Page 111 - NNS 2014 Program & Abstract Book

Operation Brain Trauma Therapy (OBTT). The University of Mi-
ami site tested levetiracetam in our model of fluid percussion (FP)
TBI. Male Sprague-Dawley rats were anesthetized and underwent
moderate FP (1.8-2.1 atm) TBI. Rats were randomized into four
groups and administered levetiracetam 15 min post-TBI. Animal
groups were TBI-54 mg/kg (n = 12), TBI-170 mg/kg (n = 12), TBI-
Veh (n = 12) or Sham (n = 12). Rats were tested on day 7 post-injury
for sensorimotor function using the gridwalk and cylinder task. On
days 13–21, rats were assessed for cognitive function utilizing the
simple place task, probe trial and working memory task. On day 21,
brain tissue was processed for histological assessment. One-way
ANOVA was not significant for any of the sensorimotor tasks. For
the hidden platform task, two-way repeated measures ANOVA for
latency was significant for days and group. Both TBI levetiracetam
treated groups exhibited lower latencies vs. TBI-Veh and Sham.
There was a significant difference between groups for the probe
trial (p < 0.05) with both levetiracetam groups performing at sham
level. In the working memory task, latency repeated measures
ANOVA was significant for trial (p < 0.001), but not group, or
group x trial. However, both levetiracetam groups performed better
on this task than TBI-Veh. Histopathological analysis for lesion
volume was not significant between groups. Single dose treatment
of levetiracetam early after FP TBI improved cognitive function
but did not decrease histological damage. Levetiracetam shows
promise for future studies assessing dosage optimization and
therapeutic window after TBI, and evaluation in advanced models.
Support: US Army W81XWH-10-1-0623.
Key words
behavior, fluid percussion, neuroprotection, OBTT, traumatic brain
injury
C2-08
DOSE-RESPONSE EVALUATION OF SIMVASTATIN IN THE
MIAMI FLUID PERCUSSION MODEL OF TRAUMATIC
BRAIN INJURY: AN OBTT CONSORTIUM STUDY
Bramlett, H.M., Furones-Alonso, O., Sanchez-Molano, J., Sequiera,
D., Moreno, W., Dietrich, W.D.
University of Miami Miller School of Medicine, Department of
Neurlogical Surgery, Miami, USA
Simvastatin (SIM) is a cholesterol lowering agent that has dem-
onstrated other beneficial effects including reducing cytokine lev-
els, brain edema, and improving histological and behavioral
outcome after traumatic brain injury (TBI). SIM was chosen as the
fourth drug to be tested by the multicenter consortium Operation
Brain Trauma Therapy. The UM site tested SIM in our model of
fluid percussion TBI. Male Sprague-Dawley rats were anesthetized
and underwent moderate fluid percussion (FP; 1.8-2.1atm) TBI.
Rats were randomized into four groups and administered SIM 3 hr
post-TBI followed by daily PO dosing (14d). Animal groups were
TBI-1mg/kg (n = 10), TBI-5mg/kg (n = 10), TBI-Veh (n = 10) or
Sham (n = 10). Rats were tested on day 7 post-injury for sensori-
motor function (gridwalk, cylinder task). On days 13–21, rats were
assessed for cognitive function utilizing the simple place task,
probe trial and working memory task. On day 21, brain tissue was
processed for histology. One-way ANOVA was not significant for
the cylinder task but was for left forelimb gridwalk footfaults
(p = 0.045). TBI-Veh was significantly worse vs. sham (p < 0.05).
For the hidden platform task, two-way repeated measures ANOVA
for latency was significant for group · days (p < 0.05). TBI SIM
1mg/kg treated groups exhibited higher latencies vs. TBI-Veh and
Sham. There was no significant difference between groups for the
probe trial. Repeated measures ANOVA for working memory la-
tency was significant for trial (p < 0.001), but not group or group ·
trial. Lesion volume or cortical volume loss was not significant
between groups. We conclude that sustained treatment with SIM
after FP produced a modest motor benefit but surprisingly led to
either worse or unimproved cognitive function and did not decrease
histological damage. Although several studies have shown an im-
provement with SIM treatment after TBI, other dosing strategies or
routes of administration should be considered. Support: US Army
W81XWH-10-1-0623.
Key words
behavior, fluid percussion, neuroprotection, OBTT, traumatic brain
injury
C2-09
EVALUATION OF LEVETIRACETAM IN THE WRAIR PBBI
MODEL: STUDIES FROM THE OPERATION BRAIN TRAU-
MA THERAPY (OBTT) CONSORTIUM
Caudle, K.L., Pedersen, R., Sun, J., Flerlage, W., Faden, J.,
Mountney, A., Schmid, K.E., Shear, D.A., Tortella, F.C.
Walter Reed Army Institute of Research, Silver Spring, MD
Operation Brain Trauma Therapy (OBTT) is a multi-center con-
sortium established to provide cross-model preclinical screening of
emerging TBI therapies. Levetiracetam, the fifth drug selected for
testing by the OBTT, is an anti-epileptic drug that has previously
demonstrated potent anti-seizure effects following penetrating bal-
listic-like brain injury (PBBI) and neuroprotective effects in other
TBI models. Using the standard OBTT protocol, this study assessed
the therapeutic efficacy of levetiracetam on neurobehavioral and
neuropathological outcomes in the WRAIR PBBI model of severe
TBI. Unilateral frontal PBBI was produced in the right hemisphere
of isoflurane anesthetized rats (10% injury severity level). Levetir-
acetam (West-Ward Pharmaceuticals, 54 or 170 mg/kg) was ad-
ministered as a single IV infusion at 15 m post-injury. Motor and
cognitive testing was conducted using the Rotarod at 7 and 10 days,
and Morris water maze (MWM) from 13–17 days post-PBBI, re-
spectively. Rotarod testing revealed similar deficits across all injury
groups with mean latencies reduced by 34 – 9% (vehicle), 36 – 13%
(54 mg/kg), and 41 – 11% (170 mg/kg) vs. sham. However, no sig-
nificant improvement in motor outcome was detected following
administration of levetiracetam. MWM results revealed significant
deficits in all injury groups with the average latency to find the
hidden platform (across testing days) increased by 123 – 23% (ve-
hicle), 108 – 17% (54 mg/kg), and 127 – 14% (170 mg/kg) vs. sham.
Although no significant therapeutic effect was detected on spatial
learning in the MWM acquisition trials, an intermediate therapeutic
benefit was observed on the probe (missing platform) trials where
animals treated with levetiracetam (both doses) did not differ from
either sham or PBBI. Overall, the results of the current study indicate
that a single post-injury infusion of levetiracetam does not confer
significant therapeutic benefit in the PBBI model. However, given
the promising results obtained in the other OBTT models, and
positive independently obtained results using extended dosing in the
WRAIR PBBI model, levetiracetam merits further study. Supported
by U.S. Army Grant W81XWH-10-1-0623.
Key words
cognitive, Keppra, levetiracetam, motor, operation brain trauma
therapy OBTT, traumatic brain injury TBI
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