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
1
, Ronan Power
2
,
James Geddes
1
1
University of Kentucky, SCoBIRC, Lexington, USA
2
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
ª
) 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
1
, Sindhu Kizhakke Madathil
2
, Travis Stewart
1
,
Jinhui Chen
3
, Kathryn Saatman
1
1
University of Kentucky, SCoBIRC, Physiology, Lexington, USA
2
Walter Reed Institute, Center for Neuroscience, Bethesda, USA
3
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