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sleep architecture and (2) identify the extent to which severe pene-
trating TBI alters sleep homeostasis. Aim_1: Naı¨ve rats were dosed
with oral caffeine or zolpidem and Aim_2: Animals were subjected to
10% unilateral, frontal penetrating ballistic-like brain injury (PBBI).
Continuous EEG recordings were initiated immediately following
drug administration or PBBI surgery.
Caffeine produced significant reductions in total sleep with con-
comitant increases in wakefulness. All stages of sleep-wake activity
were significantly altered; the majority of changes were measured
immediately and sustained for 4h. Zolpidem produced significant re-
ductions in wakefulness and increases in slow wave sleep (SWS).
Zolpidem reduced rapid eye movement (REM) sleep during the initial
12h, with residual suppression effects evident 24h later. Lastly, PBBI
produced rapid reductions in total wakefulness and REM sleep with
increases in SWS. PBBI-injured rats showed delayed REM onset,
fewer sleep-stage transitions and increased sleep disruptions. These
abnormalities persisted through the initial wake and subsequent sleep
cycles. Notably, PBBI-injured rats displayed bioelectrical discordance
with injury-induced alterations in REM and SWS sleep more promi-
nent/persistent within the injured hemisphere.
Overall, these results demonstrate 1) that drugs routinely used
during deployment can significantly alter the sleep signature and 2)
alterations in baseline patterns of sleep disturbances in the PBBI
model. Notably, disruption in REM sleep, which was most prominent
following severe TBI, is also associated with decreases in memory
consolidation, reduced reaction reflexes and increased mental health
comorbidities. Further studies are needed to determine the extent
drug-induced reductions in REM sleep may pose as risk factors in TBI
recovery.
Keywords: sleep, TBI, caffeine, ambien
D8-25
SELECTIVE BRAIN COOLING REDUCES MOTOR DEFI-
CITS INDUCED BY COMBINED TRAUMATIC BRAIN IN-
JURY, HYPOXEMIA AND HEMORRHAGIC SHOCK
Lai Yee Leung
, Ying Deng-Bryant, Bernard Wilfred, Katherine
Cardiff, Xiaofang Yang, Christopher Vandermerwe, Deborah Shear,
Frank Tortella
Walter Reed Army Institute of Research, Brain Trauma Neuropro-
tection and Neurorestoration Branch, Silver Spring, USA
This study examined the effects of selective brain cooling (SBC) on
neurobehavioral deficits that were shown to be exacerbated by
hypoxemia and hemorrhagic shock (i.e., polytrauma) in a rat model
of penetrating ballistic-like brain injury (PBBI). Rats were randomly
assigned into two groups (n
=
20/group with mortality rate of 33%):
PBBI
+
polytrauma without SBC (control) and PBBI
+
polytrauma
with SBC (SBC). All animals received unilateral 5%PBBI, followed
by 30-min hypoxemia (fraction of inspired oxygen
=
0.1) and then
30-min hemorrhagic hypotension (mean arterial
pres-
sure
=
40 mmHg). Fluid resuscitation was given immediately fol-
lowing hypotension. SBC was initiated 15 min after fluid
resuscitation and brain temperature was maintained at 32–33 C (core
temperature at 37.5 C) for 4 hours under isoflurane anesthesia.
Control animals received the same procedures minus the cooling. At
7, 10, 14 and 21 days post-injury, motor function was assessed using
the rotarod task. Cognitive function was assessed using the Morris
water maze at 13–17 days post-injury. Significant improvement in
motor functions were detected in SBC-treated polytrauma animals at
7, 10 and 21 days post-injury compared to the control group
(p
<
.05). However, no significant beneficial effects were detected on
cognitive measures following SBC treatment in the polytrauma an-
imals. Preliminary data on systemic inflammatory response at 21
days post-injury showed the untreated control group had a slightly
higher serum level of interleukin-1 beta (IL-1b) than the SBC group
(138
–
19 vs 121
–
26 pg/ml), but the difference was not statistically
significant. In the presence of polytrauma, TBI patients often require
more robust therapeutic interventions to prevent secondary systemic
and brain insults. Our data suggested that SBC effectively reduced
motor deficits following TBI/polytrauma. Similar findings have been
demonstrated in animals subjected to isolated TBI. Such neuropro-
tective effects may be associated with the reduced inflammatory
responses, as reflected by the serum-level of cytokines. Further in-
vestigation will focus on cerebral inflammatory response to SBC
treatment.
Keywords: Polytrauma, therapeutic hypothermia, selective brain
cooling, hypoxemia, hemorrhagic shock
D8-26
EVALUATION OF GLIBENCLAMIDE IN THE WRAIR PBBI
MODEL: STUDIES FROM THE OPERATION BRAIN TRAU-
MA THERAPY (OBTT) CONSORTIUM
Ying Deng-Bryant
, Stefania Mondello, Lai Yee Leung, Janice
Gilsdorf, Rebecca Pedersen, Justin Sun, William Flerlage, Frank
Tortella, Deborah Shear
Walter Reed Army Institute of Research, Center for Military Psy-
chiatry and Neuroscience, Silver Spring, USA
Glibenclamide is a sulfonylurea receptor 1 (SUR1) channel antagonist
that is FDA approved for treating Type 2 diabetes. Glibenclamide was
selected for testing by the Operation Brain Trauma Therapy (OBTT)
Consortium based on published research demonstrating that blocking
SUR1 with low-dose glibenclamide provides significant therapeutic
benefit in pre-clinical models of stroke and traumatic brain injury
(TBI). The current study evaluated the potential therapeutic effect of
glibenclamide on neurobehavioral recovery in the WRAIR penetrating
ballistic-like brain injury (PBBI) model. Unilateral frontal PBBI was
produced in the right hemisphere of anesthetized rats (10% injury
severity level). Glibenclamide (Sigma Aldrich) was given as a single
dose via intraperitoneal injection (10
l
g/kg) at 10 min post-injury,
immediately followed by continuous subcutaneous infusion using
Alzet osmotic minipumps with infusion rates of 1
l
l/h for 7 consec-
utive days. Motor function and cognitive performance were assessed
using the Rotarod and the Morris water maze (MWM), respectively.
Brains were perfused and processed for histopathological analysis.
Rotarod testing revealed significant motor deficits in all injury groups
with overall mean latencies reduced by 42
–
9% in the vehicle treated
group, and 44
–
7% in the glibenclamide treated group (p
<
.05 vs
sham). MWM task for cognitive evaluation demonstrated significant
deficits in all injury groups with the average latency to locate the
hidden platform (average all testing days) increased by 71
–
17% in
the vehicle treated group, and 92
–
19% in the glibenclamide treated
group (p
<
.05 vs sham). Additionally, histopathological analysis in-
dicated significant gross morphological changes, including mean le-
sion volume, in all injured groups. However, no significant therapeutic
effects were detected on Rotarod, MWM parameters or on histological
metrics. Overall, the results of this study indicate that continuous
infusion of low dose glibenclamide was not effective in promoting
significant neurofunctional and/or histopathological recovery in the
PBBI rat model. Supported by U.S. Army Grant W81XWH-10-1-
0623
Keywords: PBBI, Behavior
A-122