129 / 198
tended to be associated with time until death (p
=
0.09), suggesting
that TNF
a
levels account for some E2 variance influencing mortal-
ity. Acute serum TNF
a
and E2 were highly correlated (r
=
0.54,
p
= <
0.001) among non-survivors, but not among survivors (r
=
0.10,
p
=
0.38). Sub-acute serum TNF
a
and E2 were not correlated (r
=
-
0.08, p
=
0.64). Acute serum and CSF TNF
a
showed a modest
correlation (r
=
0.21, p
=
0.05), but age-adjusted CSF TNF
a
levels
were not associated with mortality (p
=
0.07). Acute serum TNF
a
was associated with E2 and 6-month mortality risk, suggesting
possible systemic TNF
a
mortality effects. Future studies should
examine whether acute serum TNF
a
manipulation might impact
acute E2 production and survival post-TBI.
Keywords: rehabilomics, Tumor Necrosis Factor-
a
, estradiol, se-
rum
C7-19
ANTI-INFLAMMATORY DRUGS SHIFT PROPORTIONS OF
ACTIVATED MICROGLIA FOLLOWING EXPERIMENTAL
DIFFUSE BRAIN INJURY
Jack Reddaway
3,1,2
, Jenna Ziebell
1,2
, Megan Evilsizor
1,2
, Aida
Khodadad
1,2
, Ryan Hart
1,2
, Jonathan Lifshitz
1,2
1
University of Arizona, Child Health, Phoenix, USA
2
Barrow Neurological Institute at Phoenix Children’s Hospital, Child
Health, Phoenix, USA
3
University of Bath, Biology and Biochemistry, Bath, UK
Neuroinflammation contributes to secondary pathology of diffuse
traumatic brain injury (TBI). If not tightly controlled, neuroinflamma-
tion may modify the function of neuronal circuits. Circuits govern be-
havior; with alterations to circuits behavioral morbidities can eventuate.
We hypothesized that over the counter anti-inflammatory drugs would
mitigate neuroinflammation (microglial activation) thus reducing be-
havioral morbidities following experimental diffuse TBI in rats. To
model moderate diffuse TBI, adult male rats were subjected to mid-
line fluid percussion injury. Fifteen minutes post-injury, rats were
injected (intraperitonealy) with acetaminophen (40 or 20 mg/kg), as-
pirin (20 or 10 mg/kg), ibuprofen (60 or 20 mg/kg) or equal volume
vehicle. Subsequent injections were given twice daily for one week.
Sham rats were not included, as no changes in neuroinflammation
occur with surgery. Brains were collected 7 days post-injury (dpi), and
immunostained for microglia (Iba-1). Microglial proportions (rami-
fied, activated, rod or amoeboid) were analyzed in the sensory cortex,
a region harboring neuropathology. Sensory cortex of vehicle-treated
rats had predominantly activated microglia. Acetaminophen and
ibuprofen treated rats, showed a shift in the proportion of activated
microglia towards ramified morphology in sensory cortex. Whereas,
aspirin-treated rats showed a shift in proportion of activated microglia
to rod microglia in sensory cortex. To determine the effects of treat-
ment on neuroinflammation and behavior, an additional group of rats
were brain-injured and treated with acetaminophen (40 mg/kg), aspi-
rin (20 mg/kg), or vehicle. Treatments were chosen due to effective-
ness in shifting microglial proportions without excessive weight loss
(noted in ibuprofen groups). Behavioral morbidity was assessed in
brain-injured rats via the whisker nuisance task at 28 dpi. Over the
counter anti-inflammatory drugs have the capacity to alter neuroin-
flammation. We suggest that shifts in proportions away from activated
microglia will be associated with reduced behavioral morbidities.
Partially supported by NIH NINDS R01NS065052 and PCH Mission
Support Funds.
Keywords: Microglia, Anti-inflammatory drugs, Behavioral mor-
bidity, Diffuse brain injury
C7-20
P75NTR MEDIATES SYSTEMIC INFLAMMATORY RE-
SPONSES BY MODULATING DIFFERENTIATION OF MYE-
LOID CELLS
Sangmi Lee
1
, Neel Singhal
1
, Amity Lin
1
, Jeff Sacramento
1
, Leda
Mannent
2
, Marie-Noelle Castel
2
, Benoit Canolle
2
, Sandrine Delbary-
Gossart
2
, Badia Ferzaz
2
, Jacqueline Bresnahan
1
, Michael Beattie
1
1
University of California San Francisco, Brain and Spinal Injury
Center, Department of Neurological Surgery, San Francisco, USA
2
Sanofi, R&D, Chilly-Mazarin, France
Traumatic brain injury (TBI) leads to pro-inflammatory responses in
both CNS and peripheral organs. The inflammatory responses may be
involved in the subsequent development of clinical systemic inflam-
matory response syndrome, which eventually causes immune dys-
function and increases susceptibility to infection in chronic TBI
patients.
Previously, we found that blocking the p75NTR signaling pathway
by SARA, a selective p75NTR antagonist, inhibits tissue damage and
increases functional behavioral outcomes after cortical contusion in-
jury (CCI) TBI in rats. Strikingly, blocking p75NTR signaling reduces
microglia activation as well as leukocyte trafficking into the injured
brain.
Here, we demonstrated the possible role of p75NTR in peripheral
immune cell responses after TBI. Using a CCI-TBI model in C57Bl/6
WT mice, flow cytometric analysis showed that the population of
inflammatory monocytes (CD11b
+
Ly6C
high
) was significantly in-
creased in circulation and the injured brain at 1 week, but down-
regulated at 6 weeks after TBI. However, the population of mature
myeloid cells (CD45
high
CD11b
+
, CD45
high
CD11b
+
F480
+
and
CD45
high
CD11b
+
CD11c
+
) was significantly increased and accumu-
lated in the injured brain for 6 weeks after TBI. Interestingly, in-
flammatory monocytes (CD11b
+
Ly6C
high
) were accumulated in
spleen after TBI. We also demonstrated significantly increased gene
expression of pro-inflammatory mediators by qRT-PCR in spleen after
TBI. Interestingly, mice treated with daily SARA reduced the number
of inflammatory monocytes/macrophages in circulation, the injured
brain, and spleen. In addition, SARA treatment results on the inhi-
bition of TBI-induced pro-inflammatory mediators in the spleen.
Further, we found that TBI reduces TCR signaling, which was re-
versed by SARA.
Together, our new findings suggest that p75NTR mediates pro-
inflammatory responses by modulating myeloid differentiation in
circulation and SARA restores T cell function in spleen, which is
critical for immune susceptibility and may contribute to the thera-
peutic effects of SARA after TBI.
Keywords: p75NTR, traumatic brain injury, systemic inflammation,
inflammatory monocytes
C7-21
SIMULTANEOUS EXPRESSION OF M1/M2 MACROPHAGE
POLARIZATION PHENOTYPES FOLLOWING TBI
Lara-Kirstie Riparip,
Josh Morganti
, Susanna Rosi
UCSF, Neurosurgery, San Francisco, USA
Focal traumatic brain injury induces a wide array of inflammatory
responses principally mediated by cells of the innate immune sys-
tem, such as microglia and macrophages. Much attention has been
paid as of late to categorize the neuroinflammatory response fol-
lowing TBI within the linear constraints of macrophage polarization
A-93