neu-

rons residing in the neurogenic niche of the dentate gyrus (DG) in the

hippocampus, a brain structure required for learning and memory, are

particularly vulnerable to TBI. The inability to restore this population

of hippocampal immature neurons following TBI has been causally

A-117