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C7-02
OMEGA-3 DERIVED LIPID MEDIATORS DIFFERENTIALLY
IMPACT FUNCTIONAL OUTCOME, SLEEP, AND MICRO-
GLIAL ACTIVATION AFTER EXPERIMENTAL TBI
Jordan Harrison
3,1,2
, Rachel Rowe
1,2
, Timothy Ellis
4
, Nicole Yee
2
,
Bruce O’Hara
5
, P. David Adelson
1–3
, Jonathan Lifshitz
1–3
1
Barrow Neurological Institute at Phoenix Children’s Hospital,
Translational Neurotrauma Research, Phoenix, USA
2
University of Arizona College of Medicine–Phoenix, Child Health,
Phoenix, USA
3
Arizona State University, Neuroscience, Tempe, USA
4
Midwestern University, College of Osteopathic Medicine, Glendale,
USA
5
University of Kentucky, Biology, Lexington, USA
Traumatic brain injury (TBI) initiates a cascade of secondary injury
processes, including inflammation. Therapies which resolve the in-
flammatory response may promote neural repair without exacerbating
injury. Omega-3 fatty acids, including docosahexaenoic acid (DHA),
have shown efficacy in improving outcome from experimental TBI
with little known regarding specific mechanisms. Endogenous lipid
mediator derivatives of omega-3 fatty acids termed resolvins have
recently been characterized in the active resolution of peripheral
inflammation. We hypothesized that administration of exogenous
resolvins RvE1 or AT-RvD1 would alleviate injury-induced post-
traumatic sleep and functional impairments through modulation of
inflammation. Experimental groups included midline FPI brain-in-
jured mice administered RvE1, AT-RvD1, or saline and counter-
balanced with sham mice. Resolvins or saline were administered
intraperitoneally for seven days beginning 3 days prior to TBI. Im-
mediately following TBI, sleep was monitored for 24 hours. Sensor-
imotor outcome was assessed by rotarod 1–7 days post-injury (DPI).
Cognitive function was evaluated using novel object recognition
(NOR) at 6DPI. At 7DPI, morphological activation of microglia was
semi-quantified using Iba-1 immunolabeling. AT-RvD1, but not
RvE1, treatment mitigated motor and cognitive deficits. RvE1 treat-
ment significantly increased post-traumatic sleep compared to all
other groups and RvE1-treated mice displayed a lower proportion of
activated rod microglia in the cortex compared to other brain-injured
groups. Due to this convergence in efficacy, AT-RvD1 may impart
functional benefit through mechanisms other than resolving inflam-
mation. AT-RvD1, a derivative of DHA, may contribute to the ther-
apeutic efficacy of omega-3 fatty acids following CNS trauma. Future
studies will explore therapies to increase the availability of endoge-
nous resolvins after injury.
Support: Bruce and Diane Halle Foundation, NIH R21-NS072611
Keywords: traumatic brain injury, resolvin, behavior, mouse, in-
flammation
C7-03
POST-TRAUMATIC SLEEP AS A BIOINDICATOR OF IN-
FLAMMATION: NOVEL TNF-R INHIBITORS RESTORE
FUNCTION FOLLOWING EXPERIMENTAL TBI
Rachel Rowe
1,2
, Jordan Harrison
1,2
, Hongtao Zhang
3
, David Hesson
3
,
Adam Bachstetter
4
, Linda Van Eldik
4
, Mark Greene
3
, Jonathan
Lifshitz
1,2
1
Barrow Neurological Institute at Phoenix Children’s Hospital,
Translational Neurotrauma Research, Phoenix, USA
2
University of Arizona, College of Medicine–Phoenix, Child Health,
Phoenix, USA
3
University of Pennsylvania, Perelman School of Medicine, Phila-
delphia, USA
4
University of Kentucky, College of Medicine, Lexington, USA
Diffuse traumatic brain injury (TBI) acutely increases sleep in the
mouse. During this acute window of post-traumatic sleep, cortical
levels of inflammatory cytokines, including tumor necrosis factor
(TNF), are significantly increased, suggesting a relationship between
sleep and inflammation. Here, we hypothesize that post-traumatic
sleep serves as a bioindicator of injury-induced inflammation to
screen novel therapeutics for efficacy in promoting neurological re-
covery from TBI. Novel inhibitors of TNF receptor (TNF-R) activa-
tion were synthesized and screened for
in vitro
efficacy of TNF
pathway inhibition (IkB-phosphorylation). Then, candidate com-
pounds were screened for
in vivo
efficacy in modulating post-
traumatic sleep. Mice (n
=
33) were subjected to sham or diffuse brain
injury (midline-FPI). Cohorts received novel TNF-R inhibitors
(Compound-7;SGT11;F002) or vehicle intraperitoneally immediately
following injury. Sleep was recorded via non-invasive cages. Over 6
hours post-injury, brain-injured vehicle-treated mice slept signifi-
cantly more than sham mice (F(1,11)
=
6.8;p
=
0.02). Brain-injured
mice treated with Compound-7 (F(1,8)
=
5.4;p
=
0.04) or SGT11
(F(1,7)
=
7.7;p
=
0.03) slept significantly less than vehicle-treated
mice, suggesting a therapeutic potential. Compounds were then tested
for efficacy in improving functional recovery (n
=
38). SGT11 restored
sensorimotor (rotarod;(F(3,34)
=
6.6;p
=
0.001) and neurological
function (modified neurological severity score;(F(3,34)
=
4.1;p
=
0.01).
Cognitive function (novel object recognition) was restored by both
SGT11 (t(18)
=
2.17;p
=
0.0143) and Compound-7 (t(14)
=
2.196;p
=
0.0454). Injury-induced increases in cortical microglial activation
were evident for all treatments. Compound-7 and SGT significantly
decreased cortical inflammatory cytokines 3 hrs post-TBI (n
=
24). In
summary, post-traumatic sleep served as an effective bioindicator to
screen novel compounds for the treatment of experimental TBI. In
summary, pharmacological inhibition of the TNF pathway accelerated
recovery of function following TBI and measurement of post-trau-
matic sleep may facilitate precision medicine through the identifica-
tion of therapeutic candidates for neurological injury.
Funding: NIH-NINDS-R21-NS072611, SfAZ
Keywords: TBI, TNF, sleep, novel therapeutics
C7-04
IMMUNE-MODULATORY HYDROGEL CARRIERS FOR
STEM CELL THERAPY AFTER TRAUMATIC BRAIN INJURY
Melissa Alvarado-Velez
, Shraddha Srivastava, Michelle LaPlaca,
Ravi V. Bellamkonda
Georgia Institute of Technology, Biomedical Engineering, Atlanta,
USA
Traumatic Brain Injury (TBI) is a serious clinical problem that affects
1.7 million Americans annually. Neural stem cell (NSC) transplantation
is a promising treatment for TBI, which is characterized by neuronal
loss. However, poor cell survival post-transplantation hinders potential
gains. A major contributor to the survival of NSCs is the response of the
immune system that recognizes the transplanted cells causing active
rejection. Currently, experiments investigating the effect of human
neural stem cells on rodent models of brain injury require the use
of immune-deficient animals or systemic immune-suppression. In
this study, we test the hypothesis that Fas ligand (FasL), a apoptosis
inducing ligand against host T cells, will engender localized
immune-suppression at the site of NSC transplantation and result in
A-87